The long term goals of this project are to delineate the mechanisms of autoimmune disease. The murine experimental autoimmune thyroiditis model of an organ specific autoimmune disease will be used in this study. There are two specific aims in this proposal. 1. During organ specific autoimmune disease, self-tolerance is lost and autoantibodies to indiginous antigens arise through, as yet, an unknown mechanism. There are two possible pathways through which auto Ab may arise. In the germline immunoglobulin variable gene repertoire, there exist autoreactive V genes. Pathologic autoantibodies may be derived from these autoreactive, germline encoded V genes. Alternatively, autoreactive antibodies could arise from non-autoreactive germline V genes as a result of post- immunization somatic mutation. The first pathway could be explained totally by a loss of immunoregulation without the need of an antigen driven maturation process. The second pathway would necessitate an the presence of antigen to drive maturation, however, the process may be initiated by a unrelated antigen. We therefore, plan to clone, using recombinant DNA technology, the V genes of anti-mouse thyroglobulin (MTg) Ab developing during the disease process. The selection of V genes used will be compared to that of """"""""natural"""""""" Ab that are autoreactive with MTg. The results from these experiments could point to one these pathways and give insight into the processes which induce autoimmune disease. 2. In the EAT model, disease can be easily induced by immunization with mouse thyroglobulin. The specific determinants involved in this induction process are not known. By chemical or enzymatic cleavage of MTg, we propose to define specific peptide sequences which are pathogenic or which can induce protective immunosuppression. Using the DNA probes derived from the amino acid sequence of these peptides, the location of these sites within the MTg molecule will be determined. Furthermore, we will attempt to distinguish determinants associated with development of disease from those which are involved in inducing autoantibody production alone. These finding would further our understanding of the nature of autoantigenic determinants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR031632-05
Application #
3156061
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1983-09-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rose, N R (1994) Avian models of autoimmune disease: lessons from the birds. Poult Sci 73:984-90
Jabs, D A; Kuppers, R C; Saboori, A M et al. (1994) Effects of early and late treatment with anti-CD4 monoclonal antibody on autoimmune disease in MRL/MP-lpr/lpr mice. Cell Immunol 154:66-76
Kuppers, R C; Epstein, L D; Outschoorn, I M et al. (1994) The IgG2a antibody response to thyroglobulin is linked to the Igh locus in mouse. Immunogenetics 39:404-11
Rose, N R (1994) Thymus function, ageing and autoimmunity. Immunol Lett 40:225-30
Kuppers, R C; Outschoorn, I M; Hamilton, R G et al. (1993) Quantitative measurement of human thyroglobulin-specific antibodies by use of a sensitive enzyme-linked immunoassay. Clin Immunol Immunopathol 67:68-77
Rose, N R; Burek, C L (1991) The interaction of basic science and population-based research: autoimmune thyroiditis as a case history. Am J Epidemiol 134:1073-8
Rose, N R (1991) Characteristics of autoimmune disease. J Invest Dermatol 96:87S
Rose, N R; Talor, E (1991) Antigen-specific immunoregulation and autoimmune thyroiditis. Ann N Y Acad Sci 636:306-20
Talor, E; Rose, N R (1991) Hypothesis: the aging paradox and autoimmune disease. Autoimmunity 8:245-9
Kuppers, R C (1991) The frequency of LPS-responsive B cells to autologous and heterologous thyroglobulin. Cell Immunol 132:94-101

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