The effect of immune complex composition on complement activation and complement dependent complex release

The complement activating capacity and complement dependent complex release activity (CRA) of immune complexes (IC) formed at different antigen:antibody ratios were investigated. The correlation between antibody avidity, precipitating capacity and the effect of these parameters on Fcdependent biological functions was studied in BSA-anti-BSA and OA-anti-OA systems. The results suggest that antibody excess favours the complement activating effect of ICs. No correlations between antibody precipitating capacity and avidity was found. However, antibody avidity and complement activating capacity were related: the higher the avidity index of antibodies, the higher the complement activation. The kinetics of CRA are not directly influenced by these characteristics of antibodies. The intercalation of C3b into the lattice interferes not only with the primary antigen—antibody bonds, it may result in the rearrangement of the lattice through the disruption of the non-specific intermolecular interactions.     

IgE and immune complex glomerulonephritis

A case is presented of immune complex proliferative glomerulonephritis associated with peripheral eosinophilia, renal deposits of IgE, and eosinophils in glomeruli and interstitial tissue. Two sequential renal specimens are described. This study also reviews prior reports of IgE in glomerulonephritis and discusses possible explanations for the presence of IgE.     

The modulation of immune complex aggregation by classical pathway-mediated reactions

Classical pathway (CP)-triggered reactions of complement-modulated immune complex (IC) aggregation (tetanus toxoid/human anti-tetanus toxoid-IgG; ICs of equivalence) were investigated turbidimetrically during the early stages of reaction. Monospecific Fab'- or Fab-fragments (rabbit) directed against certain complement components were used to block the complement function in normal human serum (NHS). Additionally, parts of the reactions were studied using purified complement components. C1q in serum generated by the addition of EDTA as well as purified C1q were found to increase the IC aggregation. In contrast to C1q, macromolecular C1 is able to inhibit IC aggregation, whereas additional participation of C-1 INH reversed this process. The cooperation of the remaining CP proteins (C4, C2, C4bp, and I) reconstituted the inhibition capacity of the complement. Whereas C3 supported significantly inhibition, a significant influence of other effector pathway (EP) components (C5-C9) was not detectable turbidimetrically.     

The serology of autologous immune complex nephritis in the rat

The serological response has been studied in rats developing autoimmune complex nephritis, following injection of chemically modified kidney antigen. The results suggest that a change takes place from IgM to both IgM and IgG anti-kidney antibodies. This response can be distinguished from the naturally occurring IgM antitissue antibodies.     

Circulating immune complexes in rats with autologous immune complex nephritis

Autologous immune complex nephritis (Heymann nephritis) was actively induced in rats by immunization with high (10 mg.) and low (1 mg.) doses of renal tubular epithelial antigen in complete Freund's adjuvant. The development of proteinuria and granular capillary wall deposition of IgG confirmed the previously well described membranous nephropathy which characterizes this experimental disease. Circulating immune complexes were demonstrated by both the fluid phase and solid phase C1q binding assays in both high and low dose experimental groups. The prevalence of such immune complexes was significantly greater in the experimental than in the control groups immunized with adjuvant alone or liver homogenate in adjuvant. The circulating immune complexes bound to C1q were 16 to 23 S in size and were proven to contain a renal tubular antigen. These data, in combination with the previous demonstration of renal tubular antigen and its antibody in kidneys from rats with autologous immune complex nephritis, are consistent with a circulating immune complex pathogenesis of this model of the actively induced autologous immune complex nephritis in rats.     

Pathophysiological aspects of immune complex diseases

Summary Immune complexes (IC) may be pathophysiologically active in correlation with the nature and size of the antigen, the type and the quality of the antibody, and the concentration of both. Those parameters are decisive for the composition and the lattice structure of IC. Pathogenic effects are induced: by complement activation and generation of biologically active C split products via the classical and the alternative pathway, by interaction with Fc and complement receptors resulting in exocytosis of lysosomal contents including degradative enzymes, cationic proteins, vasoactive amines and mediators effective on lymphocytes and macrophages; by direct and indirect activation of the Hageman factor followed by stimulation of the kinin, coagulation and fibrinolysis system; and by modulation of the immune response via the afferent and the efferent branch. All those mechanisms seem to be involved in the induction of lesions along the vessel wall in the various privileged organs.     

Pathophysiological aspects of immune complex diseases

Summary Elimination of IC by the phagocytic system occurs mainly by macrophages and contrarotates to the pathogenic effect. Decisive to prevent systemic IC disease is the capacity of the phagocytic system. In the case of its saturation, the danger of the occurrence of IC disease is greatly enhanced. Conclusive evidence seems to exist that IC of extremely small or extremely high lattice structure (precipitates) are less pathogenic than soluble IC of medium network. Small IC in extreme antigen and antibody excess or precipitates exhibit a reduced complement activating potency. Small IC in extreme antigen or antibody excess hardly interact in vitro with membrane receptors and do not induce IC disease when injected or formed in vivo. Highly lattices IC, especially precipitates, are eliminated extremely quickly from the circulation, mainly by macrophages and there deposition in the kidney is significantly reduced. Thus, lack of quality of the antibody to precipitate the antigen and a reduced capacity and effectivity of the phagocytic system to eliminate the IC may be extremely important in the generation of IC diseases. Facing the overwhelming and partly even inconsistant data of this topic, one may doubt whether IC diseases may be regarded to be a defined and coherent disease. Too many variables and questions exist concerning the nature of the antigen, especially in tumor and autoimmune diseases, concerning the quality of the antibody and the characteristics of the pathogenic IC and concerning localization and the elimination process. Nevertheless, common pathophysiological pathways of IC diseases may be recognized.     

Complement deficiency and immune complex disease

Conclusions Study of patients with complement deficiency has supplied important insights into the physiological importance of this component of the innate immune system. The most surprising finding to emerge from the study of such patients is the strong link between deficiencies of classical pathway proteins and susceptibility to SLE. This observation has stimulated many studies into the relationship between the complement system and processing mechanisms for immune complexes, which we have reviewed in this chapter. Although it is clear that complement deficiency is associated with several abnormalities of immune complex processing in vivo, the challenge still remains to provide a convincing link between these and the development of SLE.     

Weber-Christian panniculitis with immune complex glomerulonephritis

The etiology of Weber-Christian panniculitis is unknown. A case is presented in which an association is found between immune complex glomerulonephritis and a relapse of Weber-Christian panniculitis. This case adds to the literature, implicating immune system dysfunction in the pathophysiology of this disease.     

Morphogenesis of immune complex glomerulonephritis]

Morphological changes in the kidneys in nonspecific ulcerative colitis were studied and the following variants of the kidney involvement were established: (1) allergic changes manifested by membraneous and mesangio-proliferative glomerulonephritis, renal vasculitis, phenomena of stromal desorganization with lymphoid and histiocyte infiltrations; (2) metabolic changes manifested by various kinds of degeneration of the tubular apparatus including changes typical of potassium-deficient nephropathy; (3) toxic -- necrotic nephrosis and (4) infectious -- nonsuppurative and suppurative interstitial nephritis.     

The immune complex: possible ways of regulating the antibody response

B cells express antigen, Fc and complement receptors on their surfaces and can thus bind all three components of an immune complex. In addition to the direct effects that they exert on cells, immune complexes may affect localization, presentation and digestion of antigen. In this article, Birgitta Heyman discusses recent developments in antibody-mediated regulation of the humoral immune response, with emphasis on in vivo systems where antigens are injected together with highly purified IgM or IgG antibodies in the absence of adjuvants.     

The pathogenetic role of free-circulating antibody in autologous immune complex glomerulonephritis

Autologous immune complex glomerulonephritis is an established model of chronic glomerulonephritis which very closely resembles membranous glomerulopathy in man. The disease can be induced in certain rat strains by immunization with tubular brush-border antigen (FxlA) in Freund's complete adjuvant. This procedure is believed to result in circulating immune complexes consisting of anti-FxlA antibody and FxlA antigen, which are deposited along the glomerular basement membrane. Since previous studies have indicated the presence of FxlA antigen in the glomerular basement membrane of normal rat and suggested an in situ formation of immune aggregates at this site as the pathogenetic mechanism in heterologous immune complex glomerulonephritis, the validity of the same mechanism in the pathogenesis of autologous immune complex glomerulonephritis was studied. In an investigation into the pathogenesis of the this model an association was found between the serum titre of autologous anti-FxlA antibody and the presence of immune aggregates in the glomerular basement membrane. Unilateral perfusion of normal kit kidneys with IgG eluted from kidneys of rats with autologous immune complex glomerulonephritis resulted in a binding of autologous anti-FxlA antibody at the subepithelial side of the glomerular basement membrane. These results indicate a pathogenetic role for circulating anti-FxlA antibody and demonstrate that rat anti-FxlA antibody is able to bind to FxlA antigens present in the glomerular basement membrane. Although these experiments do not exclude a possible role for circulating immune complexes, a pathogenetic mechanism of in situ formation of subepithelial immune aggregates in autologous immune complex glomerulonephritis is strongly suggested.     

The role of H-2 in apoferritin-induced murine immune complex glomerulonephritis

The role of the major histocompatibility complex in the development of apoferritin induced immune complex glomerulonephritis was studied in H-2 congenic B10 mice. The glomerular lesions varied strikingly among the three different strains studied. The B10 (H-2b) mice had minimal mesangial expansion or no lesions at all. The B10.BR (H-2k) mice had mesangial expansion and proliferative glomerulonephritis without crescents or interstitial mononuclear cell infiltration. In contrast, the B10.D2 (H-2d) mice had necrotizing glomerulonephritis with crescents and an interstitial mononuclear cell infiltrate. Immunofluorescence and electron microscopy demonstrated only minimal mesangial deposits in B10 (H-2b) mice, predominantly mesangial deposition in the B10.BR (H-2k) mice, and mesangial and subepithelial immune complex deposits in B10.D2 (H-2d) mice. These morphologic differences correlated with functional abnormalities. Only the B10.D2 (H-2d) mice developed proteinuria, hematuria, and elevated blood urea nitrogen. They also had the most elevated antiapoferritin IgG levels. These experiments demonstrate that differences in the pathologic lesions and susceptibility to immune complex glomerulonephritis can be seen in animals that differ only at the H-2 locus. This model will lend itself to the study of the mechanisms by which the major histocompatibility complex influences the development of immune complex glomerulonephritis.