The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture's disease

Abstract

Goodpasture's disease is closely associated with HLA, particularly DRB1*1501. Other susceptible or protective HLA alleles are not clearly elucidated. The presentation models of epitopes by susceptible HLA alleles are also unclear. We genotyped 140 Chinese patients and 599 controls for four-digit HLA II genes, and extracted the encoding sequences from the IMGT/HLA database. T-cell epitopes of α3(IV)NC1 were predicted and the structures of DR molecule-peptide-T-cell receptor were constructed. We confirmed DRB1*1501 (OR = 4·6, P = 5·7 × 10^-28 ) to be a risk allele for Goodpasture's disease. Arginine at position 13 (ARG13) (OR = 4·0, P = 1·0 × 10^-17 ) and proline at position 11 (PRO11) (OR = 4·0, P = 2·0 × 10^-17 ) on DRβ1, encoded by DRB1*1501, were associated with disease susceptibility. α_134-148 (HGWISLWKGFSFIMF) was predicted as a T-cell epitope presented by DRB1*1501. Isoleucine₁₃₇ , tryptophan₁₄₀ , glycine₁₄₂ , phenylalanine₁₄₃ and phenylalanine₁₄₅ , were presented in peptide-binding pockets 1, 4, 6, 7 and 9 of DR2b, respectively. ARG13 in pocket 4 interacts with tryptophan₁₄₀ and forms a hydrogen bond. In conclusion, we propose a mechanism for DRB1*1501 susceptibility for Goodpasture's disease through encoding ARG13 and PRO11 on MHC-DRβ1 chain and presenting T-cell epitope, α_134-148 , with five critical residues.

Keywords: HLA; MHC; Goodpasture's disease; anti- glomerular basement membrane disease; epitope.