Update on antiglomerular basement membrane disease

Abstract

Antiglomerular basement membrane (GBM) disease is a rare form of autoimmune glomerulonephritis often accompanied by lung haemorrhage and characterized by circulating and deposited antibodies that bind basement membrane type IV collagen antigens in the glomerulus and lung alveolus. We review recent findings regarding disease pathogenesis and therapy. The target autoantigens are the noncollagenous (NC1) regions of the α3 and to a lesser extent the α5-chains of type IV collagen, which are exposed following disruption of the α3-α4-α5 collagen heterotrimer allowing autoantibody binding. In addition, antigen-specific T cells are found in the circulation of acute patients at higher frequencies than in healthy controls. These are prevented from inducing damage in healthy individuals or during disease remission, by α3(IV)NC1-specific Treg and possibly through destructive antigen processing of autoreactive peptides. Drugs inducing lymphocyte depletion, such as alemtuzumab, may disrupt these natural lymphocyte regulatory processes and promote disease. With regards to therapy, few advances have been made, with the exception of isolated case reports of the use of rituximab and mycophenolate mofetil in resistant disease. Immunity towards the α3(IV) NC1 is effectively regulated in health but conformational changes in the antigen, alterations in its processing, modifications of B cells and Tregs, following certain environmental events, in susceptible individuals, promote disease induction.