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Figure 3 Complex between a viral peptide epitope of poliovirus and a neutralizing antibody Fab (as displayed by computer modeling). The structural and chemical complementarity between antigen and antibody shows clearly, and negative charges in the antigen binding pocket evidently contribute to binding. (Reproduced with permission from Wien et al (1995).)

Figure 3 Complex between a viral peptide epitope of poliovirus and a neutralizing antibody Fab (as displayed by computer modeling). The structural and chemical complementarity between antigen and antibody shows clearly, and negative charges in the antigen binding pocket evidently contribute to binding. (Reproduced with permission from Wien et al (1995).)

These cells are erythrocytes in human and nonhuman primates and platelets in various rodents and sub-primates - including mice, guinea pigs and rabbits. Studies in primates have shown that circulating erythrocytes rapidly interact with exogeneously infused or in vivo formed immune complexes and carry them to the hepatic and splenic reticuloendothelial system, where the complexes are stripped from the erythrocytes and further processed by the mononuclear phagocytes. Decomplementation of the animals, thereby preventing association of C3b to immune complexes, makes immune complex fixation to erythrocytes impossible, facilitating diffuse deposition of immune complexes outside the reticuloendothelial tissues. CR1 in humans is found not only on erythrocytes, from which it was isolated in the late 1970s by Fearon, but also on neutrophils, monocytes and lymphocytes. The presence of such receptors on lymphocytes provides an immunoregulatory function of immune complexes; their fixation to lymphoid tissues permitting prolonged immune recognition of the antigen and, perhaps, the maintenance of immunological memory.

The interaction of immune complexes with complement leads to ionic fixation of the globular domains of Clq to the Cy2 domain of IgG, or the Cp3 domain of IgM after these antibodies have formed immune complexes. The IgG- and IgM-binding site on the Clq globular domains is strongly electrostatic. The IgG residues involved in the binding to Clq are charged residues, Glu318, Lys320 and l.ys322. Subsequent C4b and C3b binding further contribute to coating of immune complexes by complement. In the circulation at any one time, the proportion of immune complexes bound to erythrocytes is dependent not only on the rate of binding but also on inactivation of CR1-bound C3b, which leads to release of the immune complexes from the erythrocyte surface. The released complexes remain coated with iC3b and C3dg and are incapable of activating complement any further but maintain a capacity to cause an inflammatory response. The enzyme responsible for C3b inactivation is factor I: its concentration and activity determine release reactions and hence influence the kinetics of the exchange of immune complexes between erythrocytes and plasma.

It is at the level of the reticuloendothelial system -mainly in liver and spleen - that immune complexes become discharged from the erythrocytes in transit through the circulation. The iC3b- or C3dg-bearing immune complexes remain in the reticuloendothelial system, where they interact with iC3b receptors (CR3,CDllb) or C3dg receptors (CR4, GDI Ic) that are expressed on phagocytic cells. Failure of the erythrocyte shuttle transport system or dysfunction of the different processing steps of immune complexes in the reticuloendothelial system may lead to a chronic persistence of complexes in the circulation, thereby predisposing to their entrapment in kidney, skin, lungs, retina and other organs.

The complement system thus emerges as the major immune complex-processing protein system that confers upon a variety of circulating and tissue fixed cells the potential to dispose of these complexes. Human erythrocytes are now known to autonomously inhibit the complement-mediated solubilization of immune complexes bound to their surface, suggesting that these cells would control some physicochemical properties of the complexes they carry.

At the beginning of the twentieth century, Arthus described a clinical syndrome that developed after the injection of horse serum into rabbits, and Clemens von Pirquet recognized that antigens not only induce antibodies but are also responsible for serum sickness. Immune complexes were identified as the toxic products responsible for tissue injury of individuals with serum sickness. We now know that, for the Arthus reaction to occur, relatively large amounts of immune complexes have to be localized in the vessel walls and in perivascular areas. Both passively adsorbed and locally formed immune complexes will react with complement and induce release of anaphy-latoxins, such as C3a and C5a, and cytokines, which enhance vascular permeability and generate other chemotactic factors, attracting polymorphonuclear leukocytes to the site of the lesion. An increase in vascular permeability evidently favors the leakage of circulating immune complexes into the extravascular compartment. In vitro studies further suggest that the binding of immune complexes to tissue components may cause direct, complement- and inflammatory cell-independent tissue injury by stimulating oxygen radical release.

At this stage, inflammation becomes largely dependent on interaction of immune complexes with the Fc receptor apparatus. In fact, FcR signaling on such cell types as macrophages, neutrophils and natural killer (NK) cells recruits cellular tyrosine kinases, followed by elevation of intracellular calcium and release of inflammatory leukotrienes, prostaglandins and hydrolases and the transcription of genes encoding for cytokines.

Immune complexes containing IgG suppress interferon 7 (IFN7)-induced activation of the FC7RI gene by preventing tyrosine phosphorylation, a finding that explains the impairment of tumoricidal activity and enhancement of major histocompatibility complex (MHC) class II expression in macrophages by immune complexes. A considerable diversity of cellular responses to immune complexes thus emerges, which is largely due to actions at different types of FcR. In turn, FcRs are themselves under control of various cytokines. Thus, a network of regulatory factors exists which can become disturbed by immune complexes. Furthermore, immune complexes are now known to induce and stimulate interleukin 10 (IL-10) production from macrophages, thereby inhibiting antimicrobial responses (e.g. against Listeria monocytogenes). In turn, immune complexes induced IL-10 production when experimentally used to provoke acute alveolitis, an activity that is favorable for the host, because IL-10 decreases tumor necrosis factor a (TNFa) production, thereby attenuating injury. IL-10 thus downregulates not only inflammation directed at foreign invaders but also at self constituents (Figure 4).

Since the original definition of serum sickness, a great variety of diseases have been found to resemble the immune complex model described in rabbits. Particularly well studied are the autoimmune hemolytic disease and chronic membranous glomerulonephritis in New Zealand black mice. Further immune complex-type diseases in animals involve viral antigens such as Aleutian disease of mink, lymphocytic choriomeningitis, in which immune com-plex-induced lesions develop, and lactic dehydrogen-ase-elevating virus (LDV) infection in mice, with the production of often lifelong levels of circulating immune complexes.

Augmented production of immune complexes, and/or their reduced removal, plays a crucial role in

Figure 4 Intervention of immune complexes with opposing sets of cytokines. Immune complex-induced increased production of IL-4 and IL-10, and immune complex-induced suppression of IFN7. IL-10 suppresses IFN-y-production by helper T lymphocytes and NK cells. In addition, IL-10 suppresses the production of several proinflammatory, macrophage (M<J>)-derived cytokines, including TNFu, IL-1a, IL-1(j, IL-6, IL-8, granulocyte-macrophage and granulocyte colony-stimulating factors. IL-10 also inhibits expression of MHC class II antigen on monocytes and upregul-ates inducible nitric oxide synthase in macrophages. Exogen-ously administered IL-10 has been shown to protect rats from lung injury after intrapulmonary deposition of IgG immune complexes. CTL, cytotoxic T lymphocyte.

Figure 4 Intervention of immune complexes with opposing sets of cytokines. Immune complex-induced increased production of IL-4 and IL-10, and immune complex-induced suppression of IFN7. IL-10 suppresses IFN-y-production by helper T lymphocytes and NK cells. In addition, IL-10 suppresses the production of several proinflammatory, macrophage (M<J>)-derived cytokines, including TNFu, IL-1a, IL-1(j, IL-6, IL-8, granulocyte-macrophage and granulocyte colony-stimulating factors. IL-10 also inhibits expression of MHC class II antigen on monocytes and upregul-ates inducible nitric oxide synthase in macrophages. Exogen-ously administered IL-10 has been shown to protect rats from lung injury after intrapulmonary deposition of IgG immune complexes. CTL, cytotoxic T lymphocyte.

the pathogenesis of many immune complex-related diseases in humans, as illustrated by systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and HIV infection. Table 1 lists a number of nosological entities in which immune complexes play a relevant immunopathological role and in which their therapeutic removal may improve the patient's condition.

Because complement is so important to immune complex processing, adverse conséquences with regard to humoral immune defense are understandable in hypocomplementemic patients. I11 patients with inherited complement deficiencies, increased serum concentrations of immune complexes are found associated with deficiencies of components of the classical pathway of complement activation Cl, C4 and C2. In acquired complement deficiency, however, low levels of these and other components (C3, C5, C5b-9) may be a result of chronic complement activation either by the inflammatory process or directly by immune complexes. This is mostly reflected by the demonstration of low levels of C3, C4 and other components and high levels of the complement component breakdown products C3dg, C3a and C5a. In many patients, the levels of circulating immune complexes and those of complement breakdown products correlate significantly.

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