The synovium in seropositive rheumatoid arthritis (RA) is capable of producing marked amounts of immunoglobulin. Up to 5-10% of the synovial antibody repertoire has rheumatoid factor (RF) activity, which is thought to be intimately involved in disease pathogenesis. However, the three idiotypes most commonly expressed by IgM RF paraproteins (Wa, Po and Bla) appear to be a minor component of synovial RF. Thus, the genetic composition of the RA synovial antibody repertoire, both non-RF and RF, is unknown. This proposal outlines analysis of the antibody repertoire expressed in rheumatoid synovium to test the hypothesis that synovial immunoglobulin production is antigen-driven and, thus, involved in disease pathogenesis. Data from murine models validate this approach. Sequence analyses of antibody repertoires in MRL/lpr mice suggest that autoantibodies generated during nonspecific stimulation by LPS are polyclonal and reflect the germline repertoire; whereas in autoimmune states, self-reactive antibodies are clonally related and characteristic of antigen-driven production. Murine models also suggest that the physico-chemical properties of specific V germline elements influence the manifestations of autoimmune disease. Thus, polymorphism in the genomic repertoire may be an additional, independent factor in disease susceptibility. The antibody repertoires of cDNA libraries made from rheumatoid synovial cells will be characterized at the nucleotide sequence level, seeking evidence of restriction in V region utilization in Cmu- and Ckappa-containing transcripts. Sequences will be compared to germline and pathologic gene segments. Evidence of oligoclonal expansion will be sought by analyzing the VH-DH-JH joins of Cgamma- and Calpha-containing transcripts and the Vkappa-Jkappa joins. The extent of somatic mutation will provide further evidence regarding possible antigen-driven selection. Combinatorial libraries will be generated to assess antigen specificity. Candidate germline autoreactive elements will be identified, the extent of polymorphism in the human population analyzed, and possible correlation to disease susceptibility established. These studies should help elucidate a poorly understood manifestation of rheumatic disease and serve as reference for future studies of abnormal immune responses. The proposed training plan involves two years of graduate courses and initial laboratory experience (Phase I). When advisory committee criteria for advancement are met, the candidate will have three years of intensive research experience (Phase II).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Physician Scientist Award (K11)
Project #
5K11AR001867-03
Application #
3085666
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1991-09-01
Project End
1996-06-30
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Clausen, B E; Bridges Jr, S L; Lavelle, J C et al. (1998) Clonally-related immunoglobulin VH domains and nonrandom use of DH gene segments in rheumatoid arthritis synovium. Mol Med 4:240-57
Bridges Jr, S L; Koopman, W J; Lee, S K et al. (1995) Immunoglobulin gene expression in rheumatoid arthritis. Agents Actions Suppl 47:23-35
Bridges Jr, S L; Lee, S K; Johnson, M L et al. (1995) Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in patients with rheumatoid arthritis and in normal individuals. J Clin Invest 96:831-41
Lee, S K; Bridges Jr, S L; Kirkham, P M et al. (1994) Evidence of antigen receptor-influenced oligoclonal B lymphocyte expansion in the synovium of a patient with longstanding rheumatoid arthritis. J Clin Invest 93:361-70
Bridges Jr, S L; Lee, S K; Koopman, W J et al. (1993) Analysis of immunoglobulin gamma heavy chain expression in synovial tissue of a patient with rheumatoid arthritis. Arthritis Rheum 36:631-41