Autoepitopes and alloepitopes of type IV collagen: Role in the molecular pathogenesis of anti-GBM antibody glomerulonephritis

Anti-glomerular basement membrane (anti-GBM) antibodies elicited by autoimmune or alloimmune mechanisms are associated with aggressive forms of rapid progressive glomerulonephritis. Pathogenic anti-GBM autoantibodies and alloantibodies target the noncollagenous (NC1) domains of the alpha 3 alpha 4 alpha 5(IV) collagen, a major GBM component. In autoimmune anti-GBM glomerulonephritis, a breakdown of immune self-tolerance leads to the activation of autoreactive B and T cells recognizing epitopes within the alpha 3NC1 subunit. In the GBM, the conformational epitopes targeted by anti-GBM autoantibodies are structurally sequestered within the alpha 3 alpha 4 alpha 5NC1 hexamer complex formed upon assembly of collagen IV chains into trimeric molecules and networks. Autoantibodies selectively bind to and dissociate a subset of alpha 3 alpha 4 alpha 5NC1 hexamers composed of monomer subunits, whereas hexamers containing NC1 dimer subunits are resistant to dissociation by autoantibodies. The crypticity of alpha 3NC1 autoepitopes suggests that self-tolerance to alpha 3(IV) collagen is broken by structural alterations of the native alpha 3 alpha 4 alpha 5NC1 hexamer that unmask normally sequestered epitopes, triggering an autoimmune reaction. Post-transplant anti- GBM nephritis in the renal allograft of transplanted Alport patients is mediated by an alloimmune reaction to the NC1 domains of alpha 3 alpha 4 alpha 5(IV) collagen, present in the allograft GBM but absent from Alport basement membranes. Alloantibodies from patients with autosomal-recessive Alport syndrome predominantly bind to the alpha 3NC1 domain, whereas alloantibodies from X-linked Alport patients target preferentially, though not exclusively, epitopes within the alpha 5NC1 subunit. The accessibility of the alloantigenic sites within the alpha 3 alpha 4 alpha 5NC1 hexamers, contrasting with the crypticity of autoantigenic sites, suggest that different molecular forms of alpha 3 alpha 4 alpha 5( IV) collagen initiate the immunopathogenic responses in the two forms of anti- GBM disease. Advances in elucidating the structure of the GBM antigen and the identification of the pathogenic B and T cell epitopes, along with new insights into the pathogenic mechanisms at cellular and molecular level will facilitate the development of targeted strategies for prevention, detection, and treatment of human anti- GBM antibody glomerulonephritis. Copyright (c) 2007 S. Karger AG, Basel.