Cell mediated injury in autoimmune anti-glomerular basement membrane disease is defined by a critical T cell epitope in humanized mice (123.33)

Abstract

Abstract Human anti-glomerular basement membrane (GBM) disease has strong associations with HLA DRB1*1501. The target autoantigen is the non-collagenous domain of the α3 chain of Type IV collagen, α3(IV)NC1. T cell epitopes of α3(IV)NC1 were identified by immunizing mouse MHC-/-, HLA DRB1*1501 transgenic (1501tg) mice with overlapping 20mers. They defined a HLA DRB1*1501 restricted epitope (aa128-147) not reactive in HLA DRB1*0101 transgenic (0101tg) or C57BL/6 mice. 1501tg mice were immunized with α1(IV)NC1, α3(IV)NC1 or α1/α3 chimeric molecules, made by inserting the α3 aa17-31 (C2) or aa127-141 (C6) into the non-immunogenic α1 backbone. 1501tg mice immunized with α3(IV)NC1 or C6 responded to aa128-147 but not to aa8-27, but α1(IV)NC1 or C2-immunized mice did not respond to either peptide. CD4+ T cell clones, made from 1501tg mice and transferred into naive 1501tg mice, induced disease with necrotizing and crescentic glomeruli, albuminuria and renal failure, and glomerular CD4+ T cell and macrophage infiltrates. To determine if immunization with the restricted epitope causes disease, 1501tg or 0101tg mice were crossed with FcγRIIB-/- mice (Fcγ receptors are implicated in disease susceptibility). Immunization with either whole α3(IV)NC1 or the identified restricted epitope induced glomerulonephritis in 1501tg.FcγRIIB-/- mice but not in 0101tg.FcγRIIB-/- mice. These studies demonstrate that T cell responses in anti-GBM disease are defined by a HLA DRB1*1501 restricted T cell epitope.