Abstract

Autoantibodies against thyroid peroxidase (TPO) are present in the sera of virtually all patients with active Hashimoto's thyroiditis. Understanding the precise molecular interaction between autoantibodies and TPO is a necessary step towards understanding the basis of the autoimmune response and, ultimately, towards the goal of immunotherapy for this very common autoimmune disease. The goals of this proposal are: 1. CLONING AND EXPRESSION OF THE TPO AUTOANTIBODY GENE REPERTOIRE We have cloned a panel of human TPO autoantibodies, but hose in the repertoire remain, particularly for: . autoantibodies with linear epitopes (denatured TPO) . autoantibodies with lambda L. chains . autoantibodies whose epitopes lie outside the immunodominant region A wide repertoire of TPO autoantibodies is also required to study the role of autoantibodies in antigen presentation to T cells. We will use the combinatorial library to complete the TPO autoantibody repertoire for genes and epitopes. We will use the combinatorial library to complete the TPO autoantibody repertoire for genes and epitopes. 2. 3D STRUCTURE OF THE TPO IMMUNODOMINANT REGION AND ITS AUTOANTIBODIES Definition of the precise interaction between TPO autoantibodies and its antigen will require over-expression, purification and crystallization of selected molecules for x-ray diffraction analysis. We will study the following: . TPO autoantibody Fab to the immunodominant Fab to the immunodominant region . TPO . TPO: autoantibody Fab complexes. 3. ROLE OF AUTOANTIBODIES IN THE PRESENTATION OF TPO TO T CELLS Monoclonal human TPO autoantibodies provide unique tools for studying the influence of autoantibodies on the processing and presentation of TPO to T cells. For this purpose, we will: . Establish and characterized a panel of TPO-specific T cell clones. . Study the influence of TPO autoantibody epitopes on TPO presentation to TPO specific T cells. . Study the ability of TPO-specific T cell clones to drive TPO autoantibody production by memory B cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK036182-17
Application #
6329330
Study Section
Endocrinology Study Section (END)
Program Officer
Akolkar, Beena
Project Start
1985-07-01
Project End
2001-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
17
Fiscal Year
2001
Total Cost
$319,376
Indirect Cost

  Institution

Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048

  Publications

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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