EXCEEDTHE SPACEPROVIDED. Graves' disease is a common human autoimmune disorder caused by autoantibodies that stimulate the TSH receptor (TSHR). There are no spontaneous animal models of the disease. We will use two induced mouse models; 'naked' TSHR-DNA vaccination, and the 'Shimojo' approach (injecting TSHR-expressing fibroblasts). With these models, we will analyze the following issues in the immune response to the TSHR:- 1. Influence of micro-organisms or lack of self tolerance: We will study the titers and functional activity of TSHR antibodies induced by TSHR-DNA vaccination in combination with microbial products, as well as in TSHR-knockout mice that cannot acquire self tolerance to the TSHR. 2. CYtokine and cellular interactions: Wild type mice and B-cell knockout mice will be used to determine (a) which cytokines are produced by splenocytes challenged with TSHR-protein; (b) whether CD4+ or CD8+ T cells are involved in the response; (c) if B cells are required to induce memory T cells specific for the TSHR, 3, Epitopes recognized by TSHR-specific T cells: Synthetic TSHR peptides will be used to determine the epitopes recognized by T cells (a) cloned from TSHR-DNA vaccinated BALB/c mice; (b) TSHR knockout mice that lack tolerance to the TSHR; (c) mice transgenic for HLA that predispose (DR3) or protect against (DQ6) Graves' disease. Naturally 3rocessed TSHR peptides will also be studied, 3. Co-stimulatory signals: The role of co-stimutatory molecules will be explored (a) in vitro by using antibodies to block CD40/CD40-1igand and CD28/B7-1/2 interactions; (b) in vivo using mice with disrupted genes ('knockouts') for CD28, CD40, B7-1 or B7-2; (c) in vivo by injecting mice with anti-B7-1 (or control) together with TSHR -fibroblasts (that express B7-1). 5. Role of TSHR cleavage and shedding: We heavily glycosylated A subunit plays a role non-cleaving or shedding TSHR; (b) examining antigens (such as TPO) to the mannose receptor PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Endocrinology Study Section (END)
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Spain, Lisa M
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Cedars-Sinai Medical Center
Los Angeles
United States
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McLachlan, Sandra M; Aliesky, Holly A; Rapoport, Basil (2018) Aberrant Iodine Autoregulation Induces Hypothyroidism in a Mouse Strain in the Absence of Thyroid Autoimmunity. J Endocr Soc 2:63-76
McLachlan, Sandra M; Lesage, Sylvie; Collin, Roxanne et al. (2017) Genes Outside the Major Histocompatibility Complex Locus Are Linked to the Development of Thyroid Autoantibodies and Thyroiditis in NOD.H2h4 Mice. Endocrinology 158:702-713
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McLachlan, Sandra M; Aliesky, Holly; Banuelos, Bianca et al. (2017) Variable Effects of Dietary Selenium in Mice That Spontaneously Develop a Spectrum of Thyroid Autoantibodies. Endocrinology 158:3754-3764
McLachlan, Sandra M; Rapoport, Basil (2017) Thyroid Autoantibodies Display both ""Original Antigenic Sin"" and Epitope Spreading. Front Immunol 8:1845
Rapoport, Basil; Banuelos, Bianca; Aliesky, Holly A et al. (2016) Critical Differences between Induced and Spontaneous Mouse Models of Graves' Disease with Implications for Antigen-Specific Immunotherapy in Humans. J Immunol 197:4560-4568
Rapoport, Basil; McLachlan, Sandra M (2016) TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective. Endocr Rev 37:114-34
Rapoport, Basil; McLachlan, Sandra M (2016) TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective. Endocr Rev 2016:23-42
Rapoport, Basil; Aliesky, Holly A; Banuelos, Bianca et al. (2015) A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor. J Immunol 194:4154-61
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