The primary focus of this project is to study the thyroid-specific proteins that are the target of the immune system in Graves' disease and Hashimoto's thyroiditis. These proteins include the TSH receptor, the thyroid "microsomal" antigen, and other autoimmune thyroid disease-related antigens (ATRA's). The goal is to expand our information on the identity, character and regulation of expression of these "auto"-antigens. Specifically it is proposed to perform the following studies: 1. Molecular cloning of the TSH receptor. a) Isolation of a full-length cDNA for HHB, the putative TSH receptor gene, from a new human thyroid cDNA library that will be constructed. The nucleotide and derived primary amino acid sequence of HHB will be determined. b) Study of the specificity of the cell-free translated HHB protein with a panel of antisera from patients with autoimmune thyroid disease. c) Expression of the full-length HHB cDNA in non-thyroid eukaryotic cells. d) If HHB turns out not to be the TSH receptor, we will select new clones or use clones obtained by other laboratories to perform the studies described above. 2. Studies on the cloned microsomal antigen/thyroid peroxidase (TPO) a) Identification of the B-cell epitope(s) on TPO in Hashimoto's thyroiditis. b) Identification of the T-cell epitope(s) in Hashimoto's thyroiditis, and the generation of TPO specific T-cell clones. c) Development of sensitive and specific assays for the microsomal/TPO antigen using recombinant antigen. 3. Studies on ATRA 1 and other automimmune thyroid disease-related (ATRA) antigens that may be recognized in future studies. a) Isolation of a full-length cDNA clone for the recently identified ATRA 1, and determination of its nucleotide and derived primary amino acid sequence. b) Study of the specificity of the ATRA 1 protein by immunoprecipitation of the cell-free translated protein with a panel of antisera from patients with autoimmune thyroid disease. c) Expression of the ATRA 1 protein in non-thyroid eukaryotic cells. d) Isolation of ATRA 1 genomic clones in order to study the promoter region of this gene and its potential regulation by TSH.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK036182-05
Application #
3234528
Study Section
Endocrinology Study Section (END)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Chen, Chun-Rong; Hamidi, Sepehr; Braley-Mullen, Helen et al. (2010) Antibodies to thyroid peroxidase arise spontaneously with age in NOD.H-2h4 mice and appear after thyroglobulin antibodies. Endocrinology 151:4583-93
McLachlan, Sandra M; Rapoport, Basil (2007) Thyroid peroxidase as an autoantigen. Thyroid 17:939-48
Guo, Jin; McLachlan, Sandra M; Rapoport, Basil (2006) Antibodies focused on the human autoantibody immunodominant region are induced by B lymphocytes that constitutively express thyroid peroxidase diverted to the major histocompatibility complex II pathway. Thyroid 16:343-9
Quaratino, Sonia; Ruf, Jean; Osman, Mohamed et al. (2005) Human autoantibodies modulate the T cell epitope repertoire but fail to unmask a pathogenic cryptic epitope. J Immunol 174:557-63
McLachlan, Sandra M; Nagayama, Yuji; Rapoport, Basil (2005) Insight into Graves' hyperthyroidism from animal models. Endocr Rev 26:800-32
Guo, Jin; McLachlan, Sandra M; Pichurin, Pavel N et al. (2005) Relationship between thyroid peroxidase T cell epitope restriction and antibody recognition of the autoantibody immunodominant region in human leukocyte antigen DR3 transgenic mice. Endocrinology 146:4961-7
Chazenbalk, G D; Pichurin, P N; Guo, J et al. (2005) Interactions between the mannose receptor and thyroid autoantigens. Clin Exp Immunol 139:216-24
McLachlan, Sandra M; Braley-Mullen, Helen; Chen, Chun-Rong et al. (2005) Dissociation between iodide-induced thyroiditis and antibody-mediated hyperthyroidism in NOD.H-2h4 mice. Endocrinology 146:294-300
Guo, Jin; Pichurin, Pavel N; Morris, John C et al. (2004) Naked deoxyribonucleic acid vaccination induces recognition of diverse thyroid peroxidase T cell epitopes. Endocrinology 145:3671-8
Latrofa, Francesco; Phillips, Martin; Rapoport, Basil et al. (2004) Human monoclonal thyroglobulin autoantibodies: epitopes and immunoglobulin genes. J Clin Endocrinol Metab 89:5116-23

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