In Situ Formation of Immune Complexes and the Role of Complement Activation in Glomerulonephritis

Abstract

Most forms of immunologically mediated human renal disease are associated with deposits of immunoglobulin in granular immune complex form in renal glomeruli. These deposits may develop in a subepithelial, subendothelial, mesangial or mixed distribution. The histological, immunopathological and functional equivalents of these human immune complex nephropathies can be produced experimentally by the production of immune complex deposits in situ, either as a consequence of antibody binding to several cell or basement membrane antigens or through initial localization of an antigen or antibody followed by immune complex formation at the site of tissue injury. Several mechanisms can lead to in situ immune complex formation including electrical interactions between capillary wall anionic sites and oppositely charged antigens or antibodies, glomerular localization of non-immune cationic proteins followed by binding of anionic antigens or antibodies, chemical affinity between certain antigens and structural components of the glomerulus itself and mesangial uptake of circulating antigenic macromolecules. Local immune complex formation appears to be the predominant mechanism which leads to subepithelial immune complex deposits, whereas subendothelial and mesangial deposits may result from either local deposit formation or preformed immune complex trapping.

When antigen and antibody combine to form immune complexes within the glomerulus, complement activation is a major mechanism which leads to immune tissue injury. When complement is activated at an in-tramembranous, subendothelial or mesangial site, neutrophils recruited through immune adherence or chemotactic mechanisms usually participate in causing the injury that results. However, recent studies document an important role for a C5b-9 complement membrane attack (CMA) complex mechanism in producing antibody-mediated glomerular disease, particularly that associated with subepithelial immune complex deposits. The mechanism by which C5b-9 induces glomerular damage has not been defined but may involve a non-lytic effect on glomerular cell metabolism leading ultimately to an altered glomerular permeability to proteins.