Our belief is that autoimmune disorders are usually based upon infectious agents, the autoimmunity often depending upon molecular mimicry between virally-encoded proteins and normal tissue proteins. We will explore this concept in two diseases: infectious mononucleosis (IM) and rheumatoid arthritis (RA). In IM, we have already established that IgM autoantibodies are present, which react with numerous normal tissue proteins and also with the glycine-alanine repeat in the Epstein-Barr virus (EBV) encoded EBNA-1 protein. In the IgM -- greater than IgG isotype switch of anti-EBNA-1, which occurs in an unusually delayed time scale, the antibodies lose their cross reactivities with normal tissue proteins. We will attempt to define mechanisms for this loss of crossreactivity of the anti-EBNA-1 antibodies, exploring: 1) the possible role of anti-idiotypic antibodies; 2) the nature of the T cell reactivity with EBNA-1 synthetic peptides and with fusion proteins representing the tissue antigens; and 3) the phenotypes and functional potentials of the reactive T cells. In RA, we will explore T cell reactivities with EBV-encoded antigens for two purposes: 1) to discern any possible disposition of RA patients' lymphocytes as a group to react differently from control lymphocytes with the peptides studied; and 2) to discern whether B lymphocytes with given HLA Class II characteristics, defined by classical typing sera, monoclonal antibodies, or family studies, present the peptides differently from other B lymphocytes, e.g. autoantigenically. To determine whether T lymphocytes activated in vivo as part of the RA disease process exhibit anti-EBV (EBNA-1 or LYDMA) reactivity or autoimmune reactivity, we will grow out synovial T lymphocytes in interleukin-2 with intermittent anti CD3, clone them, and then examine them against autologous B cells or synovial cells with and without added EBV-associated peptides. The presence in synovial and salivary tissues of EBV encoded antigen or EBV DNA will be sought by immunoperoxidase staining and by in situ hybridization, respectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR021175-11
Application #
3155153
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1977-12-01
Project End
1993-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
11
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037
Handley, H H; Yu, J; Yu, D T et al. (1996) Autoantibodies to human heat shock protein (hsp)60 may be induced by Escherichia coli groEL. Clin Exp Immunol 103:429-35
Vaughan, J H; Nguyen, M D; Valbracht, J R et al. (1995) Epstein-Barr virus-induced autoimmune responses. II. Immunoglobulin G autoantibodies to mimicking and nonmimicking epitopes. Presence in autoimmune disease. J Clin Invest 95:1316-27
Vaughan, J H; Valbracht, J R; Nguyen, M D et al. (1995) Epstein-Barr virus-induced autoimmune responses. I. Immunoglobulin M autoantibodies to proteins mimicking and not mimicking Epstein-Barr virus nuclear antigen-1. J Clin Invest 95:1306-15
Handley, H H; Ngyuen, M D; Yu, D T et al. (1995) Purification of recombinant human Hsp60: use of a GroEL-free preparation to assess autoimmunity in rheumatoid arthritis. J Autoimmun 8:659-73
Petersen, J; Rhodes, G; Roudier, J et al. (1990) Altered immune response to glycine-rich sequences of Epstein-Barr nuclear antigen-1 in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum 33:993-1000
Zuraw, B L; Lotz, M (1990) Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma. J Biol Chem 265:12664-70
Kouri, T; Petersen, J; Rhodes, G et al. (1990) Antibodies to synthetic peptides from Epstein-Barr nuclear antigen-1 in sera of patients with early rheumatoid arthritis and in preillness sera. J Rheumatol 17:1442-9
Rhodes, G; Smith, R S; Rubin, R E et al. (1990) Identical IgM antibodies recognizing a glycine-alanine epitope are induced during acute infection with Epstein-Barr virus and cytomegalovirus. J Clin Lab Anal 4:456-64
Kouri, T; Crowley, J; Aho, K et al. (1990) Occurrence of two germline-related rheumatoid factor idiotypes in rheumatoid arthritis and in non-rheumatoid seropositive individuals. Clin Exp Immunol 82:250-6
Vaughan, J H (1989) Infection and autoimmunity. Curr Opin Immunol 1:708-17

Showing the most recent 10 out of 18 publications