The applicant has for some time been studying the antibody response to dsDNA that characterizes the autoimmune disease, systemic lupus erythematosus. She has shown that anti-dsDNA antibodies are encoded by somatically mutated variable region genes and are structurally similar to antibodies to foreign (bacterial) antigen. In a series of experiments performed in mice, a novel fusion partner, NSO bcl-2 that constitutively expresses the bcl-2 anti-apoptosis gene has been shown to rescue auto-reactive B cells that routinely arise by somatic mutation during the course of an immune response to the pneumococcal hapten phosphorycholine. The studies now proposed are designed to determine whether in the course of a human immune response to pneumococcus, B cells are generated which acquire dsDNA binding as a result of somatic mutation. The applicant will compare the splenic B cell response to pneumococcal polysaccharide of SLE patients and of non-autoimmune individuals. She will develop B cell geneologies to see when in the course of B cell activation, autospecificity is generated and when, in non-autoimmune individuals, DNA binding B cells are eliminated. In addition, she will study the pathogenicity of anti-dsDNA antibodies by analyzing the fine specificity differences among anti-dsDNA antibodies using peptide libraries to identify mimotopes for dsDNA. Using these peptides and in vivo assays of antibody deposition in the kidney, she will determine if there are correlations between fine specificity and pathogenicity. Analysis of peptide mimotopes may also provide clues to protein antigens that might be involved in either the activation or target organ binding of anti- dsDNA antibodies. These peptide mimotopes may constitute valuable new reagents that can be explored as therapeutics, both to block anti-dsDNA deposition in tissue and to induce tolerance in pathogenic B cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR032371-18
Application #
6171800
Study Section
Special Emphasis Panel (ZRG2-EI (01))
Program Officer
Gretz, Elizabeth
Project Start
1983-04-01
Project End
2001-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
18
Fiscal Year
2000
Total Cost
$450,684
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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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