The purpose of this proposal is to investigate the pathogenesis of autoantibodies in """"""""organ-specific"""""""" autoimmune diseases using autoimmune thyroid disease (AITD) as a model. This will include investigations into the role different B cell subsets (such as those bearing the CD5 antigen) play in producing autoantibodies and a comparison between local and systemic B cell auto-activity in order to evaluate how each lymphocyte population relates to the autoimmune process. Important epitopes on known thyroid autoantigens will be identified and characterized to determine whether there are common epitopes or specific types of molecules involved in the genesis of autoimmune disorders. The biological activity of autoantibodies directed against various types of autoantigen epitopes (including oligosaccharides, glycolipids and proteins) will be determined to clarify how autoantibodies alter cellular physiology. In addition, it is hoped to identify new autoantigens relevant to the autoimmune process. Studies to be performed in this proposal include isolation of lymphocytes from both the thyroid and peripheral blood of patients with AITD. These cells will then be separated into B cell subpopulations with panning techniques and FACS sorting. Isolated B cells will be expanded and transformed with Epstein Barr Virus or directly fused with heteromyeloma cells to produce monoclonal antibodies. Binding to different thyroid antigens will be assessed with multiple types of immunoassays, and specific epitopes on known autoantigens will be identified according to composition and structure. All monoclonal antibodies will also be evaluated in multiple bioassays of thyroid cell function to relate physiologic alterations to specific antibody-epitope interactions. New antigens will be identified and isolated through the use of affinity columns, and cloned from thyroid cDNA libraries when appropriate. These studies should help to elucidate why autoantigens are recognized by the immune system and will determine the function of autoantibodies in both autoimmune pathogenesis and the modification of cellular physiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI030501-05
Application #
2065662
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1990-05-01
Project End
1995-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Baker, J R; Arscott, P; Johnson, J (1994) An analysis of the structure and antigenicity of different forms of human thyroid peroxidase. Thyroid 4:173-8
Ross, P V; Koenig, R J; Arscott, P et al. (1993) Tissue specificity and serologic reactivity of an autoantigen associated with autoimmune thyroid disease. J Clin Endocrinol Metab 77:433-8
Baker Jr, J R; Fosso, C K (1993) Immunological aspects of cancers arising from thyroid follicular cells. Endocr Rev 14:729-46
Bermann, M; Magee, M; Koenig, R J et al. (1993) Differential autoantibody responses to thyroid peroxidase in patients with Graves' disease and Hashimoto's thyroiditis. J Clin Endocrinol Metab 77:1098-101
Maastricht, J; Koenig, R J; Kaplan, M M et al. (1992) Identification of localized autoantibody epitopes in thyroid peroxidase. J Clin Endocrinol Metab 75:121-6
Arscott, P; Rosen, E D; Koenig, R J et al. (1992) Immunoreactivity to Yersinia enterocolitica antigens in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 75:295-300