Negatively-charged amino acids at the peptide-binding pocket of HLA-DPB1 alleles are associated with susceptibility to anti-topoisomerase I-positive systemic sclerosis.

We investigated shared characteristics of amino acid sequences in the at risk HLA-DPB1 alleles in systemic sclerosis (SSc). Amino acid sequences and their structural features of HLA-DP molecules in 127 Korean SSc patients and 548 healthy Korean controls were analyzed with a focus on known HLA-DP binding motifs. The binding grooves containing more negatively-charged triplets (NCT) had higher odds ratios of anti-topoisomerase I antibody (ATA)-positive SSc. In particular, the co-existence of a NCT at position 82-85 and more than one additional NCT were critical for increased risk of ATA-positive SSc. Molecular dynamic simulations showed that the model peptide with positive charge from topoisomerase I fits more closely into HLA-DP alleles possessing more NCTs. ATA-positive SSc patients share NCTs at the peptide-binding groove of HLA-DPB1 molecules.