Table of contents :

malformations regressive processes progressive processes hypertrophy hyperplasia dysplasia cancer / neoplasm / tumor

defensive processes immune response innate immune response inflammation / flogosis (post-flogistic) repair adaptive immune response primary adaptive immune response secondary adaptive immune response immunopathological processes hypersensitivity reactions autoimmune reactions transplant complications transplant rejection graft-versus-host disease (GvHD) prognosis web resources

The classification of disease according to kind(s) of process evoked by the aetiological factor(s) is mainly used by pathologists because every kind of process may arise from a limited set of aetiological factors and because it often allows to produce a diagnosis and a prognosis.

• congenital malformation (see also multisystem birth defects) : a morphologic defect of an organ or larger region of the body, resulting from an intrinsically abnormal developmental process.
• malposition / allotopia / displacement / dystopia / heterotopia : abnormal or anomalous position of an organ or part
• ectopia : malposition, especially if congenital.
• chorista : defective development due to, or characterized by, displacement of the primordium.
• choristoma : a mass of tissue that is normal histologically, but not for the site in which it is located
• dermoid : a congenital choristoma consisting of skin and its dermal appendages
• coloboma : an absence or defect of tissue, particularly, a defect of ocular tissue, usually due to malclosure of the fetal intraocular fissure, or sometimes from trauma or disease.
• hamartia : a defect in tissue combination during development.
• hamartoma : a benign tumor-like nodule composed of an overgrowth of mature cells and tissues that normally occur in the affected part, but with disorganization and often with one element predominating.
• nevus :
• nevus cell / nevocyte : a polymorphic, melanin-containing cell variously postulated to be a normal mature melanocyte or a modified one, or to be derived from a Schwann cell or an embryonal nevoblast. Such cells occur in aggregations, or nests (theques), in the epidermis and reach the dermis by a kind of centripetal extrusion (abtropfung), and are the main constituents of nevocytic nevi.
• phakomatoses
• congenital epulis / epulis of newborn
• hamartomatosis : the development of multiple hamartomas.
• fistula : an abnormal passage or communication, usually between two internal organs, or leading from an organ to the surface of the body. Such passages may also be created experimentally to obtain body secretions for physiologic study.
• blind or incomplete fistula : a fistula that is open at one end only; it may open only upon the cutaneous surface of the body (external blind fistula) or on an internal mucous surface (internal blind fistula)
• complete fistula : an abnormal passage in the body, each end of which opens on a mucous surface or on the cutaneous surface of the body.
• external fistula : an abnormal communication between a hollow organ and the external surface of the body.
• internal fistula : an abnormal communication between two internal organs.
• parietal fistula : an abnormal passage in the body wall, ending blindly or communicating with an internal organ or body cavity.
• parapedesis : passage of body substances into channels not normally conveying them, as of bile pigments into the blood capillaries
• environmental stress : organisms limit protein synthesis by storing inactive ribosomes that are rapidly reactivated when conditions improve. As a measure for molecular motion, temperature is one of the most important environmental factors for life as it directly influences structural and hence functional properties of cellular components. Sress proteins includes the HSPs, the glucose-regulated proteins (GRPs) and ubiquitin. The stress proteins may be grouped by molecular weight ranging from the large 110 kDa HSP110 to ubiquitin at 8 kDa. These proteins serve as cellular chaperones, participating in protein synthesis and transport through the various cellular compartments. Because these proteins have unique cellular localizations, the chaperone function of the stress proteins often involves a transfer of peptides between stress proteins as the peptide is moved between cellular compartments. For example, HSP70 is a cytosolic and nuclear chaperone, which is critical for the transfer of cellular peptides in the mitochondrion through a hand-off that involves mitochondrial HSP60 at the inner mitochondrial membrane. Similarly, cytosolic proteins are transferred from HSP70 to gp96 as they move into the endoplasmic reticulum. The central role of the stress proteins in the transfer of peptides through the cell may be responsible for the recently recognized importance of the stress proteins in the modulation of the immune system^ref. This importance in immune regulation is best addressed using the danger model of the immune response. This model states that the basic function of all cells of the organism is appropriately timed death "from natural causes". This type of cell death, or apoptosis, generates no stress signals. If, on the other hand, a cell is "murdered" by an infectious agent or dies an untimely death due to necrosis or ischemia, the cell undergoes a stress response with the liberation of stress protein-peptide complexes into the extracellular environment upon cell lysis. Not only do they serve as a "danger signal" to alert the immune system to the death of a cell under stress, but their role as protein carriers allows the immune effector cells to survey the peptides released by this stressed cell and to activate against new or unrecognized peptides carried by the stress protein^ref
• cold shock : in response to temperature downshift, a number of changes occur in cellular physiology such as, (i) decrease in membrane fluidity, (ii) stabilization of secondary structures of nucleic acids leading to reduced efficiency of mRNA translation and transcription, (iii) inefficient folding of some proteins, and (iv) hampered ribosome function. Cold-shock response and adaptation has been quite extensively studied in Escherichia coli and Bacillus subtilis. A number of cold shock proteins (CSPs) are induced to counteract these harmful effects of temperature downshift. Mesophiles like Escherichia coli, which are adapted to living at both warm temperatures inside animals and cooler ambient temperatures, respond to low temperatures (10-15°C) by adjusting membrane lipid composition and increasing the production of proteins that act as "RNA chaperones" required for transcription and translation and proteins that facilitate ribosomal assembly. During this response, bulk transcription and translation slow or come to an almost complete stop, while a set of about 26 cold-shock genes is preferentially and transiently expressed. This protein set, however, is different from that expressed under heat shock conditions and predominantly comprises proteins such as helicases, nucleases, and ribosome-associated components that directly or indirectly interact with the biological information molecules DNA and RNA. Interestingly, in contrast to the heat shock response, to date no cold-specific sigma factor has been identified. Rather, it appears that the cold shock response is organized as a complex stimulon in which post-transcriptional events play an important role. At least some of the proteins encoded by these genes are essential for survival in the cold, but none plays an exclusive role in cold adaptation, not even the "major cold-shock protein" CspA and none is induced de novo. The majority of these proteins binds nucleic acids and are involved in fundamental functions (DNA packaging, transcription, RNA degradation, translation, ribosome assembly, etc.). Although cold-induced activation of specific promoters has been implicated in upregulating some cold-shock genes, post-transcriptional mechanisms play a major role in cold adaptation; cold stress-induced changes of the RNA degradosome determine a drastic stabilization of the cold-shock transcripts and cold shock-induced modifications of the translational apparatus determine their preferential translation in the cold. This preferential translation at low temperature is due to cis elements present in the 5' untranslated region of at least some cold-shock mRNAs and to trans-acting factors whose levels are increased substantially by cold stress. Protein CspA and the three translation initiation factors (IF3 in particular), whose stoichiometry relative to the ribosomes is more than doubled during the acclimation period, are among the trans elements found to selectively stimulate cold-shock mRNA translation in the cold^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8}. Protein Y, an Escherichia coli stress protein, fills the tRNA- and mRNA-binding channel of the small ribosomal subunit to stabilize intact ribosomes. Protein Y inhibits translation initiation during cold shock but not at normal temperatures by competing with conserved translation initiation factors that, in bacteria, are required for ribosomal subunit dissociation. The mechanism used by protein Y to reduce translation initiation during stress and quickly release ribosomes for renewed translation initiation may therefore occur widely in nature^ref. In contrast, yeast, which are adapted to cooler temperatures, show a relatively minor cold shock response after temperature shifts from 30° to 10°C but respond with a dramatic increase in the synthesis of trehalose and a heat shock protein when exposed to freezing or near-freezing temperatures. Progression through the cell cycle is temperature sensitive, but the relationship is not straightforward. In culture, many types of mammalian cells fail to undergo the G₂/M transition after cooling from 37°C to 16-20°C (moderate hypothermia). However, progression through G₁ and S is not blocked at these temperatures, nor is progression through mitosis in cells cooled after they have become committed to the division process. Thus, at least one pathway is present during G₂-but not during G₁, S or mitosis-that is selectively disrupted at or below a critical temperature. As a result, a prolonged (24-48 hr) exposure to moderate hypothermia can be used to enrich cultures for G₂ cells. A brief (1 hr) exposure to severe hypothermia (4-10°) is also reported to induce a high degree of mitotic synchrony (up to 80%) in some mammalian cultures. Although the mechanism behind this synchronization remains vague, it may involve a cell cycle checkpoint, triggered in response to the cold shock, that transiently inhibits the G₁/S transition^ref. We live on a cold planet where > 80% of the biosphere is permanently < 5°C, and yet comparatively little is known about the genetics and physiology of the microorganisms inhabiting these environments. Based on molecular probe and sequencing studies, it is clear that Archaea are numerically abundant in diverse low-temperature environments throughout the globe. In addition, non-low-temperature-adapted Archaea are commonly exposed to sudden decreases in temperature, as are other microorganisms, animals, and plants. Considering their ubiquity in nature, it is perhaps surprising to find that there is such a lack of knowledge regarding low-temperature adaptation mechanisms in Archaea, particularly in comparison to what is known about archaeal thermophiles and hyperthermophiles and responses to heat shock^ref.
• heat shock : since its discovery in 1962 by Ritossa, the heat shock response has been extensively studied by a number of investigators to understand the molecular mechanism underlying the cellular response to heat stress. The most well characterized heat shock response is induction of the heat shock protein (HSPs) that function as molecular chaperones and exert cell cycle regulatory and anti-apoptotic activities. While most investigators have focused their studies on the toxic effects of heat stress in organisms such as severe heat stress-induced cell cycle arrest and apoptosis, the cellular response to fever-ranged mild heat stress has been rather underestimated. However, the cellular response to mild heat stress is likely to be more important in a physiological sense than that to severe heat stress because the body temperature of homeothermic animals increases by only 1-2°C during febrile diseases. Mild heat stress does have some beneficial role in organisms via positively regulating cell proliferation and differentiation, and immune response in mammalian cells^ref. In Escherichia coli the heat shock response is, controlled by the sigma factor s32, which acts as a master regulator that specifically directs RNA polymerase to transcribe from the HSP promotors. Heat shock factor Hsf in nonvertebrate animals and homologous heat shock factor Hsf1 in vertebrate animals are key transcriptional regulators of the stress protein response. Hsf/Hsf1 is constitutively present in cells but is, typically, only active during periods during which cells are experiencing a physical or chemical proteotoxic stress. It has become increasingly clear that regulation of Hsf/Hsf1 activity occurs at multiple levels: the oligomeric status of Hsf/Hsf1, its DNA-binding ability, posttranslational modification, transcriptional competence, nuclear/ subnuclear localization, as well as its interactions with regulatory cofactors or other transcription factors all appear to be carefully controlled^ref. The existence of HSP receptors on antigen-presenting cells (APCs) was hypothesized in 1994. The first such receptor, CD91 / LRP / a₂-macroglobulin R, was identified and characterized in 2000. The pace of attribution has quickened since and during 2002-2004 alone, 6 putative HSP receptors have been identified. These include CD40L, LOX-1, CD36 / thrombospondin receptor / p95^{gpIV / gpIIIb}, TLR2, TLR4 and SR-A^ref. During the heat shock response in mouse cells, a small noncoding RNA polymerase III transcript from short interspersed elements (SINE) that are abundant in the mouse genome and historically considered to be "junk DNA", B2 RNA, associates with RNA polymerase II and represses transcription of specific mRNA genes. These studies define a unique transcriptional regulatory mechanism involving an RNA regulator and reveal how mRNA transcription is repressed upon heat shock. Moreover, B2 RNA is transcribed'^ref. arimoclomol (source : CytRx Corp.) is a coinducer of HSPs. The heat-shock transcription factor 1 (HSF1) has an important role in the heat-shock response in vertebrates by inducing the expression of heat-shock proteins (HSPs) and other cytoprotective proteins. HSF1 is present in unstressed cells in an inactive monomeric form and becomes activated by heat and other stress stimuli. HSF1 activation involves trimerization and acquisition of a site-specific DNA-binding activity, which is negatively regulated by interaction with certain HSPs. Here we show that HSF1 activation by heat shock is an active process that is mediated by a ribonucleoprotein complex containing translation elongation factor eEF1A and heat shock RNA-1 (HSR1). HSR1 is constitutively expressed in human and rodent cells and its homologues are functionally interchangeable. Both HSR1 and eEF1A are required for HSF1 activation in vitro; antisense oligonucleotides or short interfering (si)RNA against HSR1 impair the heat-shock response in vivo, rendering cells thermosensitive. The central role of HSR1 during heat shock implies that targeting this RNA could serve as a new therapeutic model for cancer, inflammation and other conditions associated with HSF1 deregulation^ref.
• hyperoxia
• hypoxia
• other perturbations
• regressive processes
• progressive processes

• hypertrophy : the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells

Aetiology :
• adaptive hypertrophy : increase in size in response to changed conditions, as, for example, increased thickness of the walls of a hollow organ when the outflow is obstructed.
• functional hypertrophy : hypertrophy of an organ or part caused by its increased activity.
• compensatory hypertrophy : that which results from an increased workload due to some physical defect, as occurs in one kidney when the other is absent or destroyed by disease.
• complementary hypertrophy : increase in size of the remaining part of an organ to take the place of a portion which has been lost.
• vicarious hypertrophy : hypertrophy of an organ in consequence of the failure of another organ of allied function
• concentric hypertrophy : hypertrophy of a hollow organ in which there is increased thickness of the walls with no enlargement in external size, with diminished capacity.
• eccentric hypertrophy : hypertrophy of a hollow organ in which there is dilatation of its cavity and enlargement of its external size.
• false hypertrophy : enlargement due to an increase in only one constituent element of an organ or part, commonly the stroma.
• true hypertrophy : enlargement due to an increase of all the component elements of an organ or part.
• numeric hypertrophy : that which is due to an increased number of structural elements.
• physiologic hypertrophy : temporary increase in the size of an organ produced by physiologic activity, as in the female breast during pregnancy and lactation.
• simple hypertrophy : that which is due to a simple increase of the number of structural elements.
• unilateral hypertrophy : overgrowth of one side of the entire body or of a portion of one side, as of the face.
• xenoma (tumor) / xenom : a symbiotic complex formed by hypertrophying host cells and multiplying intra-cellular parasites, e.g. certain micro-sporidians.
• hyperplasia : abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue.
• inflammatory hyperplasia : hyperplasia brought about by inflammation
• Swiss-cheese hyperplasia : hyperplasia of a tissue which on section shows openings as in Swiss cheese
• adenosis : the abnormal development or formation of gland tissue
• seroma : a tumor-like collection of serum in the tissues
• cancer (neoplasm)
• pseudotumor / pseudoneoplasm / false tumor : an enlargement that resembles a tumor; it may result from inflammation, accumulation of fluid, or other causes, and may or may not regress spontaneously
• inflammatory pseudotumor (IPT) : a general term for a rare space-occupying tumorlike mass of unknown etiology representing an inflammatory reaction, occurring in a variety of organs and composed of granulation tissue with leukocyte infiltration (histopathologically by aggregates of inflammatory lymphocytes, plasma cells (plasma cell granuloma), neutrophils, and fibroblasts (inflammatory myofibroblastic tumor (IMT))). It can mimic malignancy on clinicoradiological and pathological examination. IPT is a quasineoplastic lesion that most commonly involves the lung and the orbit (expecially conjunctiva) (rarely simultaneously^ref), but it has been reported to occur in nearly every site in the body (heart^ref, gastrointestinal tract (multifocal omental mesenteric IPT presumed to result following an Entamoeba histolytica infestation^ref), adrenal gland, iliopsoas muscle, CNS, and spleen). Sporadic cases have been reported in the trunk, genitourinary tract, and extremities as well as in the head and neck (the areas most commonly involved are the orbit and paranasal sinuses^ref, but they have been also described in the nasal septum^ref,  larynx, pterygomaxilar space, tonsils, ears, gingiva and other periodontal tissues). Of critical importance is this entity's correct histopathologic diagnosis that differentiate it from malignant neoplasms such as spindle cell carcinoma and fibrosarcoma, benign tumors such as neurofibroma, and other pseudoneoplastic lesions such as nodular fasciitis. Correct diagnosis is followed by wide local excision to prevent recurrence; however, treatment must be tailored to the location of tumor and the condition of the patient. Because IPT mimic malignant tumors both clinically and radiologically, the radiologist should be familiar with this entity and help avoid unnecessary radical surgery when possible. Diagnostic accuracy of cytology for IPT is low (42%). IPT shows hypercellular smears (on FNA) with an admixture of various cell types including inflammatory cells with predominance of plasma cells, fibroblastic proliferation, granulation tissue formation, and atypical-appearing histiocytes with enlarged nuclei and intranuclear inclusions. Fibroblastic proliferation with mitoses may mimic mesenchymal neoplasms. Cytomorphology is nonspecific and IPT usually is a diagnosis of exclusion
• calcifying fibrous pseudotumor (CFP) is one of the most unusual benign tumors of childhood and is located mostly in soft tissues, pleura^ref, and peritoneum, and rarely lung^ref. Microscopically, the lesion is mostly composed of dense collagenous tissue, with sparse benign spindle cells, a rich inflammatory infiltrate and scattered calcifications, sometimes laminated. IHC, spindle cells are vimentin⁺, SMA^-, desmin^-, S100 protein^-, CD34^-, CD99^- and Bcl2^-.
• mycobacterial pseudotumor (MP) is a rare pathologic presentation of both Mycobacterium tuberculosis and non-tuberculous mycobacterial disease, hitherto reported to occur only in immunosuppressed patients with or without HIV-1 infection. This lesion shares close pathologic resemblance to certain mesenchymal neoplasms, particularly Kaposi's sarcoma (KS), from which it must be properly differentiated due to distinct prognosis and therapy. It can obliterate the lumen of the appendix vermiformis^ref
• emperipolesis is random passage of one cell through the cytoplasm of another one^ref with no physiologic consequence for either of them.
• emperipolesis is particularly frequent in megakayocytes (MK), 5% of which are normally found engulfed with other cell types, most frequently neutrophils or red blood cells (Zucker-Franklin D. Atlas of Blood Cells Function and Pathology. Bologna, Italy: Edi Ermes; 2003). Increased frequency of neutrophil emperipolesis within the MKs is observed in the majority of patients who experience extreme thrombocytosis, whether myeloproliferative or reactive^ref, and is not necessarily associated with marrow fibrosis. The MK abnormalities observed in patients with idiopathic myelofibrosis also include increased emperipolesis of neutrophils within MKs^{ref1, ref2}. The significance, however, of this observation is not clear, because emperipolesis of neutrophils within MKs increases in other stress-related conditions not necessarily associated with marrow fibrosis, such as recovery after sublethal irradiation^ref, aging^ref, and altered MK maturation associated with the gunmetal mutation^ref.
• histiocytes showed emperipolesis (i.e. intact lymphocytes within the cells) (which should be differentiated by lymphohistiocytosis)
• various CNS diseases (oligodendrocytes within astrocytes) showing destruction of myelin or inflammation of the white matter, including multiple sclerosis, cerebral infarct, chronic metabolic disorders and CJD^ref.
• emperipolesis in pleural mesothelial cells in a patient with chronic lymphocytic leukemia^ref.
• defensive processes
• innate immune response
• hemostasis
• inflammation or flogosis : a localized protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. It is characterized in the acute form by the classical signs of
• pain (dolor), a critical component of host defense, is exacerbated by proinflammatory chemokines. When CCR1:TRPV1/HEK293 cells were pretreated with CCL3, the sensitivity of TRPV1, as indicated by the Ca²⁺ influx, was increased 3-fold. RT-PCR analysis showed that a spectrum of chemokine and cytokine receptors is expressed in rat dorsal root ganglia (DRG). Immunohistochemical staining of DRG showed that CCR1 is coexpressed with TRPV1 in >85% of small-diameter neurons. CCR1 on DRG neurons was functional, as demonstrated by CCL3-induced Ca²⁺ ion influx and PKC activation. Pretreatment with CCL3 enhanced the response of DRG neurons to capsaicin or anandamide. This sensitization was inhibited by pertussis toxin, U73122, or chelerythrine chloride, inhibitors of Gi-protein, phospholipase C, and protein kinase C, respectively. Intraplantar injection of mice with CCL3 decreased their hot-plate response latency^ref.
• heat (calor)
• redness (rubor)
• swelling (tumor)
• loss of function (functio laesa)
Histologically, it involves a complex series of events, including dilatation of arterioles, capillaries, and venules, with increased permeability and blood flow; exudation of fluids, including plasma proteins; and leukocytic migration into the inflammatory focus.
• acute inflammation : inflammation, usually of sudden onset, characterized by the classical signs (see inflammation), in which the vascular and exudative processes predominate.
• subacute inflammation : a condition intermediate between chronic and acute inflammation, exhibiting some of the characteristics of each.
• chronic inflammation : inflammation of slow progress and marked chiefly by the formation of new connective tissue; it may be a continuation of an acute form or a prolonged low-grade form, and usually causes permanent tissue damage.
• adhesive inflammation : that which promotes the adhesion of contiguous surfaces.
• atrophic, cirrhotic, fibrosing or sclerosing inflammation : a form which results in atrophy and deformity.
• hypertrophic inflammation : inflammation marked by increase in the size of the elements composing the affected tissue.
• catarrhal inflammation : a form which affects principally a mucous surface, and which is marked by a copious discharge of mucus and epithelial debris.
• focal inflammation : one that is confined to a single spot or to a few limited spots.
• diffuse inflammation : one that is both interstitial and parenchymatous or is spread over a large area.
• disseminated inflammation : one that has a number of distinct foci.
• metastatic inflammation : one that is reproduced in a distant part by the conveyance of infectious material through the blood vessels and lymph organs.
• granulomatous inflammation : an inflammation, usually chronic, characterized by the formation of granulomas
• plastic, productive, proliferous or hyperplastic inflammation : one which leads to the formation of new connective tissue fibers.
• necrotic inflammation : inflammation attended by death of the affected tissue.
• obliterative inflammation : inflammation of the lining membrane of a cavity or vessel, producing adhesions between the surfaces and consequent obliteration of the lumen.
• interstitial inflammation : one that primarily affects the stroma of an organ.
• parenchymatous inflammation : one that primarily affects the essential tissue elements of an organ.
• pseudomembranous inflammation : an acute inflammatory response to a powerful necrotizing toxin, such as the diphtheria toxin, characterized by the formation on a mucosal surface, most often in the pharynx, larynx, respiratory passages, and intestinal tract, of a false membrane composed of precipitated fibrin, necrotic epithelium, and inflammatory white cells.
• seroplastic inflammation : inflammation accompanied by both serous and plastic exudation.
• simple inflammation : that in which there is no flow of pus or other product of inflammation.
• specific inflammation : one that is due to a particular microorganism.
• toxic inflammation : one that is caused by a poison, such as a bacterial product.
• traumatic inflammation : one that is caused by an injury.
• ulcerative inflammation : that in which necrosis on or near the surface leads to loss of tissue and creation of a local defect (ulcer).
• acute phase reaction or response (APR) : a group of physiologic processes occurring soon after the onset of infection, trauma, inflammatory processes, and some malignant conditions.
• acute phase reactants (APR) : TLRs=> NFkB => IL-1, IL-6 and TNF-a =>
• acute phase proteins (APPs) :
• positive APPs (dramatic increase in their plasma concentration is the most prominent change of APR and increases ESR)
• type-1 APPs are those that require the synergistic action of IL-6 and IL-1 for maximum synthesis
• C-reactive protein (CRP) : peak up to 1000-fold the upper reference value within 8-10 hours. t = 19 hrs, so its plasma concentration decreases before ESR lowering.

CRP is a risk factor for ...
• total mortality
• acute myocardial infarction (AMI)
• sudden cardiac death
• stroke
• type II diabetes mellitus
• metabolic syndrome
• body mass index (BMI)
• cigarette smoking
• heavy drinking
• no ethanol consumption
• HRT in postmenopausal women
• age
CRP is a protective factor for ...
• weight loss
• drinking in moderation
• orosomucoid / a₁ acid glycoprotein 1 (AGP1) and orosomucoid / a₁ acid gp 2 (elevation 2-5 fold)
• serum amyloid A (SAA) component (1, 2, and 4) : peak up to 1,000-fold the upper reference value.
• type-2 APPs are those that require IL-6 only for maximal induction, while IL-1 frequently suppress their expression.
• fibrinogen ABg (2-5 fold elevation, but late-onset)
• haptoglobins (1-1, 2-1 and 2-2) (2-5 fold elevation)
• a₂-macroglobulin (in rabbits and rats, but not in humans)
• proteases inhibitors
• a₁-antichimotrypsinogen (2-5 fold elevation)
• a₁-antitrypsin / a₁-antiplasmin
• a₂-antiplasmin 1
• a₂-antiplasmin 2
• complement factors
• lectin activation pathway
• mannose-binding protein (MBP)
• alternative activation pathway
• factor-B (Bf)
• classic activation pathway
• C1 inhibitor (C1-INH)
• C2
• C4 (elevation < 2 fold)
• C4 binding protein (C4BP)
• common lytic pathway
• C3 (elevation < 2 fold)
• C5
• C8
• C9
• coagulation factors
• factor VIII
• von Willebrand factor (vWF)
• antithrombin III / heparin cofactor I
• heparin cofactor-2
• prothrombin
• plasminogen
• plasminogen activator inhibitor-1 (PAI-1)
• serum amyloid-P (SAP) component: only in mouse, no significant change in humans
• iron metabolism and reactive oxygen species
• heme oxygenase 1 (HO-1)
• hemopexin (Hpx) (elevation < 2-fold)
• apoferritin
• lactoferrin
• ceruloplasmin (Cp) / ferroxidase (elevation < 2-fold)
• SOD2
• calprotectin is a stable calcium- and zinc-binding anti-inflammatory APP found in the cytosol of neutrophilic granulocytes and monocytes : marked susceptibility to zinc deprivation is a general characteristic of pathogenic fungi^ref. This factor is composed of 8 and 14 kDa subunits, S100 calcium binding protein A8 (calgranulin A) / MRP8 and S100 calcium binding protein A9 (calgranulin B) / MRP14). Calprotectin has higher specific activity to induce apoptosis than the individual subunits, and that the mechanism is exclusion of zinc from target cells^ref. Calprotectin is stable in feces for several days after excretion, can be measured readily with commercially available assay, and correlates well with radiolabeled autologous leukocytes excretion, which is more difficult to perform. A single fecal calprotectin measurement may aid gastroenterologists in the differential diagnosis of Crohn's disease and IBS. Its use could decrease the number of invasive or radiological investigations undertaken in the latter group of patients^ref.
• fibronectin (Fn)
• kallikreins
• LPS binding protein (LBP)
• procalcitonin (ProCT / PCT) : in microbial infections and in various forms of severe systemic inflammation, circulating levels of calcitonin precursors (CTpr), including the prohormone ProCT, normally found in the serum of healthy persons, increase severalfold to several thousand-fold, and this increase often correlates with the severity of the condition and with mortality^ref. During severe systemic infections it is produced by extrathyroidal tissues. In the absence of infection, the extra-thyroidal transcription of the CALC-I gene is suppressed and confined to selective expression in neuroendocrine cells found mainly in thyroid and lung. In these neuroendocrine cells, the mature hormone is processed and stored in secretory granules. A microbial infection induces a ubiquitous increase in CALC-I gene expression and a constitutive release of CTpr from all tissues and cell types throughout the body^ref. Thus, under septic circumstances, the entire body could be viewed as an endocrine gland. Indeed, the transcriptional expression of CT-mRNA is more uniformly up-regulated in sepsis than are the mRNAs of the classical cytokines (e.g. TNF-a and IL-6). Interestingly, there is relatively low expression of CTpr in white blood cells^{ref1, ref2}. The greater CTpr mRNA induction and CTpr peptide release from parenchymal cells compared to circulating cells appears to indicate a tissue-based rather than leukocyte-based host defence mechanism. Thus, CALC gene products may be a prototype of hormokine mediators and may follow either a classical hormonal expression or, alternatively, a cytokine-like expression pathway. The production of hormokines is mediated by as yet unknown factors and may be induced either directly via microbial toxins or indirectly via a humoral or cell-mediated host response. In sepsis, the predominance of CTpr as opposed to mature CT is indicative of a constitutive pathway within cells lacking secretion granules and hence bypassing of much of the enzymatic processing. Consequently, as is the case of most cytokines, there is very little intracellular storage of CTpr in sepsis^ref. PCT is an APP with faster kinetics than CRP, its concentration in serum rising within the few hours that follow the inception of a bacterial infection. Similarly to what occurs in humans, CTpr are also increased in septic hamsters^{ref1, ref2}. In the hamster model of sepsis, ProCT does not initiate or enhance IL-1b or TNF-a expression; however, the massive and sustained elevation of this hormone seen in sepsis can be induced in normal hamsters by administration of the cytokine TNF-a. This suggests that ProCT could be a secondary mediator which may augment and amplify, rather than initiate, the septic response^ref. Both hypocalcaemia and increased serum levels of CTpr are common findings in intensive care patients, especially those with infection and sepsis. Indeed, ionised hypocalcaemia is more pronounced with increasing severity of infection, and occurs in parallel with the marked increase of CTpr^ref. In contrast, as mentioned above, serum levels of mature CT are normal or only minimally elevated in sepsis^{ref1, ref2,ref3}. Importantly, CTpr contribute greatly to the deleterious effects of systemic infection. Administration of ProCT to septic hamsters with peritonitis doubled their death rate, which reached levels exceeding 90%, and treatment with ProCT-reactive antiserum increased the survival of septic hamsters^ref. In addition, 1-hour intravenous immunoneutralisation using an antiserum reacting specifically with porcine ProCT improved the physiological and metabolic parameters of septic pigs and greatly increased their short-term survival (from 0% to 80%). Further, recent experiments have demonstrated that such immunoneutralisation is effective even when administered after the animals are moribund. Studies have demonstrated that what is beneficial is probably immunoneutralisation of the entire ProCT molecule. There are thus several observations to indicate that ProCT is not only a necessary precursor to the biosynthesis of mature CT but also, at the high concentrations occurring in the setting of sepsis, a potentially harmful mediator involved in the septic response. Several characteristics of ProCT militate in favour of this hormokine molecule as a therapeutic target in sepsis. In contrast to the transiently increased classical cytokines, for which immunoneutralisation trials in humans have been disappointing, the massive increase in circulating CTpr persists for several days^ref. Moreover, CTpr is very frequently increased in overt sepsis, its onset is early (within 3 hr), and the diagnostic accuracy of the measurement should greatly improve patient selection for any study of the therapeutic efficacy of ProCT immunoneutralisation in humans. In sepsis, several CTpr are increased, including ProCT, N-ProCT, CT:CCP-I, immature CT, and CCP-I, any of which may have agonistic, antagonistic, or neutral effects^{ref1, ref2}. Also, several members of the calcitonin gene family of peptides comprise a functional unity. The CALC-I gene, by alternative processing of the primary RNA transcript, gives rise to two different so-called mature peptides: calcitonin (CT) and calcitonin gene-related peptide I (CGRP-I). Like CT, CGRP-I is initially biosynthesised as a larger prohormone which is subsequently cleaved into smaller precursors. It is relevant that CGRP-II, amylin, and adrenomedullin, also members of the CT gene family of peptides, are encoded on the CALC-II, -IV, and -V genes respectively. In sepsis, mRNA for CGRP-I, CGRP-II and adrenomedullin also appear to be ubiquitously expressed. Based on structural homologies, different members of these CT-gene family peptides have different profiles of bioactivity, which they exert by binding to the same family of receptors. There are two subgroups of receptors for the CT-gene family: CT receptors (CRs) and CT receptor-like receptors (CRLRs). Each member of the CT-gene family of peptides binds with differing affinities to these receptors. Accessory proteins act upon these receptors, thus altering their specific responsiveness and hence the physiological profile of action of the CT-gene peptides. These accessory proteins, which are called receptor-activity-modifying proteins (RAMPs), alter the receptors’ phenotype; they act on the CRs by modification of their genes and on the CRLRs by influencing transport to the plasma membrane. The presence, concentration, and/or timing of one or more of the three RAMPs (RAMP-1, -2, and -3) determines the specific cellular phenotype of the receptor that is ultimately expressed on the cell surface^ref. The profile of RAMP expression and activity is altered by the local milieu and is subject to humoral influences. This elegant system allows for diversification of receptor function, and hence modulates the action of the CT-gene products according to ambient needs. Thus, both in health and disease, a response to different peptides of the calcitonin gene family of peptides occurs in a dynamic and varying manner. Further studies are needed to determine whether high levels of circulating ProCT or other CTpr may blunt the effects of CGRPs and/or adrenomedullin, peptides which may otherwise be beneficial in sepsis. Several clinical studies have confirmed the superior diagnostic utility of serum levels of CTpr in sepsis and their greater reliability, compared to other markers, in following the course of illness^{ref1, ref2}. Importantly, in sepsis, the extent to which any specific CTpr peptide is increased relative to the others varies; indeed, the levels of N-ProCT and CT:CCP-I may be even higher than the ProCT values^ref. PCT is a very stable molecule in vitro, and its measurement requires only 20 ml of plasma or serum (an immunoluminometric assay of 40 ml serum or plasma) and can be done within 2 hours^ref. The commercially available 2-site assay (LUMItest^® PCT, B.R.A.H.M.S. Diagnostica GmbH, Hennigsdorf/Berlin, Germany), measures both ProCT and the conjoined CT:CCP-I by means of a luminometer. This assay is useful in detecting markedly elevated CTpr levels in sepsis. However, the current assay has the disadvantage of relative insensitivity, with an accurate detection limit of ~0.3 to 0.5 ng/mL^{ref1, ref2}. A colorimetric bedside test (PCT^®-Q, B.R.A.H.M.S. Diagnostica GmbH, Hennigsdorf/Berlin, Germany) has the advantage of providing rapid determination of circulating CTpr levels (in 30 minutes); however, the assay is only semi-quantitative and is not sensitive enoughto detect mildly or moderately elevated CTpr levels^ref. Currently, the most sensitive assay capable of measuring CTpr in normal persons utilises an antibody to N-ProCT as the free peptide and within the ProCT molecule^ref. Clinically, the authors have found the determination of circulating CTpr levels to be very useful in complex, polymorbid cases with suspected bacterial infections. For example, serum CTpr measurement can be helpful in predicting the presence of serious bacterial infection in a patient with fever but without localising signs^ref. Another important use is in patients with meningeal irritation; in this context, elevated circulating CTpr levels are highly suggestive of bacterial infection^{ref1, ref2}. The CTpr assay can also be used where renal failure is present^{ref1, ref2}. In immunocompromised patients with AIDS or neutropenia, an ultrasensitive CTpr assay is probably more desirable^{ref1, ref2,ref3}. In patients with haemodynamic shock, the finding of relatively low levels of serum CTpr suggests a nonbacterial cause (e.g. acute adrenocortical failure or haemorrhage)^ref. CTpr determination can also be useful in differentiating joint infections from autoimmune inflammation (e.g. rheumatoid arthritis)^ref. Whatever the initial triggering insult may be, markedly severe systemic inflammation per se may be reflected in increased serum levels of CTpr^ref. For example, whether or not bacterial infection has been found, moderate to marked serum CTpr increases occur in pancreatitis due to biliary obstruction or in association with necrosis, in chemical pneumonitis^ref, in burns^{ref1, ref2, ref3}, in heat stroke^ref, in mechanical trauma^ref, and following surgery^ref. Additional studies are needed to determine whether the increased serum CTpr levels in such apparently non-bacterial insults are a manifestation of translocation to the blood stream of bacteria or bacterial products (e.g. endotoxin) from the gut^{ref1, ref2}. In this context administration of endotoxin to normal human volounteers increases serum CTpr values to levels seen in sepsis^ref. In addition to endotoxin, various proinflammatory mediators have also been shown to induce CTpr, e.g. TNF-a, IL-2 or IL-6. At least one parasitic infection (malaria) may substantially increase serum CTpr^ref. In fungal infections levels are occasionally^ref, but not always^ref, high. Viral infections may be associated with mildly or moderately elevated CTpr levels^{ref1, ref2} [14, 34], and here again bacterial translocation from the gastrointestinal tract may be a factor. It is of interest that, physiologically, newborns also exhibit a considerable increase in circulating CTpr which reverses spontaneously in the first week^{ref1, ref2, ref3}. This could be interpreted as a host response to initial establishment of the normal intestinal bacterial flora^ref. If the respective reference ranges are applied appropriately, CTpr can also be used to diagnose microbial infections in newborns^{ref1, ref2, ref3}. In these circumstances an ultrasensitive CTpr assay would be preferable. CTpr is an excellent marker for severe, invasive bacterial, fungal and protozoal infections (urinary tract infections and sepsis) in children^ref. Using a cut-off range of 0.5 through 2 ng/mL, the sensitivity and specificity of PCT are 100% in discriminating bacterial meningitis from viral meningitis. Some of the 7 studies published since seemed to demonstrate the usefulness of PCT in diagnosing meningitis. Finally, PCT was used effectively to shorten unnecessary antibiotic treatment for children seen in an hospital in Paris (France) during summer 2000 : on 243 patients with infections of the lower respiratory tract, such as bronchitis and pneumonia, 83% were given antibiotics when they received normal care (chest X-rays, laboratory tests and clinical symptoms) to assess whether an infection was bacterial in nature, vs. 43% when diagnoses were made on the base of plasma procalcitonin rise (a test which takes about 1 hour) : mucous culture, which is not always accurate, indicated that only about 20% of patients in both groups had bacterial infections. Even if the procalcitonin test still results in some over-prescription of antibiotics, it improves the situation dramatically^ref. In particular, serial measurements are useful in order to monitor response to therapy. PCT is present in the plasma of healthy subjects in minimal levels (< 0.5 ng/ml). Serum procalcitonin is markedly increased a few hours after the administration of endotoxin to human volunteers and in invasive bacterial infection (sepsis, septic shock, meningitis). Procalcitonin is moderately increased in local bacterial infection (pneumonia pyelonephritis) and is unchanged in viral infections or bacterial colonization. Procalcitonin is increased in serious bacterial infections in neonates, children and adults and is currently the best diagnostic marker of severe bacterial infection, being better than leukocyte, IL or CRP counts. CRP levels can be normal in severe sepsis and some viral infections^ref. CRP, PCT, WBC and ESR have only limited value in differentiating pneumococcal or other bacterial pneumonia from viral pneumonia. If there is a high value in at least one of the markers (CRP > 80 mg/L, PCT > 1.8 mg/L, WBC > 22 x 10⁹/L or ESR > 60 mm/h), viral infections are rare. There is no combination of these markers which was sufficiently sensitive and specific to be used in clinical pediatric practice^ref. 25 clinical indications, guidelines and caveats for the interpretation of serum CTpr. Many of the patient categories discussed in this table have what was initially defined a decade ago as “sepsis”, i.e. the systemic inflammatory response syndrome associated with proven or presumptive bacterial infection. However, in patients with other conditions (e.g. pancreatitis, burns, chemical pneumonitis, trauma, surgery, severe illness due to viruses, fungi, or malarial parasites, etc.), translocation of bacteria and/or bacterial products across the intestinal wall may occur, producing a syndrome that is identical to sepsis and not uncommonly just as ominous in outcome. Furthermore, there is nothing to prevent patients with a translocation-induced sepsis-like syndrome from subsequently developing a secondary, exogenous, systemic bacterial infection. Note that in all instances, as is the case of many laboratory tests, a serum CTpr level must be evaluated with proper regard to the clinical and laboratory context of the patient studied.
• the critically ill patient with sepsis and suspected bacterial infection should have a serum CTpr determination. In most such patients with marked bacterial infection, serum values will be high, and sepsis is diagnosed^{ref1, ref2, ref3}. A lower level may indicate another cause of illness, though local infection may still be present.
• in a patient with sepsis, the initial serum CTpr value may have prognostic significance (i.e. extremely high levels correlate with mortality)^ref. Similarly, a further later increase may presage a fatal outcome^ref
• very high levels of serum CTpr may occur in septic patients with severe SIRS and presumed infection, whether or not blood cultures are positive.
• in a patient with demonstrated sepsis, a progressive decrease in an initially high CTpr commonly indicates a response to therapy, an improvement in the clinical course and a favourable outcome^{ref1, ref2}. In such circumstances, however, a more sensitive CTpr assay is usually required to evaluate significant day-to-day fluctuations and reliably detect meaningful trends.
• in the elderly patient with recent onset of confusion, anorexia or incoordination, and for whom systemic bacterial infection is being considered, serum CTpr should be determined. Such patients are often normothermic or hypothermic, may not have leukocytosis, and may not manifest other signs of SIRS, such as tachycardia or tachypnoea. Furthermore, cultures in elderly patients may present positive urinary bacterial cultures and/or bacterial colonisation of the bronchial tree, without sepsis being present. If, however, sepsis is present, serum CTpr levels will be high.
• in a febrile patient, serum CTpr levels may differentiate bacterial infection from other, non-infectious causes of fever in which serum CTpr levels will usually be considerably less elevated or normal (e.g. drug fever, sarcoidosis, familial Mediterranean fever, collagen-vascular disease, lymphoma, leukaemia, sarcoidosis, solid tumors such as hypernephroma, granulomatous thyroiditis, fever of unknown origin and factitious fever)^{ref1, ref2}. The diagnostic and predictive utility of serum CTpr assay in patients with neutropenic fever is uncertain^ref
• serum CTpr levels are considerably higher in patients with septic shock as opposed to those with cardiogenic shock or with shock due to haemorrhage or acute primary adrenocortical insufficiency^{ref1, ref2}
• in the acute respiratory distress syndrome of adults (ARDS), higher CTpr levels occur if the cause is infectious than if there is a non-infectious aetiology. However, in acute respiratory distress syndrome of the premature infant, extremely high CTpr levels often occur without evidence of bacterial infection.
• serum CTpr levels are increased in most patients with pneumonitis^ref. However, if pneumonitis or pyelonephritis is minimal, SIRS may not be present. These patients may not have increased levels of CTpr when assayed commercially, but they often will have increased levels if an ultrasensitive CTpr assay is performed. This allows early identification of the problem and, if such values subsequently increase, permits the diagnosis of early sepsis. It will need to be determined whether the increased sensitivity of an ultrasensitive CTpr assay is accompanied by a decrease in specificity and positive predictive value.
• in patients with long-term intravascular catheters (e.g. central venous pressure monitoring, renal dialysis, prolonged antibiotic therapy, chemotherapy, intravenous alimentation), a sudden increase in previously normal or only mildly elevated levels of CTpr often predicts, very early, the onset of bacterial sepsis; this diagnosis of sepsis may occasionally precede the appearance of a positive blood culture or signs of sepsis. However, for this purpose an ultrasensitive CTpr assay must be used.
• significant viral infections are usually associated with only minimal to moderate increases in serum CTpr; high levels strongly suggest bacterial super-infection. In meningitis, the high levels of CTpr encountered where the aetiology is bacterial will contrast markedly with the lower levels in the vast majority of those with a viral aetiology^{ref1, ref2}
• patients with AIDS without any associated bacterial infection do not exhibit increased CTpr as assayed by the current commercially-available assay^ref. However, an ultrasensitive CTpr assay does reveal moderate elevations.
• in acute attacks of Plasmodium falciparum malaria, serum CTpr levels are markedly elevated; levels decrease with clinical improvement^ref. Most other parasitic infestations are not acute and have not been studied.
• patients with systemic fungus infections (e.g. candidiasis, aspergillosis) may have increased serum CTpr values^ref. However, some patients have slightly or moderately increased levels^{ref1, ref2}
• in severe mechanical trauma there is an early transient increase in serum CTpr. The level peaks within 1–3 days and is proportional to the severity of the tissue injury. Furthermore, a later secondary increase in CTpr is strongly suggestive of bacterial infection^ref.
• following surgical trauma, serum CTpr shows an increase in the first 1–2 days, the level of which correlates positively with the extent of surgery^ref. After some surgical procedures a high day-one postoperative serum CTpr is predictive of mortality^ref. However, after cardiopulmonary bypass there is a particularly rigorous inflammatory cascade and marked early serum CTpr elevation does not necessarily indicate infection^{ref1, ref2, ref3}. But here, as in any postoperative patient, either a persistently high serum CTpr level or a later, marked, secondary increase strongly suggests systemic bacterial infection^ref
• in patients who have undergone heart, lung, heart-lung, or liver transplantation, high serum CTpr levels indicate bacterial infection rather than acute rejection^{ref1, ref2}. Importantly, administration of monoclonal or polyclonal anti-thymocyte globulin to treat acute rejection induces a marked increase in circulating CTpr levels even in the absence of infection^ref. Also, in a study of patients after neutropenic allogenic bone marrow transplantation, serum CTpr levels were of little value in distinguishing infection from other complications^ref
• in chemical pneumonitis due to inspiration of vomitus or to inhalation burn injury or inhalation of toxic fumes, there may be a sudden, marked increase in CTpr which is often proportional to the clinical severity of the insult^{ref1, ref2}
• in pancreatitis associated with infected necrosis or caused by biliary obstruction, serum CTpr levels are higher than in the pancreatitis of alcoholism. Furthermore, in pancreatitis in general, high levels correlate with poor outcome^{ref1, ref2}
• in burns there is a subgroup of patients who exhibit extremely high serum CTpr values in the first two days; these patients often have a rapidly fatal outcome. Patients who develop high levels later in the course often die of sepsis. Patients who never show high levels usually survive^{ref1, ref2, ref3}
• heatstroke is usually accompanied by increases in serum CTpr, the level of which may correlate with the length of cooling time required for appropriate recovery^ref.
• patients with systemic lupus erythematosus or autoimmune vasculitis do not have elevated levels of CTpr as assessed by the current commercial assay^ref. Whether an ultrasensitive CTpr assay would show elevated levels has not been determined.
• mild to moderate increases in CTpr may occur in various chronic inflammatory diseases in which neuroendocrine cell hyperplasia is a commonly associated factor (e.g. chronic obstructive pulmonary disease, chronic bronchitis, pulmonary tuberculosis, regional ileitis, ulcerative colitis). In evaluating the course of such illnesses it would be preferable to use an ultrasensitive
• CTpr assay. The lack of specificity of CTpr in surgical patients, patients with burns or patients with non-infectious inflammatory disorders could reveal the potential limitations of an ultrasensitive CTpr assay.
• circulating CTpr levels show increases in newborns which reverse spontaneously in the first week. If the correct reference ranges are applied, CTpr may nevertheless be used to diagnose microbial infections.
• patients with medullary thyroid cancer always have increased serum CTpr, as do most patients with small cell cancer of the lung or carcinoid tumour and, on occasion, patients with other neuroendocrine tumours such as phaeochromocytoma^{ref1, ref2}. The usefulness of CTpr assays in evaluating the clinical course of such patients has not been studied.
• intestinal surgery and major operations more often increase PCT, whereas it is normal in the majority of patients after minor and primarily aseptic surgery. PCT can thus be used postoperatively for diagnostic means only when the range of PCT concentrations during the normal course of a certain type of surgery is considered and concentrations are followed up^ref
• sICAM-1 concentration may be used as a diagnostic tool with high sensitivity (85%) and moderate specificity (54.3%) in neonates suspected of infection.
• negative APPs / visceral proteins
• transferrin
• albumin
• transthyretin  / thyroxin-binding prealbumin (TBPA)
• C3 (elevation < 2 fold)
• ceruloplasmin (Cp) / ferroxidase (elevation < 2-fold) : IFN-g induces Cp expression and secretion in monocytes at inflamed sites, which is then subjected to translational silencing approximately 16 hours after. IFN-g  induces phosphorylation of the ribosomal protein L13a (RPL13A) / interferon-Gamma-Activated Inhibitor of Translation (GAIT) which is released from the 60S ribosomal subunit and binds to a 29 nucleotide area of the 3'-UTR of Cp mRNA^ref
• IgG
• IgM
• retinol binding protein (RBP)
• a₂-HS glycoprotein (AHSG)
• apoA-I
During APR, some acute phase reactants including serum amyloid A (SAA) component (1, 2, and 4), ceruloplasmin / ferroxidase, and apolipoprotein J / clusterin transitory integrate HDL, which in turn loses its ability to control oxidation of small dense LDL and production of oxidized phospholipids.
• oxidized LDL (oxLDL) bind to CRP and CD204 / macrophage scavenger receptor on macrophages (promoting mature dendritic cell (DC) transition from differentiating monocytes; oxLDLs engulfement leads to formation of foam cells) and lumenal surface of endothelial cells stimulating cytokine secretion via PPARd, thus being part of a nonspecific innate immune response.
• (oxLDLs)lysophosphatidylcholine (lysoPtc / LPC) acts through GPCRs PAFR, LOX-1, GPR4 and G2A, but the initiator GPCR is unknown : furthermore it is bound by the APP CRP.
• immunization with a model oxidized LDL — malondialdehyde-modified LDL (MDA-LDL) — promotes a T_h2-type response that, through the production of IL-5, increases the titre of natural IgM antibody T15/EO6 (specific for phosphorylcholine head group of oxidized phospholipids in MDA-LDL) secretion by activating B1 lymphocytes. Moreover, the presence of these natural antibodies correlates with protection from atherosclerosis as T15/EO6 natural antibody can block the uptake of oxidized LDL by macrophages, which contribute to the pathogenesis of atherosclerotic lesions through the formation of lipid-loaded foam cells. The development of atherosclerosis in LDLR-deficient mice given a high-fat diet is associated with T_h1-cell responses^ref. There are important implications for strategies that inhibit the actions of IL-5 to treat asthma and other allergic diseases.
• oxLDL is taken up much more rapidly by macrophages than native LDL and this may explain in part the generation of foam cells in the developing fatty streak lesion of atherosclerosis^ref. There is now a good deal of evidence to support the view that oxidation of LDL is a significant element in the pathogenesis of atherosclerosis, including the demonstration in several different animal models that antioxidants inhibit lesion progression^{ref1, ref2, ref3, ref4}. Most recently it has been shown that vitamin E inhibits lesion progression in the apoE-knockout model and that this correlates nicely with a decrease in the extent of isoprostane formation by nonenzymatic oxidation of arachidonic acid^ref (6). Strong support for the hypothesis is provided by the recent report that targeted disruption of the gene for 12/15-LOX profoundly inhibits atherosclerosis in the apoE-deficient mouse^ref. During oxidation of LDL there is a progressive decrease in the number of reactive lysine epsilon amino groups^ref. It has been generally assumed that these amino groups are blocked by reaction with short-chain aldehydes derived from the peroxidation of polyunsaturated fatty acids (e.g., malondialdehyde or 4-hydroxynonenal)^{ref1, ref2}. This conjugation of aldehydic fragments with lysine amino groups was believed to be responsible for converting native LDL into a form recognized by macrophage scavenger receptors. This was a logical conclusion drawn in part by analogy with the several modifications that were shown to generate modified LDL recognized by the scavenger receptors, i.e., acetylation^ref, treatment with malondialdehyde^ref, and so on. There was little or no consideration of the possibility that some of the masking of lysine amino groups might be due to conjugation with core ester aldehydes (i.e., phospholipids in which the sn-2 polyunsaturated fatty acid has been oxidatively degraded leaving a shortened fatty acid fragment, still esterified to the glycerol backbone, but terminating with an aldehydic function, or polyunsaturated cholesteryl esters in which the fatty acid has been similarly degraded leaving a new exposed aldehydic function). The possibility that such core ester aldehydes might play a significant role was raised by studies in this laboratory demonstrating that both the apolipoprotein moieties and the lipid moieties of OxLDL could bind to macrophage scavenger receptors and compete reciprocally with each other for that binding. It was further strengthened by the demonstration that a monoclonal antibody against oxidized phospholipids could react with both the isolated apolipoprotein and the reconstituted lipids from OxLDL^ref. Moreover, this antibody strongly inhibited macrophage binding of OxLDL, as well as that of the reconstituted lipid and protein moieties of OxLDL^{ref1, ref2}. In oxLDL, oxidized phospholipids bind to e-amino groups of Lys residues in apoB : the ability of the apoB from oxidized LDL to compete with intact oxidized LDL or with the apoB prepared from OxLDL varied directly with the number of phospholipid molecules bound per mole of apolipoprotein. The recognition of the oxidized LDL apoB by monoclonal antibody EO6 also varied according to the number of phospholipid molecules covalently attached^ref. Antibody EO6 has previously been shown to react with antigens present in atherosclerotic lesions^ref, suggesting that oxidized phospholipid-apoB adducts are also produced in vivo. Itabe et al. immunized mice with material from a human atheroma and cloned an antibody (DHL3) with anti-phospholipid activity very similar to that of EO6. This antibody also reacted with circulating oxidized human LDL and with human atherosclerotic lesions^ref. OxLDL has been separated into its protein moiety [apolipoprotein B isolated from OxLDL (Ox_apoB)] and its lipid moiety (Ox_lipid) using exhaustive organic solvent extraction, and the binding properties of the two fractions have been studied^{ref1, ref2}. Both of the isolated moieties bind with high affinity to the scavenger receptors of mouse peritoneal macrophages, and surprisingly, they exhibit marked reciprocal competition. Confirming this apparent "common epitope" between the two species, a monoclonal antibody, designated EO6, recognized both the protein and lipid moieties of OxLDL^ref. EO6 competed for binding to mouse peritoneal macrophages through a recently identified common epitope of oxidized phospholipid (PL), present either within the lipid phase of OxLDL or covalently associated with the lysine residues of the oxidized protein of OxLDL^{ref1, ref2}. Antibody EO6, which recognizes oxidized PL^ref, and 1-palmitoyl-2-(5-oxovaleroyl) phosphatidylcholine (POVPC), a product of LDL oxidation^ref, were both excellent competitors of OxLDL binding to CD36. The results suggested that >60% of the binding of OxLDL to CD36 is mediated by oxidized PL, present within the lipid phase or covalently associated with the OxapoB.

Anticardiolipin antibodies from patients with the antiphospholipid antibody syndrome recognize epitopes in both b₂-glycoprotein 1 and oxLDL^ref
• LDL modified by HOCl (HOCl-LDL) : hypochlorous acid (HOCl) produced by myeloperoxidase (MPO), an inflammator heme protein secreted by phagocytes oxidize tyrosine to 3-chlorotyrosine : when this occurs in the main protein in HDL, apolipoprotein A-I, this turns the 'good cholesterol' bad in the human artery wall and impairs ABCA1-dependent cholesterol transport, promoting atherogenesis by counteracting the established antiatherogenic effects of HDL and the ABCA1 pathway^ref. HOCl-LDL displays a number of pathophysiological effects on phagocytes and vascular cells, contributing to the initiation and maintenance of the inflammatory process during the early phase of atherosclerotic lesion development. HOCl-LDL induces chemokine release of monocytes and chemotactic migration of neutrophils^ref, initiates the respiratory burst of macrophages^ref, stimulates polymorphonuclear leukocytes to an enhanced production of superoxide anion radical and hydrogen peroxide, enhances neutrophil degranulation^ref, and inactivates lysosomal proteases^ref. HOCl-LDL further decreases nitric oxide-synthesis in endothelial cells^ref, causes endothelial leakage and stimulates leukocyte adherence to, and migration into, the subendothelial space^ref. HOCl-LDL enhances platelet reactivity and release reaction^{ref1, ref2}, and most importantly, HOCl converts LDL into a high uptake form for mouse peritoneal macrophages^ref, leading to the formation of cholesteryl ester (CE)-laden foam cells, which are the hallmark of fatty streaks and the earliest recognizable lesion of atherosclerosis. The presence of 3-chlorotyrosine in human atherosclerotic lesions^ref, the presence of HOCl-modified epitopes inside and outside monocytes/macrophages, endothelial cells, and smooth muscle cells in human and rabbit lesion material^{ref1, ref2, ref3}, and the presence of HOCl-modified apoB-100 extracted from advanced human atherosclerotic lesions^ref supported the view that the MPO/hydrogen peroxide/chloride system converts LDL into an atherogenic form under in vivo conditions. HOCl-LDL bind to SR-BI and CD36^ref.
• both type I and type II SR-A bind a diverse array of macromolecules, including bacterial surface lipids (endotoxin and lipoteichoic acid), b-amyloid fibrils, protein modified by advanced glycation (advanced glycation end products), and modified lipoproteins, e.g. acetylated LDL (ac-LDL) or copper-oxidized-LDL (Cu-ox-LDL), respectively. SR-AI/AII mediates 80% of the uptake of ac-LDL^ref
• APR can be truly acute, as in the case of a viral or bacterial infection, but it may also become chronic and result in inflammatory diseases like atherosclerosis. Also seen are fever, increased vascular permeability, and a variety of metabolic and pathologic changes.
• cytostasis : the closure of capillaries by white blood corpuscles in the early stages of inflammation.
Varieties :
• angioflogosis (usually acute inflammation) : prevalence of exudate
• clear, torbid or bloody look
• [Pr^-]_fluid > 3 g / dL
• [Pr^-]_fluid / [Pr^-]_serum > 0.5
• [LDH]_fluid > 200 U / L
• [LDH]_fluid / [LDH]_serum > 0.6
• [Glc] < 60 mg / dL
• WBCs > 1,000 / mL
• RBCs > 5,000 / mL
• positive Rivalta's reaction : a reaction for distinguishing fluids of transudation and exudation, utilizing acetic acid
• erythaematous angioflogosis
• exudative inflammation : one in which the prominent feature is an exudate.
• serous inflammation or angioflogosis : one which produces an exudation of serum.
• sero-fibrinous angioflogosis
• fibrinous angioflogosis or inflammation : one that is characterized by an exudate of coagulated fibrin.
• mucous or catarrhal angioflogosis
• mucopurulent angioflogosis
• purulent or suppurative angioflogosis or inflammation : one characterized by the formation of pus.
• abscess / abscessus : a localized collection of pus buried in tissues, organs, or confined spaces.
• acute abscess : one which runs a relatively short course, producing some fever and a painful local inflammation.
• hot abscess : an acute abscess with symptoms of local inflammation.
• chronic or cold abscess : an abscess of comparatively slow development with little evidence of inflammation
• bicameral abscess : one which has 2 chambers or pockets
• shirt-stud or collar-button abscess : a superficial abscess connected with a deeper one by a passage
• caseous or cheesy abscess : one containing cheeselike material
• diffuse abscess : an uncircumscribed abscess, the pus of which is diffused in the surrounding tissues
• dry abscess : one that disappears without pointing or breaking
• Welch's gas or tympanitic abscess : a localized collection of seropurulent material containing gas, caused by gas-forming bacteria such as Clostridium perfringens
• gravitation or gravity abscess : one in which the pus migrates or gravitates to a lower or deeper portion of the body
• worm abscess : one caused by or containing worms
• helminthic abscess : one caused by a worm, such as filaria.
• verminous abscess : one which contains insect larvae or other animal parasites.
• metastatic abscess : a secondary abscess, usually of embolic origin, in which organisms are carried by the circulation to a point distant from the primary lesion
• miliary abscess : one of a set of small multiple abscesses
• phlegmonous abscess : one associated with acute inflammation of the subcutaneous connective tissues.
• pyemic or septicemic abscess : one due to pyemia
• residual abscess : one recurring at the site where an incompletely resolved abscess occurred previously.
• satellite abscess : a secondary abscess arising from, and situated near, a primary abscess.
• sterile abscess : one from which microorganisms cannot be isolated
• stitch abscess : one that develops adjacent to a stitch or suture.
• sympathetic abscess : one arising some distance from the exciting cause
• wandering, hypostatic or migrating abscess : one that burrows in the tissues and finally points at a distance from the site of origin
• microabscess : a very small, localized collection of pus
• empyema : a collection of pus in a body cavity
• phlegmon / phlegmonous cellulitis : a spreading, diffuse inflammatory reaction to infection with microaerophilic streptococci, which forms a suppurative or gangrenous and undermining lesion that may extend into deep subcutaneous tissues and muscles, creating multiple small pockets of pus
• pyogenic membrane : a membrane which produces pus.
• prophylactic or pyophylactic membrane : a fibrinous membrane lining a pus cavity and tending to prevent reabsorption of injurious materials
• false membrane / neomembrane / pseudomembrane : a layer resembling an organized and living membrane, but made up of coagulated fibrin with bacteria and leukocytes, such as may be formed on mucous membranes in diphtheria or in the gut with Clostridium difficile infection
• haemorrhagic angioflogosis
• necrotic-haemorrhagic angioflogosis
• allergic angioflogosis
• histoflogosis (usually chronic inflammation) : prevalence of cellular phenomena => granuloma: a compact (organized) collection of mature mononuclear phagocytes (macrophages and/or epithelioid cells) which may or may not be accompanied by accessory features such as
• infiltration of other inflammatory leukocytes
• necrosis : tuberculization is  the formation of or conversion into tubercles.
• non-necrotizing or non-caseating granulomas
• sarcoidosis (vast majority of granulomas : hard tubercle, composed of discrete aggregations of large, pale-staining, epithelioid cells intermingled with histiocytes, lymphocytes, and Langhans' giant cells, sometimes surrounded by a narrow band of lymphocytes; when necrosis is present, it is minimal; tuberculitis : inflammation of or near a tubercle => fibrous tubercle is a tubercle that has undergone chronic inflammatory scarring)
• beryllium disease
• hypersensitivity pneumonitis
• drug reactions
• tuberculoid leprosy
• tuberculosis (minority of granulomas)
• foreign bodies in the tissues
• cutaneous leishmaniasis
• deep fungal infections
• Crohn's disease
• necrotizing or caseating granulomas / caseous tubercle (a tubercle having a central necrotic yellowish mass of cheesy material)
• tuberculosis (vast majority of granulomas)
• fungal infections
• rheumatoid nodules
• Wegener's granulomatosis
• necrobiotic post-surgical granulomas
• sarcoidosis (minimal and focal)
From the inner to the outer layer granuloma is made up of ...
• aetiological agent(s)
• living organism (see infective causes)
• unliving matter
• eleoma / elaioma : a tumor or swelling caused by the injection of oil into the tissues
• eleidoma (vegetal oils => reabsorbable)
• paraffinoma / vaselinoma : a chronic granuloma produced by prolonged continuous exposure to the irritation of paraffin (e.g. mineral oils in surgical prosthesis or anti-constipation emulsions), which cannot be reabsorbed
all pneumoconioses (except for anthracitosis).
• mature mononuclear phagocytes
• macrophages
• epithelioid cells : highly phagocytic, modified macrophages, resembling epithelial cells, having large, pale and vesicular nuclei with abundant, eosinophilic cytoplasm, which are characteristic of granulomatous inflammation
‡  coalescence of epithelioid cells or by nuclear division without cytoplasmic division of monocytes
• multinucleate giant cells
• Langhans' giant cells : have their nuclei arranged in a complete circle or in a horseshoe-shaped pattern at the periphery of the cells, characteristically seen in granulomatous inflammations, as occur in tuberculosis, leprosy (lepra cells / Virchow cells) syphilis, sarcoidosis, and deep fungal infections.
• foreign body giant cells (FBGC) : have clusters of nuclei scattered in an irregular pattern throughout the cytoplasm, formed by coalescence and fusion of macrophages, with only a rare internal nuclear division, characteristic of foreign body reaction (FBR) (a granulomatous inflammatory reaction evoked by the presence of an exogenous material (including almost all biomaterials) resistant to degradation in dermis or subcutaneous tissue). FBGC damage the surface of biomaterials. FBGC derive from blood-borne monocytes that enter the implantation site after surgery in response to the release of chemotactic signals and fuse in response to CCL-2 / MCP-1^ref. FBGC are not the primary determinants of capsule formation in the FBR.
• unusual complication of retained surgical material or instruments :
• surgical gauze pseudotumor^ref
• pseudotumor after lung volume reduction surgery^ref
• after gunshot injury^ref. Retained bullet fragments or grenade splinters in veterans of World War II are not uncommon. A large foreign-body–induced pseudotumor first presented > 60 years after the injury occurred^ref.
• activated lymphocytes
• fibroblasts
Web resources :Atlas of granulomatous diseases by Yale Rosen, M.D.
Staging :
• Neutrophils localization (see also Inflammation : the leukocyte adhesion cascade)

step 1) : reversible adhesion (tethering and rolling) (few seconds)

molecules on neutrophils	molecules on endothelial cells
	endothelial heparan sulfate has three functions in inflammation: by acting as a ligand for L-selectin during neutrophil rolling; in chemokine transcytosis; and by binding and presenting chemokines at the lumenal surface of the endotheliumref

step 2) : G_iPCRs-mediated adhesion activation  (few seconds) step 3) : adhesion / attachment & arrest (few seconds)

CLA-1  other syalyl-Lewis A and B molecules	p110CD62E / E-selectin / ELAM-1 / LECAM-2
CD11bCD18 / aMb2 integrin / C3biR / CR3 / Mac-1 (maybe in complexes with CD87/uPAR)	CD54 / ICAM-1 CD102 / ICAM-2 sulfated fucosylated proteoglycans  fucoidin

step 4) : diapedesis / transendothelial migration (TEM) (10')

CD31 / platelet endothelial cell adhesion molecule-1 (PECAM-1) / ENDOCAM was the first such protein shown to mediate neutrophil transmigration in vitro and in vivoref  CD102 / ICAM-2ref1, ref2 They are only relevant for leukocyte recruitment if the inflammation was triggered by IL-1b, but not if the tissue was stimulated by TNF-a or thioglycollate CD99 acts in vitro at a step after PECAM-1ref junctional adhesion molecule-A (JAM-A) participates in stimulus specific waysref  endothelial cell–selective adhesion molecule (ESAM) participates in a cytokine-independent way (F. Wegmann, B. Petri, A. G. Khandoga, C. Moser, A. Khandoga, S. Volkery, H. Li, I. Nasdala, O. Brandan, R. Fässler, S. Butz, F. Krombach, and D. V., manuscript submitted).

Leukocytes move through endothelial junctions between neighboring cells, and they can use an alternative transcellular route through endothelial cells. Although in vitro and in vivo evidence for the latter pathway exist, the transcellular route seems to be used with low efficiency. Whatever relevance it has in vivo, it is remarkable that more and more endothelial membrane proteins that are involved in this process turn out to be located at endothelial cell contacts.
2 peculiar neutrophil chemotactic behaviors are the neutrophil's ability to polarize in uniform concentrations of a chemoattractant (i.e. to break symmetry even in the absence of an external gradient of the stimulus) and its response to reversal of an attractant gradient by performing a U-turn instead of simply reversing their direction of motility :
• the "frontness" pathway is mediated by G_i, 3'-phosphoinositol lipids, and Rac and generates pseudopods via de novo polymerization of F-actin
• the "backness" pathway is initiated by G₁₂ and G₁₃ and is dependent on the activation of a Rho-dependent pathway that stimulates the activation of myosin II and the formation of actin–myosin complexes. Backness signals reduces the sensitivity of the rear and sides of a cell to chemoattractants
As a result of the divergent, opposed signals for front and back, the leading edge is more sensitive than the trailing edge, and the cell "follows its nose."
• chemical mediators of inflammation :
• produced in situ (previously synthetized and stored in the granules of eosinophils, PMNs, macrophages and T-lymphocytes or synthetized at the moment) :
• vasodilators : PGD₂, PGE₂, PGI₂/prostacyclin, NO^., SRS-A
• vasoconstrictors : TxA₂, TxB₂, PGF_2a, PGH₂, 5-HT
• permeabilizing : vasoactive amines (histamine, 5-HT), LTB₄, C3a, C5a, PAF, substance P, bradykinin, SRS-A, PGA₂, PGF_2a
• priming and positive chemotaxis : C5a, LTB₄, chemokines, LPS
• negative chemotaxis : PGD₂, PGE₂, PGI₂ / prostacyclin
• fever : IL-1a, IL-1b (=> IL-1R => COX-2 => PGE₂ => EP_{_} => preoptical area), IL-2, IL-6, IL-8,IFNs, TNF-a
• hyperalgesia : PGE₂, PGI₂/prostacyclin, bradykinin
• induction of platelet aggregation : NO^., R.O.S., TxA₂, PGE₂, PGH₂, PAF
• inhibition of platelet aggregation : PGD₂, PGI₂ / prostacyclin
• induction of T-cell proliferation : TxA₂, LTB₄
• inhibition of T-cell proliferation : PGD₂, PGE₂, PGI₂ / prostacyclin
• macrophage inhibition and eosinophils activation : 15-deoxy-D^12,14-PGJ₂ (15dPGJ₂) and 15-deoxy-D^12,14-PGD₂ (15dPGD₂)
• induction of pro-inflammatory cytokines production : LTB₄
• inhibition of pro-inflammatory cytokines production : PGD₂, PGE₂, PGI₂ / prostacyclin
• SMC contraction : SRS-A, PGF_2a, histamine
• produced in other places :
• coagulation cascade components
• kinin system
• complement (C') cascade components
• immune response. Lymphocyte migration occurs in focal structural dilations - microangiectasias - in the vessel, in which shear forces are reduced sufficiently to allow lymphocyte-endothelial cell interactions to occur. Shear stresses in normal vessels are 20 dyn/cm², but lymphocytes adhesion usually occurs at wall shear stresses of 1 dyn/cm². Furthermore, blood flow during inflammation is likely to increase the shear stresses rather than decrease them.
CCR5⁺ apoptotic leukocytes act as 'terminators' of chemokine signaling (CCL3 and CCL5) during the resolution of inflammation^ref
Cellular responses to hypoxia :
• fast (acute) responses (s to min) rely mainly on O₂-regulated ion channels
• during both systemic hypoxemia and local hypoxia :
• activation of glucose uptake by translocation of GLUT-1 and GLUT-4 from intracellular vesicles to the plasma membrane and activate preexisting GLUT-1 in the membrane (cardiac and skeletal muscle, fat tissue)
• activation of Na⁺-H⁺ exchanger (NHE)
• inhibition of K⁺-Cl^- cotransporter (KCC)
Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. HIF-1a was induced by bacterial infection, even under normoxia, and regulated the production of key immune effector molecules, including granule proteases, antimicrobial peptides, nitric oxide, and TNF-a. Mice lacking HIF-1a in their myeloid cell lineage showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. Conversely, activation of the HIF-1a pathway through deletion of VHL tumor-suppressor protein or pharmacologic inducers supported myeloid cell production of defense factors and improved bactericidal capacity. HIF-1a control of myeloid cell activity in infected tissues could represent a novel therapeutic target for enhancing host defense^ref.
• during systemic hypoxemia only :
• hyperventilation (transmitter release by electrically excitable arterial (carotid and aortic body) and airway chemoreceptors). They may have some tonic activity at the normal P_O2 levels of arterial blood (90-100 mmHg), but they begin to be fully activated with moderate levels of hypoxia (< 50-60 mmHg). K⁺ channels are closed by low P_O2 => membrane depolarization => opening of voltage-gated calcium channel => transmitter release to the extracellular milieu and, in the innervated organs, activation of afferent sensory fibers
• decreased heart output (peripheral chemoreceptors, heart muscle)
• systemic arterial vasodilation is particularly well manifested in coronary and cerebral vessels (arterial endothelium and smooth muscle, irrigated tissues)
• decreased ATP production => opening of K_ATP channels
• direct activation of K_Ca channels
• direct inhibition of L-type voltage-gated calcium channels
• nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes reduces vascular nitrites into nitric oxide^ref
• hypoxic pulmonary vasoconstriction (HPV) in pulmonary arteries and veins but greatest in small resistance arteries (vascular endothelium, resistance vessel pulmonary myocytes). HPV reduces blood flow through poorly ventilated alveoli and thus contributes to matching perfusion to ventilation and preventing systemic hypoxemia when atelectasis is present.
• relaxation of ductus arteriosus (ductus muscle)
• slow (chronic) responses (hours to days) depend on the modulation of hypoxia-inducible transcription factors :
• during both systemic hypoxemia and local hypoxia :
• activation of glucose metabolism and transport (most tissues)
• neoangiogenesis and neovascularization (vascular endothelium, hypoxic or ischemic tissues)
• tissue hypertrophy and remodeling (pulmonary arterial wall, myocardium, carotid body)
• production of vasodilators (vascular endothelium and smooth muscle)
• activation of HIF-1a by low P_O2 is detectable in < 30 min, with peak response occurring in 4 to 8 hours. On return to normoxia, activity decays with a half-life under 5 min. HIF-1 DNA binding activity is modulated within physiologic P_O2 levels. It increases about 2-fold between 20 and 6% O₂ and 10-fold between 6% and 0.5% O₂. Half-maximal activation is around 1.5% O₂ (P_O2 = 11 mmHg). One of HIF's 2 transactivation domains, the C-terminal activation domain of HIF-1a (CAD), is critical to the hydroxylation of HIF and links HIF to the well-studied transcriptional coactivators p300 and CBP, as well as SRC-1, and TIF-2.
• in the presence of O₂, hypoxic switches operate in the CAD :
• hydroxylation of Pro⁵⁶⁴ by HIF-1a prolyl 4-hydroxylase (HPH) (requiring Fe²⁺, O₂, and 2-oxoglutaric acid, and activated by NO^.) : this posttranslational modification allows an E3 ubiquitin ligase complex containing the VHL tumor-suppressor protein to bind HIF-1a and polyubiquinate it in the N-terminal activation domain (NAD) overlapping the oxygen-dependent degradation domain (ODD) (interestingly, hints at the role of prolyl hydroxylation could have been gleaned earlier if researchers had looked to the field of collagen research where, for more than 2 decades, prolyl hydroxylases have been known to use O₂ and to be highly sensitive to iron chelators and cobalt). Ascorbate / vitamin C enhances the activity of HPH and might figure into an antiangiogenic treatment. Although the only known prolyl hydroxylases (prolyl hydroxylase a_I and prolyl hydroxylase a_II, which - combined to prolyl hydroxylase b - hydroxylate collagen) can function under hypoxic conditions, hydroxylation of Pro⁵⁶⁴ is far more important than other post-translational modifications of HIF-1a (e.g. serine, threonine, and tyrosine phosphorylation, asparagine hydroxylation, glutamine deamination, glutamate g-carboxylation on residues in the vicinity of Pro⁵⁶⁴). Prolyl hydroxylase domain (PHD1 / EGLN2, PHD2 / EGLN1, and PHD3 / EGLN3) are O₂-dependent, suggesting to some that these enzymes may be responsible for oxygen sensing^{ref1, ref2}.
• hydroxylation of Asn⁸⁰³ by the Fe²⁺- and O₂-dependent enzyme factor inhibiting HIF-1 (FIH-1), which inhibits binding of CAD to CBP/p300, cofactors required for initiating expression of genes involved in oxygen-response pathways. The asparaginyl hydroxylase can work reasonably well at very low O₂ levels^{ref1, ref2}. The PHDs that control HIF seem to stop functioning at less stringent hypoxia
• in the absence of O₂ no hydroxylation occurs => no proteasomal degradation occurs => HIF-1a is upregulated.


A few favor another model in which the prolyl and asparagyl hydroxylases are regulated upstream by a proximal oxygen sensor, e.g. when mitochondria release reactive oxygen species (ROS), initiating a signal transduction pathway that in turn inactivates the prolyl and asparagyl hydroxylases. The latter model helps to explain data suggesting that overexpression of FIH and the prolyl hydroxylases is sufficient to shut off HIF activity. You can have a profound effect on the transcriptional activation and the stability of HIF by manipulating the expression levels of the enzymes. If oxygen were the direct regulator of FIH and prolyl hydroxylase activities, tight controls would need to be in place to regulate the amount of these hydroxylases in the cell. By having a single proximal regulator, an oxygen sensor, that controls the activity of the hydroxylases ... ultimately HIF stability and HIF transcriptional activity could be made more independent of the precise levels of the expression of the hydroxylases themselves. Further, the model could also explain other oxygen-dependent responses that do not require HIF; for example, mitochondrial ROS mediate hypoxic pulmonary vasoconstriction, a HIF- independent process. Unfortunately ROS levels are difficult to measure, which can make it hard to draw accurate conclusions. The oxygen tension required to trigger PHD2 is in the physiologic range. There's lots of flux and the oxygen tension is very high outside of the cell; there's a gradient. The mitochondria are active consumers of oxygen, so to really get a handle on what the oxygen tension is at the very intracellular site where prolyl hydroxylase is acting, is a very tough challenge.
HIF-1 alters WBCs so that they can survive without O₂ - a trick that is essential to their defensive role, as damaged tissues are often low in the gas. WBCs from HIF-1^-/- mice stay away from low-O₂ environments, and destroy few bacteria
Genetic alterations that increase HIF-1 activity :
• decreased ubiquitylation
• VHL loss of function^ref
• p53 loss of function^ref
• increased synthesis
• PTEN loss of function^{ref1, ref2}
• ERBB2 gain of function^ref
• SRC gain of function^ref
• signalling in a component of the pathway or an upstream activator
• PI3K-AKT-mTOR^{ref1, ref2}
• MEK-ERK signalling^ref
• EGFR signalling^ref
• IGF1R signalling^ref
• PGE₂signalling^{ref1, ref2}
• decreased nucleolar sequestration : ARF loss of function^ref
• not determined : BCL2 overexpression^ref
Under certain cellular conditions, HIF-1a is also responsible for hindering the cell's mismatch repair (MMR) system, crucial for maintaining a cell's genetic integrity : HIF-1a acts by displacing Myc, the transcriptional activator of 2 nuclear proteins, MSH2 and MSH6. In the absence of HIF-1a, Myc activates the expression of the 2 compounds, which then dimerize to form the MutSa complex—one of the mammalian versions of the MMR system. In the presence of HIF-1a, Myc cannot reach the promoters, and the expression of MutSa is inhibited
• AP-1
• EGR-1
• HMG-I(Y)
• NF-IL6
• NFkB
• during systemic hypoxemia only :
• erythropoiesis (bone marrow)
Cardinal signs of localized inflammation (Aulus Cornelius Celsus, De Re Medica, 25-35 a.C.) :
• rubor = redness
• tumor = swelling
• calor = heat
• dolor = pain
• functio laesa = loss of function (added by Galenus, 129-201 a.C.)

During systemic inflammation, body temperature is either increased (fever) or decreased (anapyrexia). Either response depends on ..
• the dose of the inflammatory agent
• the ambient temperature
• under thermoneutrality, LPS always produces fever
• subthermoneutral conditions, LPS evokes ...
• fever at lower doses
• anapyrexia at higher doses
Pathogenesis : febrigenic doses of LPS => IL-1b =>
• increased production of PGE₂ by COX-2 and mPGES-1 in vein or venular-type cerebral blood vessel and leptomeningeal cells in the ventromedial preoptic region (PO) of the hypothalamus (VMPO) => decreasing the intracellular content of cAMP. Although COX-2 plays a dominant role in mediating fever responses to i.v. LPS, at least some components of the response, including avoiding hypothermia and the induction of Fos in the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM), parabrachial nucleus (PB), and hypothalamic paraventricular nucleus (PVH), appear to depend on COX-1
• inhibition of NOS1  => decreased intracelullar content of cGMP in the PO
=> fever / pyrexia : elevation of body temperature above the normal. Although the role of preoptic cAMP and cGMP has not been directly assessed in the anapyrexia induced by LPS, it has been studied in that induced by hypoxia : the likeness between the thermoregulatory responses to hypoxia and to a high dose of LPS suggests that they may have similar mechanisms, ie a simultaneous increase in the levels of cAMP and cGMP in the PO as the result of an enhanced production and/or release of serotonin and nitric oxide, respectively
Aetiology :
• physiological stresses such as
• ovulation
• milk fever : a fever said to attend the establishment of lactationafter delivery
• excess thyroid hormone secretions
• fatigue fever : a febrile attack due to overexercise and the absorption of waste products.
• digestive fever : a slight rise of temperature during the process of digestion.
• functional fever : irregular defecation, dyspnea due to meteorism (hysterical pregnancy), insomnia, headache, fine tremors, frequent urination due to chronic visceral contraction, emotional instability, anxiety, normal laboratory examinations (CBC, a₁gp, ESR, CRP)

Therapy : i.v. BDZ
• central nervous system lesions
• central fever : sustained fever resulting from damage to the thermoregulatory centers of the hypothalamus, e.g. by brain tumors
• suspension of analeptics
• infection by microorganisms
• systemic infections
• Brucella melitensis (undulant fever)
• Coxiella burnetii
• otitis
• pharyngotonsillitis
• pyelonephritis (accompanied by renal colic)
• urethrocystitis (accompanied by stranguria)
• meningitis
• enteric fever : any of a group of febrile illnesses associated with enteric symptoms caused by salmonellae, especially ...
• typhoid fever (the prototype of the severe enteric salmonellal infections)
• paratyphoid fever
• stepladder stage : an early stage of enteric fever; so called from the peculiar form of the temperature curve.
• entericoid fever : any fever which resembles typhoid fever in its clinical manifestations.
• parenteric fever : a disease clinically resembling typhoid fever and paratyphoid fever, but not caused by Salmonella.
• viral hemorrhagic fevers : a group of diverse, severe epidemic viral infections, found in many parts of the world, mainly in tropical climates; causative viruses are often geographically restricted. They are usually transmitted to humans by arthropod bites or contact with virus-infected rodents; all the infections share certain clinicopathological features, including fever, hemorrhagic manifestations, thrombocytopenia, shock, and neurologic disturbances. The group comprises :
• Argentine hemorrhagic fever
• Bolivian hemorrhagic fever
• chikungunya ("bone-breaking fever")
• Crimean-Congo hemorrhagic fever
• dengue hemorrhagic fever
• Ebola hemorrhagic fever
• epidemic hemorrhagic fever
• Kyasanur Forest disease
• Lassa fever
• Marburg fever
• Omsk hemorrhagic fever
• Rift Valley fever
• yellow fever
• humidifier fever : a syndrome of malaise, fever, cough, and myalgia, caused by inhalation of air that has been passed through humidifiers, dehumidifiers, or air conditioners contaminated by fungi, amebas, or thermophilic actinomycetes
• any of a host of noninfectious processes, such as inflammation or the release of certain materials
• autoimmune diseases
• hypersensitivity reactions
• intermittent hepatic fever / Charcot's fever or syndrome : a fever occurring intermittently as the result of intermittent impaction of choledocholithiasis and inflammation of the bile ducts
• urolithiasis
• drug fever : a febrile reaction marked by prolonged temperature elevation during the course of administration of a drug, such as an antibiotic, antineoplastic, vaccine, etc.; it may be associated with vasculitis affecting small vessels, and usually disappears rapidly on discontinuance of the drug
• hydroxyurea (HU)
• duck fever : a type of hypersensitivity pneumonitis caused by sensitivity to duck proteins contained in duck feathers.
• land fever : a set of symptoms resembling seasickness sometimes experienced when, after an ocean voyage, the ship enters a relatively landlocked body of water.
• periodic fever : a hereditary condition characterized by repetitive febrile episodes and autonomic disturbances, occurring in precise or irregular cycles of days, weeks, or months. Transmitted as an autosomal dominant trait, it may begin at any time of life and may last for decades with temporary remissions, or may cease
• hereditary periodic fever syndromes
• periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome (PFAPA syndrome) / Marshall syndrome

Symptoms & signs : abrupt onset of fever, malaise, aphthous stomatitis, tonsillitis, pharyngitis and cervical adenopathy. The age of onset of the disease is four years, with a range of 6 months to 7 years. The syndrome is sporadic and nonhereditary
Therapy : tonsillectomy
Prognosis : long-term sequelae do not develop.
• protein fever : heightened temperature produced by the injection of protein material into the body.
• salt fever : fever associated with excess of salt in the body, due to the retention by the salt of the water normally eliminated in perspiration.
• shoddy fever : a febrile disease, with cough, dyspnea, and headache, caused by inhalation of dust in shoddy factories.
• leukemia
• Murchison-Pel-Ebstein fever or pyrexia: a cyclic fever occasionally seen in Hodgkin's disease and also associated with other diseases, characterized by irregular episodes of pyrexia of several days' duration, with intervening afebrile periods lasting for days or weeks
• thermic fever / sunstroke / insolation
• artificial fever : elevation of bodily temperature produced by artificial means, as by external heat or the injection of typhoid vaccine or malarial parasites
• therapeutic fever / pyretotherapy : treatment of a disease by raising the patient's temperature, especially by means of injecting fever-producing vaccines
• inductothermy
• aseptic fever : fever associated with aseptic wounds, presumably due to the disintegration of leukocytes or to the absorption of avascular or traumatized but uninfected tissue.
• fever of unknown origin (FUO) / pyrexia of unknown origin (PUO) / essential fever : defined in 1961 as a temperature > 38.3°C on several occasions for >= 3 weeks, with the diagnosis remaining uncertain after 1 week of hospitalization^ref, associated to systemic symptoms such as night sweats, thinning and fatigue, sometimes associated to RCCs, but for which no cause has been found. 10% remain undiagnosed. Since then, other definitions have been proposed. The initial evaluation of FUO typically involves a thorough history taking, physical examination, routine blood chemical tests, blood counts, cultures of urine and blood, and abdominal CT. Further testing is generally more invasive, and its pace depends on the patient's condition, with rapid clinical deterioration mandating an aggressive strategy. A liver biopsy yields a diagnosis in about 15% of patients with FUO^ref. Although the diagnostic yield of cultures of bone marrow in patients with FUO is usually very low, fibrin-ring granulomas in some cases suggest that a disseminated granulomatous disease is the cause of the illness.
Pathogenesis : when primed with TLR agonists or bacterial extract but not proinflammatory cytokines, hyperthermia specifically enhanced secretion of IL-12p70 by DC, without altering the secretion of IL-10, TNF-a or IL-1b. These DC induced significantly higher levels of T-cell proliferation and IFN-g production in assays of antigen presentation and MLR. Endogenous HSP70 colocalized with CD40 in DC exposed to hyperthermic conditions. Recombinant CD40-Fc fusion protein blocked the increase in IL-12p70 secretion by DC primed with bacterial extract and hyperthermia^ref
Course :
• stage of fervescence / pyretogenic or pyrogenetic stage : the stage of invasion of a febrile attack.
• continued or continuous fever : one which has gradual  onset (up to 5 days), fastigium (from day 6 to day 13) in which it varies < 1.0° to 1.5°F (< 1°C) in 24 hours, such as typhoid fever
• remittent or septic fever : a fever in which the diurnal variation is > 2° F (> 1°C), but in which the temperature never falls to a normal level
• continued-remittent fever : a fever in which in some days the diurnal variation is > 2° F (> 1°C), and in other days the diurnal variation is < 2°F (< 1°C)
• undulant fever : a particular kind of continuous-remittent fever which has increasing peaks associated with chills every 24 hrs and crisis defervescence => night sweats, arthromyalgia, headache, anorexia, alternated to afebrile periods every 1÷4 weeks such as brucellosis (some authors classify it as a type of intermittent fever)
• Haemophilus influenzae
• intermittent fever : a fever in which periods of fervescence are separted by periods of defervescence down to papyrexia, such as malaria
• cold stage / stadium frigoris : the chill or rigor period of an intermittent fever
• hot stage / stadium caloris : the period of pyrexia in an intermittent fever
• quotidian fever : fervescence each day with apyrexia at evening, such as with many infections due to decreased cortisolemia at evening
• tertian fever : fervescence each other day, such as Plasmodium falciparum (malignant), Plasmodium vivax or Plasmodium ovale (benign)
• quartan fever : fervescence every 3 days, such as Plasmodium malariae
• recurrent fever : recurrent paroxysmal fever occurring in various diseases, including borreliosis, trepanomatoses, tularemia, meningococcemia, malaria, and rat-bite fever.
• ephemeral fever : a slight fever persisting or lasting only a day or two.
• hectic fever : a fever that recurs each day, with profound sweating, chills, and facial flushing.
• defervescence : the abatement of fever.
• defervescent stage / stadium decrementi : the period of decrease in severity of a disease or fever
• defervescence by crisis : gradually
• sweating stage : the final stage of a malarial paroxysm, marked by sweating
• defervescence by lysis : rapidly
• hyperpyrexia : fever > 40°C
Associated symptoms & signs :
• asthenic fever : a fever with nervous depression, feeble pulse, and a cool, moist skin.
• sthenic fever : fever characterized by a full, strong pulse, hot and dry skin, high temperature, thirst, and active delirium.
• eruptive or exanthematous fever : any fever accompanied by an eruption on the skin during the eruptive stage / stadium fluorescentiae
• spotted or boutonneuse fever : a febrile disease typically characterized by a skin eruption, such as typhus, epidemic cerebral meningitis, and the infections caused by tick-borne rickettsiae (Rocky Mountain spotted fever, boutonneuse fever, and others)
• systemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system, definitive proof has been lacking. The TXA₂analog I-BOP and PGF_2a each increased the beating rate of the isolated atrium of wild-type mice in vitro through interaction with TP and FP receptors, respectively. The cytokine-induced increase in beating rate was markedly inhibited in atria from mice lacking either TP or FP receptors. The tachycardia induced in wild-type mice by injection of lipopolysaccharide (LPS) was greatly attenuated in TP-deficient or FP-deficient mice and was completely absent in mice lacking both TP and FP. The b-blocker propranolol did not block the LPS-induced increase in heart rate in wild-type animals. Inflammatory tachycardia is caused by a direct action on the heart of TXA₂ and PGF_2a formed under systemic inflammatory conditions^ref.
Laboratory examinations :
• phenylbutazone test : fever disappears only if due to tumor pyrogens, not to infectious agents. no longer used due to risk to induce peptic ulcers^{ref1, ref2}.
• Naprosyn test (naproxen 375 mg p.o. every 12 hours for 3 days) was used to differentiate neoplastic from infectious causes of FUO^ref
Therapy : antipyretic drugs : COX-2 inhibitors and mPGES-1 inhibitors
Web resources : Institute for Inflammation Research
• (post-flogistic) repair
• oxygen paradox / ischemia-reperfusion injury (IRI) : adverse effects of the restoration of blood flow following an ischemic episode, including cellular swelling and necrosis, edema, hemorrhage, the no-reflow phenomenon, and tissue damage by free oxygen radicals

Pathogenesis : xanthine dehydrogenase (XDH) =reversible sulfhydryl oxidation or irreversible proteolytic modification by calpain=> xanthine oxidase (XO), which catalyzes
• hypoxanthine + O₂ => uric acid + O₂^-
• O₂^- + NO^. => ONOO^- => OH
It occurs after reperfusion in :
• acute myocardial infarction (AMI) : the progression of injury, as reflected by annexin-V–OG binding, begins minutes after reperfusion and reaches a maximum in < 30 minutes, suggesting that apoptosis occurs primarily during reperfusion rather than during ischemia.
• stroke and transient focal cerebral ischemia (FCI)
• abdominal decompression for treatment of abdominal compartment syndrome (ACS)^ref
• pulmonary infarction
• renal infarction
• tissue transplantation
• Raynaud's phenomenon
• intermittent perfusion of the placenta, secondary to reduced trophoblast invasion, causes increased secretion of TNF-a, and that this contributes to the activation of maternal endothelial cells that characterizes preeclampsia^ref
Preadministration of N-acetylcysteine (NAC) has been found to attenuate the cerebral IRI in a rat model of experimental stroke by reducing expression of proinflammatory cytokines such as TNF-a, IL-1b and iNOS, activated macrophage/microglia (ED1) and apoptotic cell death^ref. TNF appears to mediate both the early and late phases of liver IRI, but it also is an essential mediator of hepatoprotective effects brought about by ischemic preconditioning^ref. IL-12 and IL-18 cause hepatic IRI in mice by suppressing anti-inflammatory cytokine expression and facilitating neutrophil-dependent^ref. Proteasomes were found to be targets of IRI of the brain and heart. Proteasome activity increased in liver models of IRI. CCL3 / MIP-1a^ref is functionally significant in the development of lung IRI (LIRI) inducing PMN leukocyte accumulation into the interstitium => neutrophil-dependent injury. B cell-deficient (mu MT) mice are protected from renal IRI : to identify the contribution of cellular vs soluble mechanism of action, serum transfer into mu MT mice partially restored ischemic phenotype, but B cell transfers did not^ref. Recent studies indicate an important role for clonally specific natural IgM antibody from the B1 lymphocyte repertoire (and probably autoantibodies present in sera of patients with systemic autoimmune disease) that activate the classical pathway of complement^ref. Recent data have demonstrated a role for CD4⁺ cells in the pathogenesis of renal IRI. Hypoxia-mediated induction/activation of the transcription factor EGR-1 has a pivotal role in lung IRI : induction of tissue factor (TF) gene expression leads to fibrin accumulation^ref. The extent of myocardial tissue damage resulting from IRI is directly related to the extent of the inflammatory response attributed, in part, to leukocyte recruitment. The inhibitory effects of corticosteroids on endothelial-leukocyte adhesion have been shown to be mediated by GR^ref through a NO-dependent mechanism via non-transcriptional activation of eNOS / NOS3^ref : because NO also has vasodilatory^ref, anti-thrombotic^ref and anti-proliferative properties^ref, the beneficial effects of corticosteroids in cardiovascular disease may extend beyond their anti-inflammatory properties. But NO + O₂^- => ONOO^- which damages cell contractility, lipids, proteins, nucleic acids, sugars, MnSOD, aconitase and TIMP => uncontrolled activation of MMPs (despite being extracellular, MMP2 can degrade TnI and TnT, but not TnC). On reperfusion or reoxygenation it is well-documented that there is an oxygen-dependent increase in total cell calcium^{ref1, ref2, ref3} which is accompanied by an increase in total mitochondrial calcium. A number of studies have shown that reoxygention is also associated with impairment of mitochondrial function^{ref1, ref2} and ultimately cell lysis in intact hearts^ref.
Prevention : pretreatment with ...
• xanthine dehydrogenase (XDH) inhibitors
• SOD
• iron chelators
• proteasome inhibition prevented IRI of the brain, heart and kidney. A major mechanism by which proteasome inhibitors may confer tissue protection is inactivation of NFkB resulting in a block of expression of cytokines and cell adhesion molecules during the reperfusion phase^ref.
• PPAR-g agonists have an anti-inflammatory effect by preventing the activation of transcription factors such as NFkB^ref
• beneficial effects of H₂ antagonists in a rat model of renal IRI are partly mediated by decreased IL-6 and VEGF mRNA expression and significant early increase in renal VEGF abundance^ref
• cardiac protection provided by treatment with a selective Rho-kinase (Rock) inhibitor is likely via anti-apoptotic effect and attenuation of ischemia/reperfusion-induced inflammatory responses^ref
• high-dose corticosteroid therapy protects the myocardium from ischemic injury^{ref1, ref2} : however, the subsequent development of cardiac rupture, which has been attributed to the genomic inhibitory effects of GR on wound healing and cardiomyocyte remodeling^ref, has limited its use of corticosteroids in AMI^ref
• NADPH oxidase-derived O₂^- plays an important role in the pathophysiology of reduced size liver combined with ischemia and reperfusion (RSL+I/R)-induced liver injury via its ability to enhance expression of TNF-a. Therapies directed toward scavenging of O₂^-, inhibiting NADPH oxidase, and/or immuno-neutralizing TNF-a may prove useful in limiting the liver injury induced by surgical procedures that require resection and I/R such as split liver or living donor liver transplantation^ref
• MMPs inhibitors (doxycycline^{ref1, ref2, ref3, ref4, ref5}, minocycline^ref)
• quinolones ?
• K_ATP channel activators preserve capability for rapid restoration of cationic/energetic status during reperfusion^{ref1, ref2, ref3, ref4, ref5}
• endothelin-converting enzyme inhibitor (FR901533) in hepatic IRI^ref
• remnants removal : as inflammation subsides, the concentration of cytokines and chemokines diminishes, resulting in a relative deficiency of survival factors for the recruited cell populations still present in the area. Increased competition for a diminishing supply of survival factors leads to a failure to inhibit default pathway of apoptosis and, consequently, increased cell death. Rapid clearance of these apoptotic cells is essential to prevent leakage of their intracellular contents and generation of a new inflammatory focus. Professional phagocytic cells such as macrophages  have a cytokine-independent survival advantage conferred by binding and/or uptake of apoptotic cells, which leads to activation of Akt (=> inhibited default apoptotic pathway) and inhibition of ERK1 and ERK2 (=> inhibited proliferation, on the contrary of necrotic cells and danger signals).
• recovery
• relative recovery : healing or connectival reintegration (organization of the exudate or of the granulation tissue)
• wound healing : a process of cure; the restoration of integrity to injured tissue.
• healing by first intention / primary adhesion : healing in which union or restoration of continuity occurs directly without the intervention of granulations, leaving no functional menomation. It occurs only when there isn't an excessive bacterial contaminations, if tissues are vital and if are not present foreign bodies or hematomas (they facilitate bacterial growth and represent a mechanical barrier between repairing tissues)
• healing by second intention (per secundam intentionem ) / healing by granulation / secondary adhesion : union by spontaneous closure of a wound with granulations which form from the base and both sides toward the surface of the wound, with loss of substance, slower than healing by first intention.
• healing by third intention/ delayed closure : wound is deliberately left open to allow maintenance of a drainage , and then surgically closed
• healing under crust : crust allows protection from exogenous germs, is a source of nutrition for tissues and is the support for the new connective tissue. Healing under crust is dangerous if infection occurs
• healing under wet clot :
• granulation :
• epithelization / epithelialization : healing by the growth of epithelium over a denuded surface, including neoangiogenesis
• desmoplasia / fibroplasia : the formation and development of fibrous tissue, as occurs normally in the healing of wounds and abnormally in some tissues
• resolution : the subsidence of a pathologic state, as the subsidence of an inflammation, or the softening and disappearance of a swelling
• vasal regression
• collagen remodeling : reorganization or renovation of an old structure, contraction of collagen fibers makes wound borders nearer
Factors affecting cicatrization :
• nutrition (hypoproteinemia, vitamin A, C, B₂, and B₆deficiencies)
• oxygen (diabetes mellitus, obesity, corticosteroids, radiation therapy, inspection)
• temperature : despite the habit of having cold operating theatres and cooled patients (cold patients would undergo vasoconstriction, and anesthesia with cold gases would impair mucociliary elevator allowing infection), this impairs the work of the surgeons
• modulation : the normal capacity of cell adaptability to its environment
• metaplasia : the change in the type of adult cells in a tissue to another form of adult cells that are not normal for that tissue.
• cytometaplasia : alteration in the form or function of a cell
• epithelial metaplasia
• goblet metaplasia of
• simple cylindric bronchial epithelial cells in chronic bronchitis
• pseudolayered cystic epithelial cells in chronic cystitis
• Clara's cells in small airways disease
• squamous metaplasia : the transformation of pseudostratified ciliated epithelium into stratified squamous epithelium, as occurs in certain pathologic conditions or may be produced experimentally.
• simple cylindric esophageal epithelial cells in chronic esophagitis
• simple cylindric bronchial epithelial cells in chronic bronchitis
• simple cylindric endometrial cells in chronic cervicitis
• mesenchymal metaplasia
• bony metaplasia of ...
• sesamoid cartilages in trachea
• costal cartilages in elderlies
• oncocytic (oxyphil) metaplasia of ...
• thyrocytes in Hashimoto's thyroiditis^ref
• adrenal cortex secondary to metyrapone therapy
• denture hyperplasia
• melanocytic nevi
• papillary cystic type of acinic cell carcinoma of parotid
• absolute recovery : resolution / parenchymal regeneration/ restitutio ad integrum : an active process of full restoration
• basal cell hyperplasia (BCH)
Recovery in specific organs :
• in pneumonitistype II pneumocyte hyperplasia and cuboid metaplasias replace type I pneumocytes during reparative processes, so impairing diffusion of gases (alveolar bronchiolization or bronchiolarization). MMP-9 / gelatinase B is required for alveolar bronchiolization, perhaps by facilitating migration of Clara cells and other bronchiolar cells into the regions of alveolar injury
• in encephalitis, hypoxic or hypoglycemic episodes in the CNS, repair to the destruction of nearby neurons during a depends on :
• microglia
• astrocytes => gliosis / astrocytosis
Pathogenesis => apoplectic or post-hemorrhagic pseudocysts
•  adaptive immune response
• primary adaptive immune response
• secondary adaptive immune response
• immunopathological processes
• hypersensitivities / hypersensitivity reactions (HSR)(i.e. excessive or inappropriate secondary immune response). Coombs-Gell classification :
• Ab-mediated or immediated hypersensitivities
• type I hypersensitivity / allergy :

Aetiology : the incidence of type I hypersensitivities has rocketed in recent years in Western countries, and the explanation for this has been the subject of much debate. Children are born with a T_h2-biased immune system, but this bias normally diminishes during the first 2 years of life in non-allergic individuals.
• the hygiene hypothesis argues that early childhood infections provide a T_h1 stimulus for the T_h2-skewed immune system of humans. The theory is that in Western countries, the reduction of childhood infections means that the immune system lacks this T_h1 stimulus and continues to maintain a T_h2 bias, which results in an increased risk of developing type I hypersensitivities. The very low incidence of type I hypersensitivities in developing countries where helminth infection - which also result in a T_h2-biased immune response - is endemic is explained by the fact that helminth infection protect against the development of type I hypersensitivities by the production of regulatory cytokines, such as IL-10. Epidemiological studies, however, indicate that Th2 cell-stimulating helminth parasites may also counteract allergies, possibly by generating regulatory T cells which suppress both Th1 and Th2 arms of immunity and anyway the route of exposure is actually more important than the T_h polarization :
• respiratory influenzavirus A infection and IFN-g produced during the acute T_h1 response can positively regulate T_h2-dependent allergic pulmonary disease after viral clearance in animals 6 to 8 weeks old, at least in part, by altering pulmonary DC function^ref. If you would do the same with, say, a gastrointestinal virus, like HAV, you would probably see a different response : furthermore influenza virus infection may have different effects from RSV or rhinoviruses, much more common in children
• the T_h2 cell-inducing gastrointestinal nematode Heligmosomoides polygyrus influences experimentally induced airway allergy to ovalbumin and the house dust mite allergen Der p 1. Inflammatory cell infiltrates in the lung were suppressed in infected mice compared with uninfected controls. Suppression was reversed in mice treated with antibodies to CD25. Most notably, suppression was transferable with mesenteric lymph node cells (MLNC) from infected animals to uninfected sensitized mice, demonstrating that the effector phase was targeted. MLNC from infected animals contained elevated numbers of CD4⁺25⁺Foxp3⁺ T cells, higher TGF-b expression, and produced strong IL-10 responses to parasite antigen. However, MLNC from IL-10-deficient animals transferred suppression to sensitized hosts, indicating that IL-10 is not the primary modulator of the allergic response. Suppression was associated with CD4⁺ T cells from MLNC, with the CD4⁺25⁺ marker defining the most active population. These data support the contention that helminth infections elicit a regulatory T cell population able to down-regulate allergen induced lung pathology in vivo^ref

• lack of HAV infection in individuals with longer 157insMTTTVP isoform of T-cell immunoglobulin domain, mucin domain 1 (TIM-1) / HAV cellular receptor 1 (HAV-cr1) / kidney injury molecule-1 (KIM-1) (which helps the virus enter the cell more efficiently and is also expressed by CD4⁺ T cells during T_h2 differentiation; present in 66% of white and blacks and 50% of Asians) renders them more likely to develop asthma and eczema. Exposure to HAV is associated with poor hygiene, large family size and attendance at day-care centres, all factors that are also inversely associated with atopy. Antibodies that mimic the immune-boosting effects of HAV without causing the disease itself or vaccination - which promotes antibody formation - may also help to prevent or even treat allergic diseases^ref.
• perturbations in the gastrointestinal (GI) microbiota composition that occur as a result of antibacterials and diet in "westernized" countries are strongly associated with allergies^ref. Antibiotics could upset the natural balance of the microbial community in the gut, causing the population of one of the gut's natural inhabitants, the yeast Candida albicans, to explode. Both PGE₂ and TxB₂ significantly enhanced serum-induced germination by C. albicans. Since these molecules also bind to albumin, this may also explain the hyphal transforming activity in serum that associates with albumin. Interestingly, short chain fatty acids (butyric acid), the product of lactic acid bacteria (LAB), inhibited germination. In addition, LAB culture supernatants as well as live LAB also inhibited C. albicans morphogenesis^ref. The yeast makes prostaglandin-like immune response modulators that can modulate immune responses and make the immune system overly sensitive. A broad range of pathogenic eukaryotic microbes (fungi^{ref1, ref2}, protozoa, and helminths) produce eicosanoids and other oxylipins by novel synthesis pathways. Why do these organisms produce oxylipins? Accumulating data suggest that phase change and differentiation in these organisms are controlled by oxylipins, including prostaglandins and lipoxygenase products. The precise role of pathogen-derived eicosanoids in pathogenesis remains to be determined, but the potential link between pathogen eicosanoids and the development of T_h2 responses in the host is intriguing. Thus, eicosanoids and oxylipins (host or microbe) may be mediators of a direct host-pathogen "cross-talk" that promotes chronic infection and hypersensitivity disease, common features of infection by eukaryotic pathogens^ref. In earlier experiments, the team had shown that these animals' lungs, unlike those of mice that had received neither the antibiotics nor the fungi, produce a moderate allergic reaction to mold. A new study shows that the treated mice also develop allergies to another substance, egg white protein. C57BL/6 mice are treated for 5 days with cefoperazone in the drinking water, followed by a single oral gavage of C. albicans. This results in alterations of GI bacterial populations and increased yeast numbers in the GI microbiota for at least 2 to 3 weeks and can drive the development of a CD4⁺ T-cell-mediated allergic airway response to subsequent mold spore (Aspergillus fumigatus) exposure in immunocompetent mice without previous systemic antigen priming. The allergic response in the lungs is characterized by increased levels of eosinophils, mast cells, IL-5, IL-13, IFN-g, IgE, and mucus-secreting cells. In the absence of antibiotics, mice exposed to Aspergillus spores do not develop an allergic response in the airways. This study provides the first experimental evidence to support a role for antibiotics and fungal microbiota in promoting the development of allergic airway disease. In addition, these studies also highlight the concept that events in distal mucosal sites such as the GI tract can play an important role in regulating immune responses in the lungs^{ref1, ref2}. To investigate the role of host genetics, BALB/c mice were tested. As with C57BL/6 mice, microbiota disruption promoted the development of an allergic response in the lungs of BALB/c mice upon subsequent challenge with mold spores. In addition, this allergic response required IL-13 (the response was absent in IL-13^–/– mice). To investigate the role of antigen, we subjected mice with disrupted microbiota to intranasal challenge with ovalbumin (OVA). In the absence of systemic priming, only mice with altered microbiota developed airway allergic responses to OVA. The studies presented here demonstrate that the effects of microbiota disruption are largely independent of host genetics and the nature of the antigen and that IL-13 is required for the airway allergic response that follows microbiota disruption^ref.
• susceptibility loci : MHC class II, FceRII, IL-4, calcium-binding atopy-related autoantigen 1, PHD finger protein 11 (PHF11), IL-13+2044G=>A is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q)^ref
• maternal total IgE levels correlate with cord blood and infant IgE levels and the development of infant eczema (specificity = 83%; sensitivity = 34%)
• traffic-related air pollution is statistically connected with enhanced allergies in the population : a combination of NOx and ozone can nitrate tyrosine, an amino acid present in all proteins, which may then go on to trigger an allergic response. Roadside dust and airborne particulate matter (PM₁₀ and PM_2.5), including pollen, contain up to 5% of proteins. Paved road dust present on the surface of streets in Southern California consists of a complex mixture of soil dust, deposited motor vehicle exhaust particles, tire dust, brake lining wear dust, plant fragments, and other biological materials. The research presented here shows that allergens from at least 20 different source materials are found in the paved road dust. These include pollens and pollen fragments, animal dander, and molds. When paved road dust is resuspended into the atmosphere by passing vehicle traffic, allergen concentrations in the air are increased above the levels that would prevail without the vehicle traffic. Using immunological assays that measure the proteins extracted from environmental samples that bind to IgE antibodies present in the blood serum of allergenic patients, it is possible to measure the allergen concentrations present in paved road dust and in airborne particle samples. Total protein contributions to monthly average airborne TSP and PM₁₀ concentrations are found to be in the range from 1 to 5.8 mg/m³, potentially accounting for a significant fraction of the airborne particulate organic material that has not been identified to date by GC/MS techniques. Results show that up to 5-12% of the allergenicity of atmospheric total suspended particulate matter samples at Long Beach and Rubidoux, CA, is attributable to paved road dust emissions. In an industrial area of urban central Los Angeles where there is less proximity to vegetation and domestic activities, the paved road dust contribution to airborne allergen concentrations is lower, accounting for approximately 0.5% of the total allergenic activity of the atmospheric particle samples. In conclusion, paved road dust when entrained into the atmosphere by passing traffic is a source of allergen exposure for the general population and could be more important in areas with more abundant vegetation or with closer proximity of populations to major highways than is the case for the Southern California air monitoring sites studied here^ref. Research from as far back as the 1930s points to nitro derivatives, particularly those of proteins, as strong immune stimulators. High concentrations of NOx and ozone under “summer smog” conditions—heavily polluted, hot, humid air—could nitrate the tyrosine residues in proteins. These modified proteins might then induce inflammation and allergy after inhalation. A reference protein and a birch pollen extract containing the prominent allergen Bet v 1 (which has 7 Tyr residues) were exposed to parts-per-billion (ppb) concentrations of NO₂ and ozone mixtures : both proteins were substantially nitrated after 30 hours at 100 ppb, a level found under low-smog conditions, and more affected after 30 hours at 200 ppb, which is reached during severe summer smog alerts. Tyrosine was also nitrated when the proteins were exposed to ambient air collected from Munich’s heavily trafficked intersections. Enzyme immunoassays have been used to determine equivalent degrees of nitration (EDN) for protein samples exposed to urban outdoor air and synthetic gas mixtures. The observed rates of nitration were governed by the abundance of nitrogen oxides and ozone, and concentration levels typical for summer smog conditions led to substantial nitration within a few hours to days (EDN up to 20%). Moreover, nitrated proteins were detected in urban road dust, window dust, and fine air particulate matter (EDN up to 0.1%), but for allergenic proteins from birch pollen left at a busy Munich road junction for a few days, that figure rises to 10%. And for allergenic proteins exposed to smog in the laboratory, nitration rose to 20%^ref. Previous research has shown that nitrated proteins bind more strongly to IgE antibodies. Preliminary results suggest that the nitrated proteins are significantly more active at boosting allergies by giving normal and nitrated proteins to mice. Proteins that are easiest to nitrate might trigger the strongest allergic reaction. It's not clear how nitrate groups increase the allergic response, but previous studies have suggested that the body uses tyrosine nitration as a marker to attract antibodies to inflamed tissue. The finding could help to develop drugs that stop nitrated proteins disrupting our immune systems. Scientists are still unsure what makes a protein allergenic, and nitration is unlikely to be the only factor. Others have suggested that traffic pollution could make urban trees emit more allergens.
During the primary immune response in predisposed individuals :
• epithelial cells produce TSLP : TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor-deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T_h2 cytokines and increased IgE. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating BMDCs to upregulate costimulatory molecules and produce the T_h2 cell-attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation^ref
• DC activation
• DCs capture antigens in mucosal surfaces and travel to regional lymph nodes
• polarization of T_h0 cells toward T_h2 cytokine secretion profile by directly producing IL-4 or by inducing IL-4 production by NK cells
• T_h2 cells induce class swith recombination (CSR) in plasma cells up to IgEs / reagins against the allergen(s) (usually it is an enzyme with 10 < M_r < 20 kDa, acting as an immunogen or as an hapten that use host molecules as immunogenic carriers)
• IgEs bind to FceRI on mast cells and basophils (up to 5^.10⁵ IgE / _cell : sensitization).



At the second challenge ...

• allergen binding to cell-bound IgEs
• anaphylotoxins
• C3a
• C3a-desArg
• C5a
... induce mast cells and basophils to undergo exocytosis of granules (degranulation : early reaction (within seconds); amplification mechanism => requires mg of Ag) containing :
• histamine : it causes its biological effects in 1-2' (mantaining activity up to 10') acting on ...
• H₁ :
• contraction of smooth muscle cells of bronchi => bronchospasmus, small bowel (abdominal colics) and uterus (Schultz-Dale reaction : an in vitro test for local anaphylactic sensitization in the guinea pig: a small amount of the antigen added to a tissue bath in which is immersed the excised uterine horn (smooth muscle) of an anaphylactically sensitized guinea pig causes contraction of the sensitized uterine muscle. Schultz employed intestinal muscle; Dale used uterine muscle from virgin guinea pigs)
• dilatation of small veins =>
• oedema
• erythema (allergic angioflogosis : increased blood flow and blood vessels permeability)
• hypotension
• axonic reflex (induction of substance P exocytosis by antidromic conduction in sensitive fibers)
• negative inotropic and dromotropic effect on ventricular and left atrial cardiomyocytes at doses < 10^-8 M
• H₂ :
• hypersecretion of H⁺Cl^- by parietal cells of stomach
• positive inotropic and chronotropic effects on ventricular and right atrial cardiomyocytes at doses > 10^-8 M
• H₃ :
• inhibition of neural norepinephrine release from orthosympathetic terminals of myocardium
• heparin activates antithrombin III acting as an anticoagulant
• tryptases
Further they produce and release :
• LTB₄ : chemotaxin for granulocytes and macrophages
• SRS-A : smooth muscle cells contraction
• PGD₂
• TNF-a
• PAF
These cause infiltrations of activated T_h2 lymphocytes, activated eosinophils, basophils and some neutrophils (late phase reaction) 5 to 12 hours after exposure to antigen, after the wheal and flare reactions of immediate hypersensitivity have diminished; it is characterized by pruritis and minor cellular infiltration. Prostaglandins are not formed. Inflammation subsides after reaching a maximum around 24 hours after exposure.
Activated mast cells, basophils and eosinophils up regulate CD40L / CD154 expression and produce IL-4, allowing a positive feeedback for a T_h2-polarized immune response.
PGD₂ and PGE₂ are produced during allergic reactions. Although PGD₂ is an important mediator of allergic responses, aspirin-like drugs that inhibit prostaglandin synthesis are generally ineffective in allergic disorders, suggesting that another prostaglandin-mediated pathway prevents the development of allergic reactions : such a pathway may be mediated by PGE₂ acting at the PGE₂ receptor EP₃. Mice lacking EP₃ developed allergic inflammation that was much more pronounced than that in wild-type mice or mice deficient in other EP subtypes. Conversely, an EP₃-selective agonist suppressed the inflammation. This suppression was effective when the agonist was administered 3 h after antigen challenge and was associated with inhibition of allergy-related gene expression. Thus, the PGE₂-EP₃ pathway is an important negative modulator of allergic reactions^ref.
The reaction may be :
• local (atopy), if the allergen remains localized at entry door, which may be :
• epidermis => dermis => wheal and erythema or wheal and flare reaction : the characteristic local cutaneous reaction consisting of an elevated, blanched wheal surrounded by a spreading “flare” of erythema that occurs within a few minutes at the site of a minor nonpenetrating skin injury and also in response to administration of allergen to an atopic individual; it is caused by release of histamine from mast cells : atopic dermatitis, angioedema and/or acute urticaria, rarely persisting for > 48 hrs
• respiratory tract =>
• increased nasal secretions (allergic rhinitis)
• bronchostenosis (bronchial asthma) => dyspnea
• conjunctiva => allergic conjunctivitis
• gastro-intestinal tract =>
• irritable bowel syndrome (IBS) : hyperperistalsis and increased secretions => diarrhoea, abdominal pain
• nausea and vomiting
• systemic (anaphylaxis), if the allergen enters the bloodstream (directly by intravenous injection or indirectly, mainly by parenteral routes, rarely by oral route) : symptoms are those of more than a kind of atopy, plus systemic arterial hypotension => anaphylactic shock (AS) => syncope => death. The target organs of guinea pigs and humans are the bronchi of the lungs. In dogs the target organ is the liver, which may accumulate up to 60% of the animal's blood. The target organs of the rabbit are the heart and lungs. Anaphylactic shock is estimated to affect up to 15% of the US population. Previous research in mice, which have a similar immune system to humans, had hinted that extreme amounts of nitric oxide (NO) throughout the body might be responsible. By injecting nitric-oxide blockers into some of the mice before attempting to give them anaphylactic shock, the researchers were able to confirm that nitric oxide produced by eNOS was indeed the culprit^ref. Mice genetically engineered to lack eNOS were immune to potentially fatal allergens, whereas mice missing iNOS fell victim to them. eNOS was always presumed innocent. Doctors could potentially use nitric-oxide blockers to help treat the condition.Mice injected eNOS inhibitors before trying to induce a shock experienced just a brief drop in blood pressure followed by a quick recovery. Unfortunately, these types of drugs are very slow-acting against anaphylaxis as they need time to accumulate in the body, so would presumably not do much good as an emergency response. But a patient sensitive to penicillin, anaesthetics, or latex could be pre-loaded with these drugs before an operation
• food-dependent exercise-induced anaphylaxis (FDEIA) : initially described in 1979^ref, FDEIA is an important and underrecognized cause of seemingly unprovoked anaphylaxis. Ingestion of particular food antigens (typically wheat), followed by exercise, triggers anaphylaxis within hours in specific FDEIA. In the nonspecific form, however, plain physical exertion on a full stomach suffices^ref. A putative mechanism is exercise-related mesenteric ischemia, leading to increased absorption of food antigens^ref. Acetylsalicylic acid is known to aggravate symptoms^ref. Pruritus, hives, or angioedema is present in more than 90% of cases and is often accompanied by upper or lower airway symptoms^{ref1, ref2}
Type I hypersensitivity can be transferred via IgE contained in transfused serum (Prausnitz-Küstner (P-K) reaction) or transplanted organs (expecially liver).
• Hektoen phenomenon : when antigens are introduced into the animal body in allergic states, there may exist an increased range of new antibody production which may include production of antibodies concerned in previous infections and immunizations.
• parallergy : a condition in which an allergic state, produced by specific sensitization, predisposes the body to react to other allergens with clinical manifestations that differ from the original reaction
• pseudo-allergic reactions (if at systemic level : anaphylactoid reaction) : same late pathogenesis and hence same symptoms of type I hypersensitivity can be caused by same mediators released via IgE-independent mechanisms.
• complement-mediated hypersensitivities have no amplification mechanism => require mg of Ag
• type II hypersensitivity : molecular mimicry cause Ab to cross-react with self Ags on host cells, resulting in cell killing by :
• immune or opsonic phagocytosis
• induction of the classical activation pathway for complement cascade followed by the lytic pathway.
• ADCC
• type III hypersensitivity / immune complex disease

Deposition of IgG- or IgM-containing immunocomplexes on :
• basal laminae of renal tubules (=> glomerulonephritis)
• joints
• choroid plexuses
• small blood vessels
... causes :
• complement activation => generation of
• C3b, which may
• attach to innocent bystander cells which may lyse due to formation of the MAC
• cause platelet aggregation =>
• release vasoactive amines contributing to edema
• microthrombi => ischemia
• anaphylotoxins => mast cell activation => edema
• C5a => attracts neutrophils which try to phagocyte iccosomes but they undergo autolysis releasing proinflammatory enzymes that local damage
• ischemia
Varieties :
• with Ab excess (Arthus phenomenon or reaction) : the development of an inflammatory lesion, with induration, erythema, edema, hemorrhage, and necrosis, a few hours after intradermal / subcutaneous injection of antigen into a previously sensitized animal producing precipitating antibody (repeated Ag injections for a long period induce high Ab titre). The lesion results from the precipitation of antigen-antibody complexes, which causes complement activation and the release of complement fragments that are chemotactic for neutrophils; large numbers of neutrophils infiltrate the site and cause tissue destruction by release of lysosomal enzymes. Symptomatology peaks within 3÷8 hrs. Sometimes it is used as an experimental method in immunological investigations :
• passive cutaneous Arthus reaction : a variation of the Arthus reaction in which a nonimmune host is inoculated with large quantities of precipitating antibody intravenously, followed by local cutaneous inoculation of antigen.
• reverse passive Arthus reaction : the reaction produced when precipitating antibody is inoculated into a skin site in an experimental animal followed in 30 minutes to 2 hours by inoculation of the homologous antigen, either intravenously or intracutaneously at the same site. Thus the usual anatomical locations of precipitating antibody and antigen in an Arthus reaction are reversed.
• with Ag excess after massive inhalation or parenteral injection of Ag. 8 to 12 days following treatment with the heterologous Ag(s), the individual experiences generalized swelling of the lymph nodes, with itching, urticaria or erythmatous eruptions : following the episode, the complexes are removed in about 2 days and the reaction subsides.
Thermal phenomena :
• cryoglobulins are Igs that undergo precipitation in the cold (standard procedure : > 48 hr at + 4°C) due to high content of hydrophobic amino acids, and can be resolubilized by heating at 37°C.

Epidemiology : prevelence = 2-3% after age 60 years
Brouet immunochemical classification :
• type I cryoglobulins (5-15%) : monoclonal IgM >> IgG > IgA > light chain from secreting B cell lymphomas (malignant paraproteinemia : immunocytoma/Waldenström macroglobulinemia, multiple myeloma). Monoclonal cryoglobulinemia is frequently asymptomatic. Symptoms are rare. When present, clinical manifestations derive from hemorheologic disturbances and include acrocyanosis, Raynaud phenomena and gangrene.
• mixed cryoglobulins : rheumatoid factors (RF) occurring in ...
• essential mixed cryoglobulinemia (EMC)
• systemic lupus erythematosus (SLE) (lupus glomerulonephritis)
• rheumatoid arthritis (RA)
• infectious diseases
• type II cryoglobulins (50-60%) : monoclonal rheumatoid factors (RF) (IgMk >> IgG) which form cryoprecipitating circulating immune complexes with polyclonal intact IgG and the F(ab')₂ fragment, as well as with the Fc fragment of autologous IgG. Symptoms only in 10%
• type II/III / oligoclonal or microheterogeneous type : oligoclonal IgM which form cryoprecipitating circulating immune complexes with polyclonal IgG. Characterized using more sensitive methods (immunoblotting, 2D-PAGE), defined by > 2 heterogeneous bands of H chains (oligoclonal IgMs or a mixture of polyclonal and monoclonal IgMs). The oligoclonal type seems to be an intermediate stage in the course of type III evolving to type II MC. In fact, during chronic active HCV infection MC may change its immunochemical type: type II MC is more stable over time than type III and oligoclonal^ref
• type III cryoglobulins (30-40%) : polyclonal rheumatoid factors (RF) which form cryoprecipitating circulating immune complexes with polyclonal IgG. Symptoms only in 10-15%
Symptoms & signs :
• palpable purpura in lower limbs (90-100%)
• Raynaud's phenomenon, subungueal hemorrhages, pustular hemorrhagic folliculitis, erythema multiforme, livedo reticularis, urticaria and ulcers (10-35%)
• intermittent arthralgias (50-95%)
• renal involvement (10-55%)
• peripheral sensitive or sensitivie-motor neuropathy
• hepatomegaly (70%)
• splenomegaly (50%)
• lymphadenomegaly (5-15%)
• Sjogren syndrome (3-40%)
• pulmonary involvement is rare
Laboratory examinations :
• blood samples are stored at 37°C until complete clotting occurs and are then centrifuged. The serum is kept at 4°C for 3-4 days. If a cryoprecipitate is visible, the sample is centrifuged at 4°C for 15 minutes to measure a cryocrit. Cryo-globulins are purified by washing at 4°C and characterized using immunofixation electrophoresis
• low C4 (90%)
• transaminitis (30%)
• proteinuria and microhematuria (50%)
• pyroglobulins (pyroglobulinemia)^ref : first described in 1954^ref, heating of the serum at 56°C for 30 min induced an irreversible gel (pyrogel)  formation that fails to redissolve on heating to 100°C; for IgM, observed with pentamers as well as monomers, but not with separated H or L chains. Amino acid analysis showed quantitative abnormalities of aspartic acid, glycine, cystine and leucine within the H chains. Solubility of the pyrogel in sodium dodecyl sulfate, the pyroglobulin's tendency to aggregate and the cystine deficit of H chains implicate conformational changes leading to hydrophobic bonding at 56degreesC in the formation of pyrogel^ref
• rubella virus^ref
• Sjogren syndrome (IgA)^ref
• paraproteinemia^ref
• ovarian lymphoma (IgMl)^ref
• systemic primary amyloidosis^ref
• k light-chain disease associated with cryoglobulinemia, pyroglobulinemia, and hyperviscosity syndrome^ref
• Waldenstrom's macroglobulinemia^{ref1, ref2}
• multiple myeloma^{ref1, ref2, ref3}
• MM and plasma cell leukemia with pyroglobulinemia and cryoglobulinemia^ref
• IgAl^{ref1, ref2} and k^ref
• IgGk^ref
• IgEk pyroglobulinemia^ref
• IgDl MM^ref and plasma cell leukemia associated with pyroglobulinemia and l pyroglobulinuria^{ref1, ref2}
• type IV or delayed-type hypersensitivity (DTH)
• during primary immune response B-1 B cells produce IgM
• complement activation by subunit or pentameric IgM generates C5a
• C5a binds C5aR on ...
• ... mast cells, causing release of the vasoactive serotonin and TNF-a
• ... platelets, causing release of the vasoactive amine serotonin
Both molecules induce expression of addressins on the luminal surface of local endothelium
• T cell recruitment into the tissues
• specific Ag/MHC complexes expressed on local APC drive CD4⁺ T_h1 polarization
• production of proinflammatory cytokines, such as IFN-g, to mediate classical late DTH. Granuloma appears gradually 10 hours after injection, with maximal intensity and size occurring between 24 and 72 hours (48 hours average) : this time is required to recruit CD4⁺ T_h1, CD8⁺ T_c1, and macrophages.
DTH responses are downregulated by T_h2 cells. Mice devoid of T cells and B cells demonstrated substantial contact hypersensitivity responses to 2,4-dinitrofluorobenzene and oxazolone. Those responses were adaptive in nature, as they persisted for at least 4 weeks and were elicited only by haptens to which mice were previously sensitized. No contact hypersensitivity was induced in mice lacking all lymphocytes, including natural killer cells. Contact hypersensitivity responses were acquired by such mice after adoptive transfer of natural killer cells from sensitized donors. Transferable hapten-specific memory resided in a Ly49C-I⁺ NK subpopulation localized specifically in donor livers^ref.
• Jones-Mote reaction / cutaneous basophil hypersensitivity : a weak type IV hypersensitivity reaction to protein antigens associated with basophil infiltration, occurring on challenge a few days after priming with a protein antigen in aqueous solution or in Freund's incomplete adjuvant
• autoimmune reactions => diseases

Presuntive evidences of autoimmune pathogenesis :
• major
• evidences of AMI and/or CMI against self antigens
• detection of infiltrated antibodies and/or lymphocytes in injured tissues
• demonstration that antibodies and/or lymphocytes can cause tissue damage
• transplacental transmission
• passive transfer on animals
• in vitro effects on cell functions
• minor
• compatible animal models
• ex juvantibus criterion : improvement of symptoms with immunosuppressive treatments
• associations with other autoimmune reactions
• no other evident aetiology
They affect 3-5% of the population : 75% are females as estradiol (E₂) affects immature B cells through E₂R up-regulating CD22, SHP1 / PTPN6, Bcl-2 and CD106 / VCAM-1 / INCAM-110 : this leads to rescue of autoreactive B cells that would have been deleted. Some autoimmune illnesses occur more frequently after menopause, others suddenly improve during pregnancy, with flare-ups occurring after delivery, while still others will get worse during pregnancy.
Aetiology :
• exogenous aetiology
• immune response against cross-reacting heterophilic Ags (molecular mimicry). E.g. :
• Forssman-Skoog Ag is Gb5 glycosphingolipid whose sugar group is as follows : a-D-GalNAc-(1->3)-b-D-GalNAc-(1->3)-a-D-Gal-(1->4)-b-D-Gal-(1->4)-D-Glc). It was first identified in sheep RBCs, and then in bacterial cell walls. It is absent in human, rabbit, rat, porcine and bovine tissues.
• Streptococcus pyogenes Ags and a human heart tissue antigen
• Escherichia coli O86 and human blood group Ag B.
• Streptococcus pneumoniae serotype XIV and human blood group Ag A.
• Proteus vulgaris OX-19 Ag and Ag(s) on Rickettsia conorii,Rickettsia prowazekii, Rickettsia typhi
• Proteus vulgaris OX-2 Ag and Ag(s) on Rickettsia conorii
• Proteus mirabilis OX-K Ag and Ag(s) on Orientia tsutsugamushi
An approximately 5-fold difference in the TcR affinity for the activating ligand results in a 50% reduction in the incidence of autoimmunity. A reduction in TcR-ligand affinity to approximately 20 times lower than normal does not induce autoimmunity despite the unexpected induction of CTLs and insulitis. Furthermore, in the absence of a key negative regulatory molecule, Cbl-b, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand. Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response^ref.
• aspecific polyclonal lymphocyte activation
• B lymphocytes
• HHV-4 / EBV
• mitogens
• T lymphocytes
• superantigens
• mitogens
• bacterial adjuvants
• endogenous aetiology : the concordance of autoimmune diseases among monozygous twins is virtually always < 50%, often in the 25-40% range. This incomplete penetrance may be due to :
• extrinsic aetiology
• distinct lymphocyte receptor repertoires in otherwise identical individuals
• initiation of disease is a quantal, stochastic event that depends on the behavior of only a single lymphocyte among the mature peripheral ones whose TcR affinity for a particular autoantigen approaches that required for strong signaling. Susceptibility alleles can affect the mean and range of net activation energy (signaling competence, the amount of costimulatory ligand available, the number and activity of inhibitory T cells, and/or the ambient levels of suppressive cytokine) closer on average to a level suitable for cellular activation. The exponential nature of cell division ensures that only a few cycles are needed to generate a large pool of effector cells, whose intracellular signaling competence seems to have increased sensitivity. This "rogue cell" model has substantial implications with respect to the possible use of prophylactic immunosuppressive strategies in gentically susceptible individuals.
• alterations in antigen presentation
• autoantigen dissequestration from an immune-privileged site
• autoantigen alteration during
• inflammation
• drug exposure
• cell death
• during necrosis, e.g.
• acute myocardial infarction (AMI)
• X-rays
• metal-catalyzed oxidative modifications
• changes induced by :
• infectious disease agents
• xenobiotic chemotherapeuticals
• during apoptosis : cleavages by caspases and granzyme B
The immune response may be cross-reactive with unaltered self proteins.
• epitope spreading : T cell reactivity is shifted from a narrow set of inducer determinant to
• other responder determinants (cryptic epitopes) on the same Ag (intramolecular spreading)
• other antigens (intermolecular spreading)
It may contribute to the variation of the autoantibody-response pattern observed in different individuals with a given autoimmune disease.
• altered functionality of APCs
• cytokine production
• costimulatory molecules
• increased activity of T_h lymphocytes
• T cell lymphomas
• cytokine production
• costimulatory molecules
• increased activity of B lymphocytes
• B cell lymphomas
• apoptosis deficiencies
• unusual TCR-binding properties can permit autoreactive T cells to escape deletion : rather than being centered on the peptide-MHC, the TCR trimer from a patient with multiple sclerosis that causes autoimmunity in transgenic mice contacted only the N-terminal peptide segment and made asymmetrical interactions with the MHC helices. The interaction was dominated by the hypervariable CDR3 loops, indicating that unconventional topologies are possible because of the unique CDR3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association^ref
• disequilibrium in cytokine production
• impaired immunoregulatory mechanisms
• proteolytic cleavage (shedding) of cell-surface TNF receptor p55 (TNFRp55) modulates TNF function, and in humans, impaired receptor shedding is linked to a group of autoinflammatory syndromes, but also increased resistance to infection with Listeria monocytogenes in knock-in mice heterozygous or homozygous for a non-sheddable TNFRp55^ref
• anti-idiotype network
• immune response against a peptide that is antisense or complementary to the autoantigen, which then induces anti-idiotypic antibodies (autoantibodies) that cross-react with the autoantigen. (e.g. proteinase-3 (PR-3))
• T_Reg lymphocytes : the Autoimmune regulator (Aire) gene, which is defective in the disorder autoimmune polyglandular syndrome type 1, has been shown to promote the thymic expression of self-antigens. Autoimmune eye disease in aire-deficient mice develops as a result of loss of thymic expression of a single eye antigen, interphotoreceptor retinoid-binding protein (IRBP). In addition, lack of IRBP expression solely in the thymus, even in the presence of aire expression, is sufficient to trigger spontaneous eye-specific autoimmunity. These results suggest that failure of thymic expression of selective single self-antigens can be sufficient to cause organ-specific autoimmune disease, even in otherwise self-tolerant individuals^ref.
• B lymphocytes that had undergone BcR revision have been isolated from ectopic germinal centers in inflamed tissues in patients with rheumatoid arthritis (RA)
• common mutations : disruption of RUNX1 binding sites in different genes have been associated with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and psoriasis
These explanations cannot account for the diversity of pathogens associated with specific autoimmunity, nor can they explain the association of one pathogen with many autoimmune diseases. General characteristics of infections, rather than specific Ag, could partake in disease induction : nonspecific, nontissue damaging (hence irrespective of additional endogenous Ag release), inflammatory events byproduct of an infection (e.g. adjuvants such as CT, anti-CD40 mAb) can induce APC maturation, causing cross-presentation of endogenous Ag to shift from cross-tolerization to cross-priming, and  hence to tissue-specific destructive autoimmune reaction.
According to some theories an autoimmune disease is the outcome of failure to control an autoimmune reaction whose original purpose was beneficial : the beneficial and the destructive response share the same antigenic specificity. E.g. an autoimmune response targeting CNS can prevent release of compounds toxic even for noninjured neurons.
Let us think about latent infections, cancer or other chronic diseases. Can it be possible that some damages may take place in form of Autoimmunities to starve the "disease causing agents" from their required nutrients (including oxygen) to resist or restrict their growth & spread or to encourage anorexia to withhold intestinal absorptions for this purpose? Can pancreatic islet cell damages in diabetes mellitus, be meant to save us from hyperinsulinemia's persistant effects? Other autoimmune diseases can also be thought for some natural body's mechanism hidden behind these "to save us as a whole at the cost of some".
Genes with a distinct expression pattern in autoimmunity (conserved among the different autoimmune diseases) are not necessarily immune response genes, but are genes that encode proteins involved in apoptosis, cell cycle progression, cell differentiation, and cell migration.
Autoantibodies can be pathogenetic or represent just an epiphenomenon or an activity marker ; they can be pathognomonic or be associated to a whole group of autoimmune diseases. Anyway they are directed against the most conserved regions of the most conserved molecules. A long CDR3 and a positively charged amino acids in CDR3 in the Ig heavy chain are 2 features that have been associated with self-reactive antibodies.
Autoantibodies are assayed on ...
• tissue sections or cultured cell lines : this doesn't allow Ag definition, but sensitivity is usually excellent (except for under-representation of Ro antigen in cellular extracts)
• cell extracts
• defined sets of autoantigens (with authentic 3D structure in order to prevent false negative results for conformation epitopes)
• ... isolated from natural sources like human tissues
• ... produced by recombinant DNA technology
Autoantigens can be classified as follows :
• autoantigens reachable by antibodies => CMI, type II and type III hypersensitivity reactions
• secreted autoantigens
• enzymes
• acetylcholinesterase (AChE)
• structural proteins
• gastric intrinsic factor (IF) (GIF)
• collagen type II (CII), a₁ chain
• collagen type IV, a₃ chain (non-collagenous NC1-domain)
• collagen type XVII, a₁ chain / BP180 / BPAG2
• human cartilage glycoprotein 39 (HCgp39) / YKL-40
• chondroitin sulfate carbohydrate moiety in decorin (a.k.a. BJ antigen)
• hormones
• insulin
• T₃, T₄ or both (hapten)
• antibodies (=> rheumatoid factor (RF)) : IgM (the most commonly detected isotype, as serologic tests measure only IgM), IgG, IgA, and/or IgE (rarely detected) containing a region outside the CDRs which can bind the C_H2 and C_H3 domains (Gm antigenic determinant) in the Fc region of human and rabbit IgGs (serum RF binds Fcg₁, Fcg₂ and Fcg₄ > Fcg₃; synovial fluid RF binds Fcg₃ > Fcg₁, Fcg₂ and Fcg₄). They are detected by :
• agglutinations
• passive hemagglutination (RF fixed on RBCs with CrCl₃) : Waaler-Rose reaction
• immunonephelometry
• ELISA
They are found in the following situations :
• autoimmune diseases
• essential mixed cryoglobulinemia (> 90%)
• classical or definite rheumatoid arthritis (RA) (50-85% of RA patients; 30% of all RF⁺)
• Sjögren's syndrome (SS) (50-85%)
• systemic lupus erythematosus (SLE) (25-50%)
• juvenile chronic arthritis (JCA)(10-25%)
• ankylosing spondylitis (AS) (5-10%)
• psoriatic arthritis (PsA) (5-10%)
• idiopathic pulmonary fibrosis (IPF) (10-25%)
• sarcoidosis
• infections
• HBV
• post-infectious mononucleosis (IF) (< 5%, self-limiting)
• leprosy (25-50%)
• tuberculosis (TB) (10-25%)
• subacute bacterial endocarditis (25-50%)
• rheumatic fever (RF) (5-10%)
• Treponema pallidum subsp. pallidum
• Plasmodium spp.
• Leishmania spp.
• Schistosoma spp.
• hepatopathies(25-50%)
• gout
• osteoarthritis (5-10%)
• healthy subjects (5%)
• preformed IC containing vitronectin (VN) and fibronectin (FN) present in sera of patients with CSS and WG bind to endothelial cells (anti-endothelial cell antibodies (AECA))
• autoantigens exposed on external layer of plasma membrane
• CD41 / a_IIb integrin / p136^gpIIb / CD31 / PECAM-1 / b₁ integrin / p130^gpIIa (95-100%)
• CD42b / glycocalicin / gpIb_a42c / gpIb_b / CD2a / p17^gpIX
• CD49 / a₂ integrin / p153^gpIa / CD31 / PECAM-1 / b₁ integrin / p130^gpIIa
• CD49f / a₆ integrin
• CD104 / b₄ integrin
• H⁺ / K⁺ ATPaseb subunit
• myelin-associated glycoprotein (MAG)
• myelin basic protein (MBP) (homologous to HBV protein and Human adenovirus type 2 protein)
• myelin oligodendrocyte protein (MOG)
• myelin protein P₀ (MPZ)
• proteolipid protein 1 (PLP1)
• P-type Ca²⁺ channel
• BP230 / BPAG1
• claudin 11
• desmoglein 1
• desmoglein 3
• SSN / ABCA7
• CYP2D6 / LKM-1
• anti-endomysial antibodies (EMA)
• transglutaminase 3 / tissue transglutaminase (tTG)
• anti-phospholipid antibodies (IgG or IgM) are directed against ...
• immunogenic protein carriers :
• a dominant target epitope defined by residues 40-43 in domain I of apoH / b₂ glycoprotein I (a member of the SCR protein family with 5 SCRs : the 5^th SCR contain an extra 20-aa C-terminal loop ending in an extra terminal disulfide bond and a Lys-rich region that functions as the major anionic phospholipid binding site)
• prothrombin
• hapten phospholipids :
• cardiolipin (CL), associated with HLA-DR3
• phosphatidylinositol (PtI)
• phosphatidylglycerol (PtG)
• phosphatidylserine (PtS), exposed during trophoblast syncytium formation
• phosphatidylcholine (PrC)
• phosphatidic acid (PA)
The antiphospholipid antibodies (aPL), but not control Ig or Ig from aPL^- patients, bound to apoptotic cells, but not to viable cells. Nuclear antigens were not recognized. Opsonization of apoptotic cells by aPL substantially enhanced recognition and binding by scavenger macrophages, with massive TNF-a secretion, possibly enhancing the immunogenicity of the autoantigens they contain^ref.
3 kinds of operative definitions exist :
• lupus anticoagulant (LAC) (increase of aPTT,INR, and dRVVT not correctable with addition of  normal plasma)
• anti-cardiolipin antibodies (aCL) / anti-M1 antibodies (see below)
• biological false-positive (BFP) test results for syphilis
Despite their name, they don't predspose to hemophilia but rather to to clotting in vivo, predominantly by interfering with the antithrombotic role of phospholipids, inhibiting of endothelial cell activation (decreased expression of adhesion molecules E-selectin, ICAM-1, and VCAM) and of monocyte adhesion, and up-regulating platelet aggregation. They are found in 2-4% of otherwise healthy individuals.The SWISS PROT protein database revealed high homology between the hexapeptides that bind to ILA-1, ILA-3, and H-3 mAbs and the membrane particles of different bacteria and viruses :
• LKTPRV sequence shows homology to 8 different bacteria (eg, Pseudomonas aeruginosa) and 5 types of viruses (ie, polyoma virus, HHV-5 / CMV, adenovirus)
• TL-RVYK sequence shows homology to 8 different bacteria, including Haemophilus influenzae, Neisseria gonorrhoeae, and Shigella dysenteriae, and to viruses such as HHV-4 / EBV and HIV-1.
• receptors
• ACTH-R
• M₃ AChR (second extracellular loop)
• gastrin receptor
• nicotinic acetylcholine receptor (N AChR) < 0.4 nmol/L
• PTPRN / IA2 / ICA 512
• PTPRN2 / IA2b / phogrin / IAR
• glycosylated TSH-R : TSH-receptor antibodies (TRAb)
• thyroid stimulating antibodies (TSAb) / thyroid-stimulating immunoglobulins (TSI) / long-acting thyroid stimulator (LATS) occur in Graves' disease
• TSH-stimulation blocking antibodies (TSBAb) (dosed with TSH-binding inhibitor immunoglobulin (TBII) assay) occur in anti-TSH-R antagonist antibody syndrome
• FceRI a chain
• autoantigens not reachable by antibodies : CMI only. Autoantibodies against such autoantigens have pathogenetic meaning only after cell death, when they can bind to their target and trigger type III hypersensitivity-like reaction. Anyway some kinds of autoantibodies can enter cell via RME or RME-independent pathways and cross the plasma membrane and reach them.
• autoantigens in the inner layer of plasma membrane
• PtS
• PtI
They are translocated on the external layer of plasma membrane (i.e. become reachable by antibodies) in cells undergoing apoptosis.
• cytoplasmic autoantigens
• amphiphysin
• glutamic acid decarboxylase 1 (GAD1) => GAD67
• glutamic acid decarboxylase 2 (GAD2) => GAD65 < 1 U/mL
• PA28g / Ki autoantigen
• restin
• cyclic nucleotide phosphodiesterase 1 (CNP-1)
• UDP glycosyltransferase 1 family members (LKM-3)
• neutrophil cytoplasm autoantigens (=> anti-neutrophil cytoplasmic antibodies (ANCA)) : after ethanol fixation ...
• diffusely granular cytoplasmic neutrophil fluorescence pattern with internuclear accentuation (C-ANCA / c-ANCA)
• proteinase 3 / AGP7 / p29 / myeloblastin (IL-1 and TNF-a induce translocation on cell membrane of neutrophils and endothelial cells). Several patients with vasculitiis and PR3-specific antibodies also have antibodies specific for complementary PR3 (cPR3) - a peptide translated from the antisense DNA strand of the PR3 gene - in the sera, absent in hose without PR3-reactive antibodies or healthy individuals. Mice injected with the middle region of human recombinant cPR-3(105-201) developed both cPR3- and PR3-specific antibodies, indicating that peptides translated from the anti-sense strand of an autoantigen, or microbial-derived peptides that mimic complementary peptide, could initiate autoimmunity. Both human and mouse cPR3 and PR3-specific antibodies did not cross-react with the same antigen but bound to each other, forming an idiotypic pair antibodies^ref.
• perinuclear fluorescence pattern with nuclear extension (P-ANCA / p-ANCA) : even these autoantigens are widely dispersed in cytoplasm but migrate in the perinuclear region during ethanol fixation procedure.
• MPO (10%)
• human leukocytary elastase (HLE) / medullasin
• a-enolase / enolase 1 / non-neural enolase
• lysozyme
• C-terminal part of BPI / CAP-57
• azurocidin
• lactoferrin
• cathepsin G
• HMG1
• HMG2
A substantial proportion of the granulocyte-specific ANA (GS-ANA) belongs to the p-ANCA family.
• atypical diffuse cytoplasmic pattern (A-ANCA / a-ANCA) are ANCA detected by IIF and not directed against the predominant ANCA antigens (i.e. PR3 and MPO), but against a variety of still ill-defined neutrophil antigens. They most frequently yield a perinuclear pattern (P-ANCA) and are found in
• inflammatory bowel diseases (IBDs)
• primary sclerosing cholangitis (PSC)
• rheumatoid arthritis (RA)
• cystic fibrosis (CF)
• leprosy
• malaria
• APSGN
• HIV-1
• Golgi apparatus autoantigens
• golgin a1 (GOLGA1)
• macrogolgin (GOLGB1)
• mitochondrial autoantigens detected from beef heart mitochondria (M2), rat liver (M4), or pig kidney (M8) (=> anti-mitochondrion antibodies (AMA))
• inner mitochondrial membrane
• anti-M1 / anti-cardiolipin antibodies (aCL) (see above) in syphilis (Treponema pallidum subsp.pallidum)
• anti-M2 / E2 component of pyruvate dehydrogenase complex (PDC) in primary biliary cirrhosis (PBC)
• anti-M7 / sarcosine dehydrogenase in certain forms of acute and chronic cardiomyopathy (infectious myocarditis ?)
• outer mitochondrial membrane
• anti-M3 (major : a firmly bound component; minor : a mercurial-insensitive Ag present in the chloroform-released ATPase preparation) in phenopyrazone-induced pseudolupus syndrome
• anti-M4 / sulfite oxidase in primary biliary cirrhosis (PBC) (always associated with anti-M2)
• anti-M5 (a digitonin-sensitive component) in UCTD :  a small population cross-reacts with cardiolipin
• anti-M6 / liver MAO-B  in iproniazid-induced autoimmune hepatitis (AIH)
• anti-M8 in primary biliary cirrhosis (PBC) (always associated with anti-M2)
• anti-M9 / glycogen phosphorylase in primary biliary cirrhosis (PBC) (do not fix complement)
Considering the similarities between bacterial and mitochondrial membranes, it is suggested that the formation of AMA of different specificities may be induced by cross-reacting antigens.
• E3 component of pyruvate dehydrogenase complex (PDC)
• dimethylglycine dehydrogenase
• mitochondrial adenine nucleotide translocase (ANT) / SLC25A6 in idiopathic dilated cardiomyopathy (IDCM). The most significant epitopes belong to the M2 and M3 hydrophilic loops.
• ribosome autoantigens
• ribosomal protein L7
• ribosomal protein P0 (expressed also on cell surface !) => psychiatric symptoms (?), more active disease, photosensitivity and malar and discoid rash in SLE
• ribosomal protein P1
• ribosomal protein P2
• ER autoantigens