Abstract

We have identified three cross reactive idiotypes on anti-double stranded DNA antibodies in systemic lupus erythematosus in man. The 3I kappa light chain idiotype is encoded by the Vk1 gene family; the F4 heavy chain idiotype by the VH3 or VH4 gene family and the 8.12 lambda light chain idiotype by the V2 gene family. Having identified the V gene families associated with the cross reactive idiotypes, we now propose to determine if particular members of these V region families encode anti-DNA antibodies and if there are polymorphisms of these V region genes that predispose to SLE. We will study multiple antibodies produced by clonally related B cell lines, B cell genealogies, to identify structural determinants of DNA binding and assess the role of antigen, and DNA in particular in the anti- DNA response. We will determine the relationship of idiotypic anti-DNA antibodies to anti-pneumococcal polysaccharide antibodies bearing the 3I or 8.12 cross-reactive idiotype. Finally, we will initiate studies aimed at defining the structural correlates of pathogenicity of anti-DNA antibodies and at identifying the T cells that participate in the anti-DNA response in SLE.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR032371-11
Application #
3156272
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1983-04-01
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
11
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Chu, Yih-Pai; Taylor, Devon; Yan, Han-Guang et al. (2002) Persistence of partially functional double-stranded (ds) DNA binding B cells in mice transgenic for the IgM heavy chain of an anti-dsDNA antibody. Int Immunol 14:45-54
Lee, H B; Diamond, B A; Blaufox, M D (2001) In vivo detection of deposition of radiolabeled lupus antikidney antibody and its inhibition by soluble antigen. J Nucl Med 42:138-40
Davidson, A; Diamond, B (2001) Autoimmune diseases. N Engl J Med 345:340-50
Kowal, C; Weinstein, A; Diamond, B (1999) Molecular mimicry between bacterial and self antigen in a patient with systemic lupus erythematosus. Eur J Immunol 29:1901-11
Manheimer-Lory, A J; Zandman-Goddard, G; Davidson, A et al. (1997) Lupus-specific antibodies reveal an altered pattern of somatic mutation. J Clin Invest 100:2538-46
Gaynor, B; Putterman, C; Valadon, P et al. (1997) Peptide inhibition of glomerular deposition of an anti-DNA antibody. Proc Natl Acad Sci U S A 94:1955-60
Irigoyen, M; Kowal, C; Young, A C et al. (1996) Molecular mapping of the 8.12 SLE-associated idiotype specificity at the single amino acid level. Mol Immunol 33:1255-65
Irigoyen, M; Manheimer-Lory, A; Gaynor, B et al. (1994) Molecular analysis of the human immunoglobulin V lambda II gene family. J Clin Invest 94:532-8
Katz, J B; Limpanasithikul, W; Diamond, B (1994) Mutational analysis of an autoantibody: differential binding and pathogenicity. J Exp Med 180:925-32
Iliev, A; Spatz, L; Ray, S et al. (1994) Lack of allelic exclusion permits autoreactive B cells to escape deletion. J Immunol 153:3551-6

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