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
• 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) : emperypolesis / 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