Molecular characterization of the target antigens of anti-glomerular basement membrane antibody disease.

The abnormal immune response to renal antigens is a significant cause of progressive glomerulonephritis and end-stage renal disease, leading to the need for dialysis or kidney transplantation. Type IV collagen of the glomerular basement membrane (GBM), an important component of the blood filtration barrier, is the target of pathogenic antibodies in two forms of anti-GBM antibody nephritis. Type IV collagen is a family of six chains that assemble into three networks with distinct composition and tissue-specific distribution. The GBM contains an alpha3.alpha4.alpha5(IV) network essential for the maintenance of kidney ultrafiltration function: the absence of this network in patients with Alport's syndrome leads to progressive glomerulonephritis. In some Alport patients that receive a kidney transplant, anti-GBM alloantibodies develop against the non-collagenous (NC1) domains of the alpha3.alpha4.alpha5(IV) collagen network, which is present in the renal allograft but absent in the Alport kidneys, causing Alport post-transplant nephritis. In Goodpasture's (GP) syndrome, anti-GBM autoantibodies target the NC1 domain of the alpha3 (IV) chain in the GBM, causing rapidly progressing glomerulonephritis. The GP epitopes have been localized to two homologous regions of the alpha3 NC1 domain, E(A) and E(B), and several populations of autoantibodies with distinct epitope specificity were purified and characterized. The epitopes of GP autoantibodies are sequestered in the NC1 hexamer that connects two adjoining triple-helical molecules. Hydrophobic amino acids have been identified in the epitope of the immunodominant GP(A) autoantibodies, suggesting that the cryptic nature of the GP epitopes is due to interactions among NC1 domains in the NC1 hexamer. Experimental anti-GBM nephritis can be induced in animal models by passive transfer of anti-GBM antibodies or by active immunization with NC1 domains of the alpha3.alpha4.alpha5(IV) network.