Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice

Francesca Menconi, Maria C. Monti, David A. Greenberg, Taiji Oashi, Roman Osman, Terry F. Davies, Yoshiyuki Ban, Eric M. Jacobson, Erlinda S. Concepcion, Wun Li Cheuk, Yaron Tomer

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still controversial. We hypothesized that specific HLA-DR pocket-sequence variants are associated with HT and that similar variants in the murine I-E locus (homologous to HLA-DR) predispose to experimental autoimmune thyroiditis (EAT), a classical mouse model of HT. Therefore, we sequenced the polymorphic exon 2 of the HLA-DR gene in 94 HT patients and 149 controls. In addition, we sequenced exon 2 of the I-E gene in 22 strains of mice, 12 susceptible to EAT and 10 resistant. Using logistic regression analysis, we identified a pocket amino acid signature, Tyr-26, Tyr-30, Gln-70, Lys-71, strongly associated with HT (P = 6.18 × 10-5, OR = 3.73). Lys-71 showed the strongest association (P = 1.7 × 10-8, OR = 2.98). This association was seen across HLA-DR types. The 5-aa haplotype Tyr-26, Tyr-30, Gln-70, Lys-71, Arg-74 also was associated with HT (P = 3.66 × 10-4). In mice, the I-E pocket amino acids Val-28, Phe-86, and Asn-88 were strongly associated with EAT. Structural modeling studies demonstrated that pocket P4 was critical for the development of HT, and pockets P1 and P4 influenced susceptibility to EAT. Surprisingly, the structures of the HT-and EAT-susceptible pockets were different. We conclude that specific MHC II pocket amino acid signatures determine susceptibility to HT and EAT by causing structural changes in peptide-binding pockets that may influence peptide binding, selectivity, and presentation. Because the HT- and EAT-associated pockets are structurally different, it is likely that distinct antigenic peptides are associated with HT and EAT.

Original languageEnglish (US)
Pages (from-to)14034-14039
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number37
DOIs
StatePublished - Sep 16 2008

Keywords

  • Gene
  • HLA
  • Hashimoto's thyroiditis
  • Major histocompatibility complex

ASJC Scopus subject areas

  • General

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