The production of pathogenic antibodies is the cause of a number of autoimmune diseases. However, the cellular and molecular mechanisms underlying the production of pathogenic autoantibodies are incompletely understood. The overall goal of the continuation of the Program Project in Autoimmunity is to develop a more comprehensive understanding of the mechanisms underlying the generation of autoantibodies. The three projects are focused on potential molecular mechanisms controlling generation of autoantibodies and involve a comprehensive and integrated analysis of a number of hypotheses potentially underlying autoantibody production in patients with autoimmune disease. The first project, of which Dr. Peter Lipsky is the principal investigator, will use a novel technique, PCR amplification of genomic DNA from individual B cells, to analyze the immunoglobulin repertoire in patients with SLE, as well as the immunoglobin genes encoding anti-Ro and anti-dsDNA antibodies. This project will examine a number of hypothesis concerning the possibility that abnormalities in V(D)J recombination, somatic hyper-mutation or clonal selection play a role in the development of autoantibodies. In the second project, Dr. Katheryn Meek will examine the hypothesis that abnormal V(D)J recombination leading to excess numbers of charged amino acids in the CDR3 region may predispose toward the production of autoantibodies. This project will use a number of approaches to probe the molecular regulation of D segment utilization and potential perturbations of this in autoimmune mice and humans. Finally, in the third project, Dr. Betty Diamond will explore the basis of the clinical observation that autoimmune diseases are more frequent in women and exacerbated by estrogen, by evaluating the impact of estrogen on repertoire selection and emergence of autoantibody producing B cells. Each of these three projects will focus on molecular mechanisms controlling repertoire generation and selection and should provide important new insights into regulation of the normal immunoglobin repertoire generation and selection and should provide important new insights into regulation of the normal immunoglobin repertoire as well as perturbations in those control mechanisms that might predispose to the production of autoantibodies in patients with autoimmune disease. It is anticipated that as a result of the proposed work, comprehensive new insights into the molecular mechanisms of autoimmunity will arise that could provide novel approaches to therapeutic interventions in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
7P01AI031229-10
Application #
6211621
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Collier, Elaine S
Project Start
1991-08-01
Project End
2002-08-31
Budget Start
2000-01-01
Budget End
2000-08-31
Support Year
10
Fiscal Year
1999
Total Cost
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
Nashi, Emil; Wang, YingHua; Diamond, Betty (2010) The role of B cells in lupus pathogenesis. Int J Biochem Cell Biol 42:543-50
Tao, Xuelian; Fan, Fred; Hoffmann, Victoria et al. (2008) Effective therapy for nephritis in (NZB x NZW)F1 mice with triptolide and tripdiolide, the principal active components of the Chinese herbal remedy Tripterygium wilfordii Hook F. Arthritis Rheum 58:1774-83
Dorner, T; Lipsky, P E (2005) Molecular basis of immunoglobulin variable region gene usage in systemic autoimmunity. Clin Exp Med 4:159-69
Ramanujam, Meera; Davidson, Anne (2004) The current status of targeting BAFF/BLyS for autoimmune diseases. Arthritis Res Ther 6:197-202
Schiffer, L E; Hussain, N; Wang, X et al. (2002) Lowering anti-dsDNA antibodies--what's new? Lupus 11:885-94
Girschick, Hermann J; Lipsky, Peter E (2002) The kappa gene repertoire of human neonatal B cells. Mol Immunol 38:1113-27
Huang, Weiqing; Sinha, Jayashree; Newman, Jeffrey et al. (2002) The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus. Arthritis Rheum 46:1554-62
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
Dorner, Thomas; Lipsky, Peter E (2002) Abnormalities of B cell phenotype, immunoglobulin gene expression and the emergence of autoimmunity in Sjogren's syndrome. Arthritis Res 4:360-71
Dorner, Thomas; Hansen, Arne; Jacobi, Annett et al. (2002) Immunglobulin repertoire analysis provides new insights into the immunopathogenesis of Sjogren's syndrome. Autoimmun Rev 1:119-24

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