Molecular mechanisms underlying HLA-DR-associated susceptibility to autoimmunity.
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 alpha 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.
Matsushita
S
S
Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, Japan.
Fujisao
S
S
Nishimura
Y
Y
D000595:Amino Acid Sequence / Q000235:genetics; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D002461:Cell Line, Transformed; D004198:Disease Susceptibility / Q000276:immunology; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000276:immunology; D007564:Japan; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D013625:Takayasu Arteritis / Q000235:genetics* / Q000276:immunology
D001324:Autoantigens; D006684:HLA-DR Antigens; D007328:Insulin; D010446:Peptide Fragments