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

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 HTand 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 peptidebinding 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.gene ͉ Hashimoto's thyroiditis ͉ HLA ͉ major histocompatibility complex H ashimoto's thyroiditis (HT) is among the most common human autoimmune diseases with a population prevalence in the United States of 1-4.6% (1, 2). HT is characterized by infiltration of the thyroid by autoreactive T and B cells causing thyroid cell death and production of anti-thyroid peroxidase (TPO) and antithyroglobulin (Tg) antibodies (reviewed in ref.3). Clinically, the disease manifests by hypothyroidism requiring thyroid hormone supplementation, and most patients develop goiter. The pathogenesis of HT is believed to involve a complex interaction between inborn genetic susceptibility (reviewed in ref. 4) and an external trigger such as infection (5) or iodine (6). As a result, thyroidspecific T cells become activated and infiltrate the thyroid. The thyroid-infiltrating T cells induce thyroid cell death, causing gradual destruction of the thyroid gland, hypothyroidism, and goiter (reviewed in ref.3).The MHC gene locus encoding the HLA glycoproteins in humans consists of a complex of genes located on chromosome 6p21 (reviewed in ref. 4). Because the HLA region is highly polymorphic and contains many immune response genes, it was the first candidate genetic region to be studied for association with HT. However, in contrast to the clear association of Graves' disease (GD) with HLA-DR3, data on HL...

An overview of the pathogenic mechanisms of autoimmune thyroid disorders

“…This thyroid autoimmunity model is Major Histocompatibility Complex (MHCⅡ) restricted, but occurs independently from mature B cells and antibodies. 16,24 Moving from these experiments in mice, the group of Schott recently studied TPO-and Tg epitope- this study supports the view that in HT a combined TPOand T-specific cytotoxic immnune response does occur. 25 In the last few years, evidence was also accumulated supporting the concept that INF-γ inducible chemokines, such as CXCL10, play an important role in the initial stages of thyroid autoimmunity.…”

Association of CTLA-4 gene polymorphisms −318C/T and +49A/G and Hashimoto's thyroidits in Zahedan, Iran

“…These genes may be considered as susceptibility factors for autoimmune thyroiditis. The main candidates in this category are the genes human leukocyte antigen (HLA)-death receptor (DR)3, HLA-DR4, HLA-DR5, cytotoxic T-lymphocyte antigen-4 (CTLA-4), protein tyrosine phosphatase, non-receptor type 22, CD40, CD25, Fc Receptor Like 3 and forkhead box P3 (16,17).…”

Hashimoto's Disease

“…**: The studied sample in Tunisian population is "Akr" family (Tandon et al, 1991). Interestingly, it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide-binding pocket is a key to the etiology of both GD and HT (Ban et al, 2004;Menconi et al, 2008).…”