Autoimmune thyroid diseases (AITD) are highly prevalent. Abundant data demonstrate a major role for genetic factors in the pathogenesis of AITD. Recently, we and others have demonstrated that the presence of arginine at position 74 of the HLA-DR31 chain (DRp1-Arg74), within the peptide binding pocket, was strongly associated with AITD. We also identified AITD-associated missense SNPs in the thyroglobulin (Tg) gene. One of those Tg SNPs showed statistical evidence for interaction with the DR(31-Arg74 variant of HLA- DR, resulting in an odds ratio of>10 for AITD. These findings suggest that molecular interactions between HLA-DR pocket variants and Tg may be central to the development of AITD. Thus, we hypothesize that certain DR pocket variants cause susceptibility or resistance to AITD by influencing the presentation of Tg peptides to T cells by antigen presenting cells (APC's). The goals of our studies are to analyze the mechanisms by which interactions between Tg peptides and specific HLA-DR pocket variants confer susceptibility to, or protection from, AITD, and to use this knowledge to develop therapies for AITD.
Our specific aims are: (1) To identify and characterize hTg peptides that bind to the disease associated HLA-DR pocket variant (DR31-Arg74) using molecular modeling, biochemical, and mass spectrometry studies. (2) To test in-vivo the presentation of hTg peptides bound by Arg74+ APC's to T-cells in an experimental autoimmune thyroiditis (EAT) model (in DR3 transgenic mice), and in AITD patients. (3) To develop, synthesize, and test altered peptide ligands that can block the development of EAT.In summary, we propose a novel multi-disciplinary approach combining computational modeling experiments with biochemical, mass spectrometry, cell culture, and in-vivo studies to dissect the interactions between hTg peptides and HLA-DR in the induction of autoimmune thyroiditis. We have the capacity and expertise to achieve these goals, expertise gained from our studies on the immunogenetics of AITD. We have already identified novel genetic variants in (e.g., DRp1-Arg74, CD40 Kozak SNP) and mechanisms leading to the development of AITD. The proposed studies will lead to a better understanding of the basic etiology of autoimmune thyroiditis. This may facilitate the development of knowledge-based treatment and prevention approaches for autoimmune thyroiditis and possibly for other autoimmune diseases that share similar pathogenetic mechanisms.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Spain, Lisa M
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Faustino, Larissa C; Lombardi, Angela; Madrigal-Matute, Julio et al. (2018) Interferon-? Triggers Autoimmune Thyroid Diseases via Lysosomal-Dependent Degradation of Thyroglobulin. J Clin Endocrinol Metab 103:3678-3687
Li, Cheuk Wun; Osman, Roman; Menconi, Francesca et al. (2017) Flexible peptide recognition by HLA-DR triggers specific autoimmune T-cell responses in autoimmune thyroiditis and diabetes. J Autoimmun 76:1-9
Blackard, Jason T; Kong, Ling; Lombardi, Angela et al. (2017) A preliminary analysis of hepatitis C virus in pancreatic islet cells. Virol J 14:237
Lee, Hanna J; Lombardi, Angela; Stefan, Mihaela et al. (2017) CD40 Signaling in Graves Disease Is Mediated Through Canonical and Noncanonical Thyroidal Nuclear Factor ?B Activation. Endocrinology 158:410-418
Hammerstad, Sara Salehi; Stefan, Mihaela; Blackard, Jason et al. (2017) Hepatitis C Virus E2 Protein Induces Upregulation of IL-8 Pathways and Production of Heat Shock Proteins in Human Thyroid Cells. J Clin Endocrinol Metab 102:689-697
Li, Cheuk Wun; Menconi, Francesca; Osman, Roman et al. (2016) Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis. J Biol Chem 291:4079-90
Lombardi, Angela; Menconi, Francesca; Greenberg, David et al. (2016) Dissecting the Genetic Susceptibility to Graves' Disease in a Cohort of Patients of Italian Origin. Front Endocrinol (Lausanne) 7:21
Tomer, Yaron; Dolan, Lawrence M; Kahaly, George et al. (2015) Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. J Autoimmun 60:32-9
Lombardi, Angela; Inabnet 3rd, William Barlow; Owen, Randall et al. (2015) Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis. J Clin Endocrinol Metab 100:E1-10
Lee, Hanna J; Li, Cheuk Wun; Hammerstad, Sara Salehi et al. (2015) Immunogenetics of autoimmune thyroid diseases: A comprehensive review. J Autoimmun 64:82-90

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