HLA alleles, especially amino-acid signatures of HLA-DPB1, might contribute to the molecular pathogenesis of early-onset autoimmune thyroid disease

Background: Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto thyroiditis (HT), which partially share immunological features. Determining the genetic basis that distinguishes GD and HT is a key to understanding the differences between these 2 related diseases. Aim: The aims of this study were to identify HLA antigens that can explain the immunopathological difference between GD and HT and to elucidate epistatic interactions between protective and susceptible HLA alleles, which can delineate the distinct function of HLA in AITD etiology. Design: We genotyped 991 patients with AITD (547 patients with GD and 444 patients with HT) and 481 control subjects at the HLA-A, HLA-C, HLA-B, DRB1, DQB1, and DPB1 loci. A direct comparison of HLA antigen frequencies between GD and HT was performed. We further analyzed an epistatic interaction between the susceptible and protective HLA alleles in the development of GD and HT. Results: We identified 4 and 2 susceptible HLA molecules primarily associated with GD and HT, respectively, HLA-B*35:01, HLA-B*46:01, HLA-DRB1*14:03, and HLA-DPB1*05:01 for GD and HLA-A*02:07 and HLA-DRB4 for HT. In a direct comparison between GD and HT, we identified GD-specific susceptible class II molecules, HLA-DP5 (HLA-DPB1*05:01; Pc = 1.0 × 10−9) and HLA-DR14 (HLA-DRB*14:03; Pc = .0018). In contrast, HLA components on 3 common haplotypes in Japanese showed significant protective effects against the development of GD and HT (HLA-A*24:02-C*12:02-B*52:01-DRB1*15:02-DQB1*06:01-DPB1*09:01 and HLA-A*24:02-C*07:02-B*07:02-DRB1*01:01-DQB1*05:01-DPB1*04:02 haplotypes for GD and HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01 haplotype for GD and HT). Interestingly, the representative protective HLA, HLA-DR13 (HLA-DRB1*13:02), was epistatic to susceptible HLA-DP5 in controlling the development of GD. Conclusion: We show that HLA exerts a dual function, susceptibility and resistance, in controlling the development of GD and HT. We also show that the protective HLA allele is partially epistatic to the susceptible HLA allele in GD.

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Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2434175100 ◽

2003 ◽

Vol 100 (25) ◽

pp. 15119-15124 ◽

Cited By ~ 123

Author(s):

Y. Ban ◽

D. A. Greenberg ◽

E. Concepcion ◽

L. Skrabanek ◽

R. Villanueva ◽

...

Keyword(s):

Amino Acid ◽

Thyroid Disease ◽

Autoimmune Thyroid Disease ◽

Amino Acid Substitutions ◽

Autoimmune Thyroid ◽

Thyroglobulin Gene

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Antibody-induced modulation of TSH receptor post-translational processing

Journal of Endocrinology ◽

10.1677/joe-07-0058 ◽

2007 ◽

Vol 195 (1) ◽

pp. 179-186 ◽

Cited By ~ 13

Author(s):

Takao Ando ◽

Rauf Latif ◽

Terry F Davies

Keyword(s):

Amino Acid ◽

Thyroid Function ◽

Thyroid Disease ◽

Antigen Processing ◽

Autoimmune Thyroid Disease ◽

Neutral Type ◽

Tsh Receptor ◽

Neutral Group ◽

Α Subunit ◽

Autoimmune Thyroid

The post-translational processing of the TSH receptor (TSHR) includes intra-molecular cleavage with the loss of a 50 amino acid ectodomain region and the formation of two subunits (α and β), followed by likely α subunit shedding. TSHR antibodies (TSHR-Abs), which are directed at the ectodomain, may influence thyroid function by stimulating or inhibiting TSHR signaling or may bind without any such influence (the neutral group of antibodies). When we examined the characteristics of a series of monoclonal TSHR-Abs, we found that many were able to inhibit receptor cleavage and enhance TSHR expression. This was especially apparent with the neutral type of TSHR-Abs directed to the cleaved region of the ectodomain (aa 316–366). Indeed, such inhibition appeared to be epitope dependent with TSHR-Abs directed to regions after residues 335–354 showing no such activity. We propose that this aberrant process, whereby TSHR-Abs influence antigen processing, is a novel mechanism for the maintenance and exacerbation of autoimmune thyroid disease.

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Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458516638558 ◽

2016 ◽

Vol 22 (9) ◽

pp. 1235-1241 ◽

Cited By ~ 8

Author(s):

Mark Obermann ◽

Tobias Ruck ◽

Steffen Pfeuffer ◽

Julia Baum ◽

Heinz Wiendl ◽

...

Keyword(s):

Multiple Sclerosis ◽

Thyroid Disease ◽

Early Onset ◽

Immune Thrombocytopenia ◽

Autoimmune Thyroid Disease ◽

Severe Thrombocytopenia ◽

Autoimmune Thyroid ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Objective: We report two cases of patients with relapsing-remitting multiple sclerosis with early-onset thrombocytopenia and autoimmune thyroid disease after the first treatment course with 60-mg alemtuzumab. Methods: Case series and review of the literature. Results: Both patients showed severe thrombocytopenia with platelet counts of 2 × 109 and 11 × 109/L, respectively, as well as increased thyroid antibodies within only a few months after initiating alemtuzumab treatment (11 and 9 months). Both patients responded considerably well to medical therapy including corticosteroids and intravenous immunoglobulins with slow platelet recovery over several weeks. Interestingly, both patients were previously treated with fingolimod and showed a marked lymphocytopenia that led to discontinuation. Conclusion: These cases emphasize the necessity of careful clinical surveillance and proper education of patients treated with alemtuzumab as proposed by the safety-monitoring program. Previous severe lymphocytopenia under therapy with other disease-modifying therapies may be a risk factor for the development of immune thrombocytopenia.

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New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

The Journal of Immunology ◽

10.4049/jimmunol.1600133 ◽

2016 ◽

Vol 197 (6) ◽

pp. 2119-2130 ◽

Cited By ~ 6

Author(s):

Timothy Daniel Kayes ◽

Gary A. Weisman ◽

Jean M. Camden ◽

Lucas T. Woods ◽

Cole Bredehoeft ◽

...

Keyword(s):

Salivary Gland ◽

Murine Model ◽

Thyroid Disease ◽

Early Onset ◽

Autoimmune Thyroid Disease ◽

Autoimmune Thyroid ◽

Autoimmune Exocrinopathy

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P232 Polymorphic amino acid variations in the peptide binding pockets of HLA-DQB1* alleles with autoimmune thyroid disease from south India

Human Immunology ◽

10.1016/j.humimm.2017.06.292 ◽

2017 ◽

Vol 78 ◽

pp. 225

Author(s):

Ramgopal Sivanadham ◽

Rathika Chinniah ◽

Padma Malini Ravi ◽

Murali Vijayan ◽

Balakrishnan Karuppiah

Keyword(s):

Amino Acid ◽

Thyroid Disease ◽

Autoimmune Thyroid Disease ◽

South India ◽

Peptide Binding ◽

Autoimmune Thyroid ◽

Binding Pockets

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SEQUENCE SIMILARITY BETWEEN THYROID SELF-PROTEIN AND HEPATITIS C VIRUS POLYPROTEIN: possible triggering mechanism of autoimmune thyroiditis

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032016000300012 ◽

2016 ◽

Vol 53 (3) ◽

pp. 185-191 ◽

Cited By ~ 4

Author(s):

Maristella de Araújo Carvalho SOUSA ◽

Raymundo PARANÁ ◽

Luís Jesuíno de Oliveira ANDRADE

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Amino Acid ◽

Amino Acid Sequence ◽

Thyroid Disease ◽

Autoimmune Thyroid Disease ◽

Molecular Mimicry ◽

Sequence Similarity ◽

Autoimmune Thyroid ◽

Virus Polyprotein

ABSTRACT Background - Exposure to viral antigens that share amino acid sequence similar with self- antigens might trigger autoimmune diseases in genetically predisposed individuals, and the molecular mimicry theory suggests that epitope mimicry between the virus and human proteins can activate autoimmune disease. Objective - The purpose of this study is to explore the possible sequence similarity between the amino acid sequences of thyroid self-protein and hepatitis C virus proteins, using databanks of proteins and immunogenic peptides, to explain autoimmune thyroid disease. Methods - Were performed the comparisons between the amino acid sequence of the hepatitis C virus polyprotein and thyroid self-protein human, available in the database of National Center for Biotechnology Information on Basic Local Alignment Search Tool. Results - The sequence similarity was related each hepatitis C virus genotype to each thyroid antigen. The similarities between the thyroid and the viral peptides ranged from 21.0 % (31 identical residues out of 147 amino acid in the sequence) to 71.0% (5 identical residues out of 7 amino acid in the sequence). Conclusion - Bioinformatics data, suggest a possible pathogenic link between hepatitis C virus and autoimmune thyroid disease. Through of molecular mimicry is observed that sequences similarities between viral polyproteins and self-proteins thyroid could be a mechanism of induction of crossover immune response to self-antigens, with a breakdown of self-tolerance, resulting in autoimmune thyroid disease.

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Critical amino acid variations in HLA-DQB1* molecules confers susceptibility to Autoimmune Thyroid Disease in south India

Genes and Immunity ◽

10.1038/s41435-017-0008-6 ◽

2018 ◽

Vol 20 (1) ◽

pp. 32-38 ◽

Cited By ~ 5

Author(s):

S. Ramgopal ◽

C. Rathika ◽

R. Padma Malini ◽

V. Murali ◽

K. Arun ◽

...

Keyword(s):

Amino Acid ◽

Thyroid Disease ◽

Autoimmune Thyroid Disease ◽

South India ◽

Autoimmune Thyroid ◽

Critical Amino Acid

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Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

Frontiers in Immunology ◽

10.3389/fimmu.2021.654406 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenjing Zhang ◽

Xuemei Chen ◽

Guodong Gao ◽

Shubin Xing ◽

Lina Zhou ◽

...

Keyword(s):

Systematic Review ◽

Respiratory Tract ◽

Thyroid Disease ◽

Early Onset ◽

Autoimmune Thyroid Disease ◽

Respiratory Tract Infections ◽

Germline Mutations ◽

Autoimmune Thyroid ◽

Therapeutic Choice ◽

Tract Infections

Background: Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled.Objective: To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions.Methods: A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed.Results: The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection.Conclusions: STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT.

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