Susceptibility to anti-glomerular basement membrane disease is strongly associated with HLA-DRB1 genes

Anti-glomerular basement membrane (anti-GBM) disease is caused by autoimmunity to a component of glomerular basement membrane. The major autoantigen has been identified as the NC1 domain of the alpha 3 chain of type IV collagen, and patients are characterized by the presence of specific autoantibodies to this molecule. In common with other autoimmune disorders, there is a strong association with HLA genes, with up to 80% of patients inheriting an HLA-DR2 haplotype. To examine the genetic 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 association of DRB1 genes with anti-GBM disease, including susceptibility (DRB1*15, DRB1*04), neutral (DRB1*03) and protective (DRB1*07) alleles. Analysis of inherited haplotypes, particularly DRB1*04 and DRB1*07 carrying haplotypes, provided further evidence that the primary association was with genes at the DRB1 locus. Comparison of the sequences of the positively and negatively associated alleles showed that polymorphic residues in the second peptide binding region of the HLA Class II antigen binding groove segregated with disease. This work supports the hypothesis that the HLA associations in anti-GBM disease reflect the ability of certain Class II molecules to bind and present peptides derived from the autoantigen to T helper cells.