Type 1 diabetes (T1D) and autoimmune thyroid diseases (AITD) frequently occur together within families and in the same individual. The co-occurrence of T1D and AITD in the same patient is one of the variants of the autoimmune polyglandular syndrome type 3 [APS3 variant (APS3v)]. Epidemiological data point to a strong genetic influence on the shared susceptibility to T1D and AITD. Recently, significant progress has been made in our understanding of the genetic association between T1D and AITD. At least three genes have been confirmed as major joint susceptibility genes for T1D and AITD: human leukocyte antigen class II, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22. Moreover, the first whole genome linkage study has been recently completed, and additional genes will soon be identified. Not unexpectedly, all the joint genes for T1D and AITD identified so far are involved in immune regulation, specifically in the presentation of antigenic peptides to T cells. One of the lessons learned from the analysis of the joint susceptibility genes for T1D and AITD is that subset analysis is a key to dissecting the etiology of complex diseases. One of the best demonstrations of the power of subset analysis is the CTLA-4 gene in T1D. Although CTLA-4 showed very weak association with T1D, when analyzed in the subset of patients with both T1D and AITD, the genetic effect of CTLA-4 was significantly stronger. Gene-gene and genetic-epigenetic interactions most likely play a role in the shared genetic susceptibility to T1D and AITD. Dissecting these mechanisms will lead to a better understanding of the etiology of T1D and AITD, as well as autoimmunity in general.
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...
In spite of the advancements in understanding the pathogenic mechanisms of Graves' disease (GD), its ultimate cause remains elusive. The majority of investigators agree that GD is likely a multifactorial disease, due to a complex interplay of genetic and non-genetic factors that lead to the loss of immune tolerance to thyroid antigens and to the initiation of a sustained autoimmune reaction. Twin and family studies support a role of genetic factors, among which the HLA complex, CD40, CTLA-4, PTPN22, FCRL3, thyroglobulin, and the TSH receptor may be involved. Among non-genetic factors, iodine, infections, psychological stress, gender, smoking, thyroid damage, vitamin D, selenium, immune modulating agents, and periods of immune reconstitution may contribute the development of the diseases. Here we review in detail the respective role of genetic and non-genetic factors in the etiology of GD, taking advantage of the great bulk of data generated especially over the past 30 years.
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