Molecular mechanisms underlying HLA-DR-associated susceptibility to autoimmunity

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We analyzed structural motifs of peptides bound to HLA-DR4 (DRB1 *0405 and DRB1 *0406) and DR9 (DRB1 *0901) and found that: (a) AxxBxC motif where A, B, and C are hydrophobic, hydrophobic, and neutral, respectively, is important for binding to DR4; (b) Gln (Q) or Ser at position C allow high-affinity binding specific to DRB1 *0406 which is strongly associated with insulin autoimmune syndrome; (c) among human insulin-derived peptide fragments, the TSICSLYQLE of the human insulin α chain, which is exposed only under reducing conditions, has the highest affinity specific to DRB1*0406 by binding with the IxxLxQ motif; (d) a short-term human insulin-specific T cell line recognizes a peptide fragment containing the IxxLxQ motif as a major T cell epitope; and (e) in the AxxB motif, where A and B need to be hydrophobic for binding to DR9, neutral Ser is exceptionally allowed at position B. The implications of our results are discussed in light of the HLA-DR4-associated susceptibility to insulin autoimmune syndrome and HLA-DR9-associated susceptibility to juvenile-onset myasthenia gravis and systemic lupus erythematosus with antiphospholipid syndrome, in particular T cell responses to autoantigens.