Susceptibility to Thyroid Autoimmune Disease: Molecular Analysis of HLA-D Region Genes Identifies New Markers for Goitrous Hashimoto's Thyroiditis

Badenhoop, Klaus; Schwarz, G.; Walfish, P. G.; Drummond, V.; Usadel, K. H.; Bottazzo, G. F.

doi:10.1210/jcem-71-5-1131

Cited by 80 publications

(39 citation statements)

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“…Many of the immunological diseases that occur with AIH, namely autoimmune thyroiditis, RA, Sjogren's syndrome and IBD have been associated with this extended haplotype [30][31][32][33][34][35][36] . The clustering of the CAIDs in AIH may suggest the shared genetic and immunological susceptibility [37,38] .…”

Section: Effects Of Aih Types Age Gender and Genetic Backgroundmentioning

confidence: 99%

Association of Extrahepatic Manifestations with Autoimmune Hepatitis

Wong

Heneghan²

2015

Dig Dis

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For many patients with autoimmune hepatitis (AIH), the presence of extrahepatic features is well recognised both at the time of presentation and during long-term follow-up. Concomitant ‘autoimmune disorders' have been described in 20-50% of patients with AIH, both in adults and children. Indeed, the presence of these associated phenomena has been incorporated into both the original and revised International AIH group scoring systems as an aid to codifying the diagnosis. In acute index presentations, non-specific joint pains sometimes flitting in nature have been reported in 10-60% of patients, and while joint swelling is uncommon, rheumatoid arthritis and mixed connective tissue disease have been reported in 2-4% of patients with AIH. For a majority of patients, these joint symptoms resolve within days of the introduction of immunosuppressive therapy. Rarer features at index presentation include a maculopapular skin rash and unexplained fever, which are features that tend to resolve quickly with treatment. Interestingly, joint pain and stiffness are also well recognised in the context of steroid withdrawal and cessation in AIH. The occasional co-presentation of AIH with coeliac disease is clinically important (1-6%), since for some patients, there is a risk of immunosuppression malabsorption, thus delaying effective treatment. Similarly, the co-existence of selective IgA deficiency (IgAD) can occur in patients with coeliac disease or in isolation. Selective IgAD as a co-existing extraheaptic feature seems to be more common in paediatric patients with AIH. For these patients, they are at an increased risk of respiratory and sinus infections. Although, typically associated with primary sclerosing cholangitis, the presence of inflammatory bowel disease (IBD; both Crohn's disease and ulcerative colitis) has been described in 2-8% of patients with AIH. Interestingly, for patients with autoimmune sclerosing cholangitis, a distinct pattern of IBD has been recently described. Other conditions have been reported at a lower frequency, including Sjogren's syndrome 1-7%, systemic lupus erythematosus 1-3% and glomerulonephritis 1%. Rarer still and at a frequency of <1% include fibrosing alveolitis, haemolytic anaemia, uveitis, mononeuritis multiplex, polymyositis and multiple sclerosis. In contrast, the reported associations between AIH and thyroiditis 8-23%, diabetes 1-10% and psoriasis 3% are commonly seen and notable in clinical practice.

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Section: Effects Of Aih Types Age Gender and Genetic Backgroundmentioning

confidence: 99%

Association of Extrahepatic Manifestations with Autoimmune Hepatitis

Wong

Heneghan²

2015

Dig Dis

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“…Earlier studies showed an association of goitrous HT with HLA-DR5 and of atrophic HT with HLA-DR3 [36,37]. Later studies have reported association of HT with HLA-DR3, HLA-DR4, or HLA-DR5 in Caucasian patients [38][39][40][41][42]. However, a recent study has shown that a molecular signature of HLA-DR pocket, determined by specific amino acids, confers a significant risk for the development of HT across HLA-DR alleles [35,43].…”

Section: Etiology and Genetics Of Htmentioning

confidence: 99%

IgG4-related disease of the thyroid glands [Review]

Kakudo

Taniguchi

et al. 2012

Endocr J

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Abstract. Recent reports on Hashimoto's thyroiditis (HT) with increased numbers of IgG4-positive plasma cells suggest that this type of HT may have a close relationship to IgG4-related disease (IgG4-RD). This unique subgroup of HT is termed as IgG4 thyroiditis and reveals distinct clinical, serological, and sonographic features from the non-IgG4 thyroiditis group. On the basis of immunostaining for IgG4, HT was divided into an IgG4 thyroiditis group and a non-IgG4 thyroiditis group. Clinically, IgG4 thyroiditis was associated with younger age group, lower female-male ratio, higher levels of thyroid autoantibodies, diffuse low echogenicity, more rapid progress requiring surgical treatment and more subclinical hypothyroidism. Serum IgG4 concentrations elevated in IgG4 thyroiditis and decreased significantly after a thyroidectomy. Histopathologically, IgG4 thyroiditis showed a higher grade of stromal fibrosis, lymphoplasmacytic infiltration, and follicular cell degeneration than non-IgG4 thyroiditis. IgG4 thyroiditis may represent IgG4-RD of thyroid gland, because it shares common histopathological characteristics with IgG4-RD in other organs. The identification of IgG4-RD of the thyroid gland opens new insights not only for patient's treatment with HT but also for the development of new therapeutic approaches for this rapidly progressive destructive subtype of HT. This article mainly focuses on reviewing the unique histopathological, clinical, and serological features of IgG4 thyroiditis group of HT. The etiology and genetic changes of HT are also discussed.

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“…Early studies showed an association of goitrous HT with HLA-DR5 (7) and of atrophic HT with -DR3 (8). Later studies have reported associations of HT with HLA-DR3 (9, 10), -DR4 (11,12), or -DR5 (13) in Caucasians. The prevalent assumption is that these discrepancies are caused by the wide variation in the diagnostic criteria for HT ranging from the simple presence of thyroid autoantibodies with focal lymphocytic infiltration to the presence of goitrous or atrophic thyroiditis characterized by gross thyroid failure (14).…”

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confidence: 99%

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

Menconi

Monti

Greenberg

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Susceptibility to Thyroid Autoimmune Disease: Molecular Analysis of HLA-D Region Genes Identifies New Markers for Goitrous Hashimoto's Thyroiditis

Cited by 80 publications

References 0 publications

Association of Extrahepatic Manifestations with Autoimmune Hepatitis

Association of Extrahepatic Manifestations with Autoimmune Hepatitis

IgG4-related disease of the thyroid glands [Review]

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

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