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© Dirk Biddle
Inflammation constitutes the body's response to injury and is a result of innate immunity reactions that occur following tissue injury by viruses, bacteria, trauma, chemicals, heat, cold or any other harmful stimuli. Following tissue injury, chemicals such as bradykinin, histamine and serotonin are released by specialized cells. This attracts neutrophils, tissue macrophages and other leucocytes to localise in an area to engulf (phagocytise) and destroy foreign substances.
Inflammation in the acute phase occurs over minutes to a few days following injury and primarily features the alteration of vascular caliber and permeability (dilation and leaking) and the involvement and entry into the surrounding tissue of circulating nuetrophils. Alternatively, chronic inflamation (late-phase inflammation) is a response to prolonged problems. Orchestrated by T-helper lymphocytes it features the recruitment and activation of T- and B-cells, macrophages, eosinophils and healing cells (fibroblasts and angioblasts). The result is sometimes the formation of pus (a mixture of neutophils and liquifaction necrosis). Granuloma, fibrosis and scar tissue may also result.
Granulomas are thus seen in certain chronic inflammation situations. They are clusters of macrophages that have stuck tightly together, typically to wall something off. Such macrophages are called epithelioid cells.
Fibrin is fibrinogen released from damaged vessels and activated by the clotting cascade when blood meets tissue juices. Fibrin forms the meshwork that controls bleeding and then becomes the framework for fibroblasts and angioblasts that will form the scar. Until the new scar is complete, the whole meshwork of immature scar is called granulation tissue. When the scar has matured, it contracts.
The inflammatory reaction is characterized by successive phases: 1. The silent phase, where cells, including resident cells in the damaged tissue, release the first inflammatory mediators (cytokines), 2. The vascular phase, where vasodilation and increased vascular permeability occur, and 3. The cellular phase, which is characterized by the infiltration of leucocytes to the site of injury.
The very first event of the inflammatory reaction, the "silent phase" is based upon the reaction of the cells and of resident cells (which may include for example macrophages, mast cells and eosinophils) of the damaged tissue. These resident cells release mediators, such as nitric oxide(NO), histamine, kinins, cytokines, seratonin and prostaglandins. The release of these vasomotor mediators from resident cells leads to the second phase of the inflammatory reaction: the vascular phase. Vascular tone and permeability are regulated by an endothelial-dependent mechanism involving the release of nitric oxide. Certain agonists signal to sensory afferents inducing the release of neuropeptides which are known to act on vascular mural structures to induce vasodilation and increase vascular permeability. Increased vasodilatation and permeability allow plasma leakage from the blood to the inflamed tissues and this facilitates the passage of leucocytes from the blood to the tissues (1).
The dynamic interactions between vascular endothelial cells, leucocytes, and platelets contribute to numerous physiologically important mechanisms. In the development of vascular inflammation a pivotal step involves leucocyte recruitment and attachment to the vascular endothelium. Freely circulating leucocytes must be attracted from the blood stream to the site of inflammation or damage so they can enter the tissues (extravasation) where their specific inflammatory response (to kill pathogens and/or promote tissue repair) may be activated. This process, known as the leukocyte adhesion cascade, is described as a sequence of adhesion and activation events having at least five steps: capture, rolling, slow rolling, firm adhesion, and transmigration (extravasation) (2). Emigration (diapedesis) of neutrophils from the vessels into the tissues occurs when the cells squeeze through the widened endothelial cell gaps, then get through the basement membrane by digesting it with enzymes (this damages the blood vessels but endothelial cells repair the damage relatively quickly). Other lymphocytes also leave vessels by this route. Once they have found their way to the tissues, the neutrophils phagocytise opsonised or otherwise foreign particles. They also degranulate, releasing enzymes into the interstitial fluid (3).
Leucocyte attachment to the endothelium is mediated by a multiple receptor/ligand system belonging to four families of related proteins. Broadly termed cell adhesion molecules (CAMs), they are the cadherins (or mucins), the selectins, the immunoglobulin (Ig) superfamily, and the integrins. Adhesive interactions between cells of the same type are coordinated by the cadherins and the Ig-superfamily, while adhesive interactions between cells of a different type occur with the help of integrins and selectins.
The selectins are themselves a family of three cell-membrane glycoprotein adhesion-molecules ; that is the L- , E- , and P-selectins . Upon infection of tissue, cytokines are secreted that mediate the expression of E- and P-selectins on the surface of vascular endothelial cells. Neutrophils are among the first cells to bind and extravasate but the process is similar for other leucocytes. P- and E-selectin exposed on the surface of activated endothelial cells display a weak affinity to cadherins (or mucins) on the membrane of passing neutrophils. Once the neutrophils are thus “loosely” captured they begin “rolling” along the endothelial surface where, in turn, cadherins on the epithelial cell surfaces present ligands to the L-selectin on the neutrophil cell membrane and serve to bind the neutrophils a little more tightly to the epithelium, beginning their “slow rolling”. As the neutrophils roll, they are activated by various chemokines (including IL-8, macrophage inflammatory protein (MIP), platelet activation factor (PAF), and C5a) that are localized on the endothelial cell surface or secreted locally by cells involved in the inflammatory process. This chemokine-mediated neutrophil activation increases the affinity of intergrins expressed on the surface of the neutrophils for members of the immunoglobulin family CAMs present on the epithelial cells. The neutrophils then become “firmly” adhered and stop rolling. The adhered neutrophils then move between adjacent endothelial cells and into the underlying tissue. This extravasation process has not been well characterised (3, 4) but once in (or even through) the vascular parenchyma , neutrophils, if fully activated, may release lytic granules (including collagenase, protease, and elastase) and toxic radicals (including hydroxyl radicals and hydrogen peroxide) that may injure the vessel wall, and which may in turn also lead to necrosis, haemorrhage, and thrombosis.
Another leucocyte commonly involved is the T-cell, which may, in the presence of cytokines (and the absence of antigens), also attach to the endothelium, damaging the vessel wall in much the same manner as neutrophils, but with the added ability to re-enter the circulation (they are however more yielding to deletion than neutrophils). The presence of cytokines may also attract monocytes and macrophages to the site of injury. These in turn may also release their own cytokines, thus attracting more leucocytes. Platelets(a particle found in the bloodstream that binds to fibrinogen at the site of a wound to begin the blood clotting process) and eosinophils may also participate in the pathogenesis of vascular injury (5).
Types of leucocytes and their noted association with specific vasculitis conditions may include (briefly): Neutrophils predominant in Cutaneous leukocytoclastic vasculitis, lymphocytes predominant in Henoch-Schönlein purpura and Polyarteritis nodosa and eosinophils predominant in Churg-Strauss syndrome. Of course many vasculitides present with mixed leucocyte infiltrates. For example, Polyarteritis nodosa can present with neutrophils, lymphocytes, histiocytes (non-motile macrophages) and some plasmacytes(mature B-cells). Eosinophils are often present as well.
The role of complement and immune complexes in leucocyte/vascular endothelial interactions will be elucidated in a later section.
Tissue destruction is then caused by both the caustic agents and by the inflammatory process itself, sometimes leading to the generation of symptoms that typify vasculitis conditions. Further, it is speculated that all the many types of allergies and many of the autoimmune diseases are examples of an inappropriately regulated inflammatory response to what should (possibly) have been a harmless, or at least a non-infectious agent. The result (eg; fibrosis ) can be more damage to the body than the irritating agent alone would have produced.
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1.http://www.freshpatents.com/Methods-of-reducing-extravasation-of-inflammatory-cells-dt20041230ptan20040265297.php
2. U, Norman K, Scharffetter-Kochanek K, Beaudet A, & Ley K. (1998) Transit Time of Leukocytes Rolling through venules Controls Cytokine-induced Inflammatory Cell Recruitment In Vivo. Journal of Clinical Investigation, 102, 1526-1533.
3. http://www.pathguy.com/lectures/inflamma.htm
4. Moore, P. and Richardson, B. (1998) Neurology of the vasculitides and connective tissue diseases Neurol Neurosurg Psychiatry, 65, 10-22.
5. http://physrev.physiology.org/cgi/content/full/79/1/181
6. Tai, P., Holt, M., Denny, P., et al. (1984) Deposition of eosinophil cationic protein in granulomas in allergic granulomatosis and vasculitis: the Churg-Strauss syndrome. British Medical Journal, 289, 400-402.
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Innate Immunity: The term 'Innate immunity' (non-specific or basic immunity) refers to the the first line of defense (pre-existing) that a species possesses against infection. This includes local barriers to infection such as skin, stomach acid, mucous, the cough reflex, enzymes in tears and saliva and skin oils.
Bradykinin: A kinin that is formed locally in injured tissue, acts in vasodilation of small arterioles, is considered to play a part in inflammatory processes, and is composed of a chain of nine amino acid residues. (M+)
Vasoactive nonapeptide (RPPGFSPFR) formed by action of proteases on kininogens. Very similar to kallidin (which has the same sequence but with an additional N terminal lysine). Bradykinin is a very potent vasodilator and increases permeability of post capillary venules, it acts on endothelial cells to activate phospholipase A2. It is also spasmogenic for some smooth muscle and will cause pain. (OMD)
Histamine: Formed by decarboxylation of histidine. Potent pharmacological agent acting through receptors in smooth muscle and in secretory systems.
Stored in mast cells and released by antigen. (See hypersensitivity). Responsible for the early symptoms of anaphylaxis. Also present in some venoms. (OMD)
A compound (C5H9N3), especially of mammalian tissues, that causes dilatation of capillaries, contraction of smooth muscle, and stimulation of gastric acid secretion, that is released during allergic reactions, and that is formed by decarboxylation of histidine. (M+)
Serotonin: A neurotransmitter and hormone (176 kD), found in vertebrates, invertebrates and plants. It is synthesised from the amino acid tryptophan by enterochromaffin cells in the gut and bronchi. It is metabolised to 5-HIAA in the liver and then excreted in the urine.
Serotonin is measured on a venipuncture specimen in cases of suspected carcinoid syndrome (where it will be elevated). The normal range is 101 to 283 ng/ml. (OMD)
A phenolic amine neurotransmitter C10H12N2O that is a powerful vasoconstrictor and is found especially in the brain, blood serum, and gastric mucous membrane of mammals -- called also 5-HT, 5-hydroxytryptamine. (M+)
Fibrosis: The formation of fibrous tissue, fibroid or fibrous degeneration. (OMD)
A condition marked by increase of interstitial fibrous tissue. (M+)
Nitric Oxide: This compound (NO) is produced from L. arginine by the enzyme nitric oxide synthase. Acts as a potent vasorelaxant via elevation of intracellular cGMP in vascular smooth muscle.
Synthesis of nitric oxide is not confined to endothelium, isoforms of nitric oxide synthase are also found in brain, neutrophils and platelets.
Synonym: endothelium derived relaxation factor. (OMD)
A poisonous colorless gas (NO) that occurs as a common air pollutant formed by the oxidation of atmospheric nitrogen and that is also formed by the oxidation of arginine in the mammalian body where it acts as a mediator of intracellular and intercellular communication regulating numerous biological processes (as vasodilation and neurotransmission). (M+)
Histamine: Formed by decarboxylation of histidine. Potent pharmacological agent acting through receptors in smooth muscle and in secretory systems.
Stored in mast cells and released by antigen. (See hypersensitivity).
Responsible for the early symptoms of anaphylaxis. Also present in some venoms. (M+)
A compound (C5H9N3) especially of mammalian tissues that causes dilatation of capillaries, contraction of smooth muscle, and stimulation of gastric acid secretion, that is released during allergic reactions. (OMD)
Kinins: One of a number of widely differing substances having pronounced and dramatic physiological effects. Some (e.g., kallidin and bradykinin) are polypeptides, formed in blood by proteolysis secondary to some pathological process, that stimulate visceral smooth muscle but relax vascular smooth muscle, thus producing vasodilation. (OMD)
Cytokine: Substance produced by a leucocyte that acts upon another cell. Small proteins or biological factors (in the range of 5-20 kD) that are released by cells and have specific effects on cell-cell interaction, communication and behaviour of other cells. Not really different from hormones, but the term tends to be used as a convenient generic shorthand for interleukins, lymphokines and several related signaling molecules such as TNF (tumour necrosis factor alpha) and interferons. Generally growth factors would not be classified as cytokines, though TGF is an exception. Rather an imprecise term. Chemokines are a subset of cytokines. (OMD)
Prostaglandin: Any of various oxygenated unsaturated cyclic fatty acids of animals that are formed as cyclooxygenase metabolites especially from unsaturated fatty acids (as arachidonic acid) composed of a chain of 20 carbon atoms and that perform a variety of hormone-like actions (as in controlling blood pressure or smooth muscle contraction). (M+)
Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel.
2. Any element or agent that effects the calibre of a blood vessel. (OMD)
Vascular Tone: Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All resistance and capacitance vessels under basal conditions exhibit some degree of smooth muscle contraction that determines the diameter, and hence tone, of the vessel.
Agonists: 1. A prime mover.
2. A drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances, thus triggering a biochemical response. (OMD)
Afferent: Moving or carrying inward or toward a central part. Refers to vessels, nerves, etc. For example: blood vessels carrying blood toward the heart, or nerves conducting signals to the brain.(OMD)
Endothelium: The layer of epithelial cells that lines the cavities of the heart and of the blood and lymph vessels and the serous cavities of the body. (OMD)
Platelet: A particle found in the bloodstream that binds to fibrinogen at the site of a wound to begin the blood clotting process. Platelets are formed in bone marrow, where they arise from cells called megakaryocytes. (OMD)
Endothelium: The layer of epithelial cells that lines the cavities of the heart and of the blood and lymph vessels and the serous cavities of the body. (OMD)
Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. (OMD)
Leukocyte Adhesion Cascade: The leukocyte adhesion cascade is a sequence of adhesion and activation events that ends with extravasation of the leukocyte, whereby the cell exerts its effects on the inflamed site.
At least five steps of the adhesion cascade are capture, rolling, slow rolling, firm adhesion, and transmigration.
Mediator: An object or substance by which something is mediated, such as
1. A structure of the nervous system that transmits impulses eliciting a specific response.
2. A chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle, or
3. A substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitised lymphocyte. (OMD)
Receptor/Ligand: Any molecule that binds to another, in normal usage, a soluble molecule such as a hormone or neurotransmitter, that binds to a receptor. The decision as to which is the ligand and which the receptor is often a little arbitrary when the broader sense of receptor is used (where there is no implication of transduction of signal). In these cases it is probably a good rule to consider the ligand to be the smaller of the two thus in a lectin sugar interaction, the sugar would be the ligand (even though it is attached to a much larger molecule, recognition is of the saccharide). (OMD)
Protein: Nitrogenous organic compounds, containing more than about 100 amino acid residues, molecular weight 8,000-200,000, in vegetable and animal matter. Proteins yield amino acids on hydrolysis and are foods assimilated as amino acids and reconstructed in the protoplasm.
Cell Adhesion Molecules (CAMs): Cell Adhesion Molecules (CAMs) are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion.
Molecules that are involved in T helper-accessory cell, T helper-B-cell, and T cytotoxic-target cell interactions. (OMD)
Cadherins: Integral membrane proteins involved in calcium dependent cell adhesion. There are three types, named after their distributions: N cadherin (neural), E cadherin (epithelial) (equivalent to uvomorulin and L CAM) and P cadherin placental). Formed of a 600 amino acid extracellular domain, containing 4 repeats believed to contain the Ca binding sites, a transmembrane domain and a 150 amino acid intracellular domain. (OMD)
Mucins: Explanation coming soon
Selectins: Group of cell adhesion molecules that bid to carbohydrates via a lectin like domain. The name is derived from select and lectin.
They are integral membrane glycoproteins with an N terminal, C type lectin domain, followed by an EGF like domain, a variable number of repeats of the short consensus sequence of complement regulatory proteins and a single transmembrane domain.
Three selectins have been identified and are distinguished by capital letters based on the source of the original identification i.e. E selectin, L selectin and P selectin. (OMD)
Immunoglobulin (Ig): see Antibody. Types include: IgA, IgG, IgB, IgD, IgE, and IgM. Most immunoglobulins are IgG (they migrate in the gamma region during electrophoresis).
Integrins: Superfamily of cell surface proteins that are involved in binding to extracellular matrix components in some cases. Most are heterodimeric with a subunit of 95 kD that is conserved through the superfamily and a more variable subunit of 150-170 kD. The first examples described were fibronectin and vitronectin receptors of fibroblasts, which bind to an RGD (Arg Gly Asp) sequence in the ligand protein, though the context of the RGD seems important and there is also a divalent cation dependence. Subsequently the platelet IIb/IIIa surface glycoprotein (fibronectin and fibrinogen receptor) and the LFA 1 class of leucocyte surface protein were recognised as integrins, together with the VLA surface protein. The requirement for the RGD sequence in the ligand does not seem to be invariable. (OMD)
Selectins: Group of cell adhesion molecules that bid to carbohydrates via a lectin like domain. The name is derived from select and lectin.
They are integral membrane glycoproteins with an N terminal, C type lectin domain, followed by an EGF like domain, a variable number of repeats of the short consensus sequence of complement regulatory proteins and a single transmembrane domain.
Three selectins have been identified and are distinguished by capital letters based on the source of the original identification i.e. E selectin, L selectin and P selectin. (OMD)
E-Selectins: Cell adhesion molecule and CD antigen that mediates neutrophil, monocyte, and memory T-cell adhesion to cytokine-activated endothelial cells. E-selectin recognises sialylated carbohydrate groups related to the lewis x or lewis a family. (OMD)
L-Selectins: Cell adhesion molecule and CD antigen that serves as a homing receptor for lymphocytes to lymph node high endothelial venules. (OMD)
P-Selectins: Cell adhesion molecule and CD antigen that mediates the adhesion of neutrophils and monocytes to activated platelets and endothelial cells. (OMD)
Cytokine: Substance produced by a leucocyte that acts upon another cell. Small proteins or biological factors (in the range of 5-20 kD) that are released by cells and have specific effects on cell-cell interaction, communication and behaviour of other cells. Not really different from hormones, but the term tends to be used as a convenient generic shorthand for interleukins, lymphokines and several related signaling molecules such as TNF (tumour necrosis factor alpha) and interferons. Generally growth factors would not be classified as cytokines, though TGF is an exception. Rather an imprecise term. Chemokines are a subset of cytokines. (OMD)
Receptor/Ligand: Any molecule that binds to another, in normal usage, a soluble molecule such as a hormone or neurotransmitter, that binds to a receptor. The decision as to which is the ligand and which the receptor is often a little arbitrary when the broader sense of receptor is used (where there is no implication of transduction of signal). In these cases it is probably a good rule to consider the ligand to be the smaller of the two thus in a lectin sugar interaction, the sugar would be the ligand (even though it is attached to a much larger molecule, recognition is of the saccharide). (OMD)
Chemokines: Cytokines that are chemotactic for leucocytes. The first member of the family was IL-8 (interleukin-8) but subsequently many other members have been identified. They can now be sub divided into two groups on the basis of the arrangement of a pair of conserved cysteines: the C x C group includes platelet Factor 4, platelet basic protein, interleukin 8, melanoma growth stimulatory protein, macrophage inflammatory protein 2. (OMD)
IL-8: A cytokine that activates neutrophils and attracts neutrophils and T-lymphocytes.
It is released by several cell types including monocytes, macrophages, T-lymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. Il-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. (OMD)
Macrophage Inflammatory Protein: A chemokine that is chemotactic for neutrophils and monocytes, stimulates macrophages, and may play a role in regulating haematopoiesis. Its two variants, mip-1alpha and mip-1beta, are 60% homologous to each other.
They are heparin-binding proteins that exhibit a number of inflammatory and immunoregulatory activities. Originally identified as secretory products of macrophages, these chemokines are produced by a variety of cell types including neutrophils, fibroblasts, and epithelial cells.
They most likely also play a significant role in respiratory tract defenses. (OMD)
Platelet Activation Factor: (Type of cytokine) A potent phospholipid activator and mediator of many leucocyte functions, including platelet aggregation, inflammation, and anaphylaxis.
It is produced in response to specific stimuli by a variety of cell types, including neutrophils, basophils, platelets, and endothelial cells. Several molecular species of platelet-activating factor have been identified which vary in the length of the O-alkyl side chain. It is an important mediator of bronchoconstriction.
Synonym: platelet-aggregating factor. (OMD
C5a Peptidase: Streptococcus pyogenes enzyme - inactivates complement 5a by cleaving at lysine 68, removing a six-amino acid fragment.
Pharmacological action: complement inactivators. (OMD)
Parenchyma: The essential elements of an organ, used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework or stroma. (OMD)
Lytic Granules: Cytoplasmic elements capable of producing rupture of cell membranes and loss of cytoplasm (see for example collegenase, protease, elastase).
Collagenase: Any of a group of proteolytic enzymes that decompose collagen and gelatin. (M+)
Proteolytic enzyme capable of breaking native collagen. Once the initial cleavage is made, less specific proteases will complete the degradation.
Collagenases from mammalian cells are metallo enzymes and are collagen type specific. May be released in latent (proenzyme) form into tissues and require activation by other proteases before they will degrade fibrillar matrix. Bacterial collagenases are used in tissue disruption for cell harvesting. (OMD)
Protease: A proteinase which is any enzyme that catalyses the splitting of interior peptide bonds in a protein. (OMD)
Any of numerous enzymes that hydrolyze proteins and are classified according to the most prominent functional group (as serine or cysteine) at the active site. (M+)
Elastase: Serine protease that will digest elastin and collagen type IV, inhibited by 1_protease-inhibitor of plasma. (OMD)
An enzyme especially of pancreatic juice that digests elastin. (M+)
Toxic Radicals: An especially reactive atom or group of atoms that has one or more unpaired electrons; especially one that is produced in the body by natural biological processes or introduced from outside (as in tobacco smoke, toxins, or pollutants) and that can damage cells, proteins and DNA by altering their chemical structure. (M+)
Hydroxyl Radicals: The univalent radical OH. This radical is characteristic of hydroxides, oxygen acids, alcohols, glycols, phenols, and hemiacetals. (OMD)
Hydrogen Peroxide: An unstable compound (H2O2) used especially as an oxidizing and bleaching agent and as an antiseptic. (M+)
Hydrogen peroxide is produced by vertebrate phagocytes and is used in bacterial killing (the myeloperoxidase halide system). (OMD)
Necrosis: The sum of the morphological changes indicative of cell death and caused by the progressive degradative action of enzymes; it may affect groups of cells or part of a structure or an organ. (OMD)", //51 "
Haemorrhage: The escape of blood from the vessels, bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm) and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. (OMD)
T-cell: Any of several lymphocytes (as in helper T-cell) that differentiate in the thymus, possess highly specific cell-surface antigen receptors, and include some that control the initiation or suppression of cell-mediated and humoral immunity (such as by the regulation of T- and B-cell maturation and proliferation) and others that lyse antigen-bearing cells - called also T-lymphocyte. (M+)
Cytokine: Substance produced by a leucocyte that acts upon another cell. Small proteins or biological factors (in the range of 5-20 kD) that are released by cells and have specific effects on cell-cell interaction, communication and behaviour of other cells. Not really different from hormones, but the term tends to be used as a convenient generic shorthand for interleukins, lymphokines and several related signaling molecules such as TNF (tumour necrosis factor alpha) and interferons. Generally growth factors would not be classified as cytokines, though TGF is an exception. Rather an imprecise term. Chemokines are a subset of cytokines. (OMD)
Platelets: A particle found in the bloodstream that binds to fibrinogen at the site of a wound to begin the blood clotting process. Platelets are formed in bone marrow, where they arise from cells called megakaryocytes. (OMD)
Fibrinogen: Soluble plasma protein (340 kD, 46 nm long), composed of 6 peptide chains (2 each of A_, B_ and _C) and present at about 2-3 mg/ml. (OMD)
A plasma protein that is produced in the liver and is converted into fibrin during blood clot formation. (M+)
Eosinophils: A white blood cell or other granulocyte with cytoplasmic inclusions readily stained by eosin. (M+)
Pathogenesis: The origin and development of disease.
Histiocytes: Long lived resident macrophage found within tissues. (OMD)
A nonmotile macrophage of extravascular tissues and especially connective tissue. (M+)
Plasmacytes: A type of non-granular, basophilic leukocyte that produces antibodies. (OMD)
A lymphocyte that is a mature antibody-secreting B-cell. (M+)
Complement: A term originally used to refer to the heat labile factor in serum that causes immune cytolysis, the lysis of antibody coated cells and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed components of complement and are designated by the symbols C1 through C9. C1 is a calcium dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower case letter suffixes, for example, C3a. Inactivated fragments may be designated with the suffix i, for example C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol for example C1 or C4b, 2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3, C1q binds to a single IgM molecule or two adjacent IgG molecules.
The alternative pathway can be activated by IgA immune complexes and also by non-immunologic materials including bacterial endotoxins, microbial polysaccharides and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3, activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins or chemotactic factors. (OMD)
Immune Complexes: Multimolecular antibody antigen complexes that may be soluble or insoluble depending upon their size and whether or not complement is present. Immune complexes can be filtered from plasma in the kidney and the deposition of the complexes gives rise to glomerulonephritis probably because of the trapping of neutrophils via their Fc receptors. (OMD)