SUSCEPTIBILITY TO ANTIGLOMERULAR BASEMENT-MEMBRANE DISEASE IS STRONGLY ASSOCIATED WITH HLA-DRB1 GENES

Anti-glomerular basement membrane (anti-GBM) disease is caused by auto immunity to a component of the glomerular basement membrane. The major autoantigen has been identified as the NC1 domain of the alpha 3 chai n of type IV collagen, and patients are characterized by the presence of specific autoantibodies to this molecule. In common with other auto immune disorders, there is a strong association with HLA genes, with u p to 80% of patients inheriting an HLA-DR2 haplotype. To examine the g enetic basis of susceptibility to anti-GBM disease in more detail, the HLA-DRB and DQB alleles inherited by 82 patients were analyzed using sequence specific oligonucleotides. This identified a hierachy of asso ciation of DRB1 genes with anti-GBM disease, including susceptibility (DRB115, DRB1*04), neutral (DRB1*03) and protective (DRB1*07) alleles . Analysis of inherited haplotypes, particularly DRB104 and DRB1*07 c arrying haplotypes, provided further evidence that the primary associa tion was with genes at the DRB1 locus. Comparison of the sequences of the positively and negatively associated alleles showed that polymorph ic residues in the second peptide binding region of the HLA Class II a ntigen binding groove segregated with disease. This works supports the hypothesis that the HLA associations in anti-GBM disease reflect the ability of certain Class II molecules to bind and present peptides der ived from the autoantigen to T helper cells.