Systemic lupus erythematosus is a systemic autoimmune disease in humans and genetically predisposed mice. Antibodies to a variety of cellular antigens, mostly nuclear in origin, have been detected in lupus sera from mice and humans; however, the autoantibody for which there is the most compelling evidence for pathological relevance is antibody to DNA. Anti-DNA antibodies deposit in kidneys either as immune complexes or by binding directly to glomerular structures and initiate glomerulonephritis. The immunological basis for the generation of anti-DNA autoantibody in mice and humans has been difficult to elucidate. The goal of the applicant's research on """"""""Antigen Driven Selection and Tolerance in Autoimmunity to DNA"""""""" continues to be directed toward understanding how autoimmunity to DNA is initiated and sustained at the level of individual DNA-specific B cells in autoimmune (NZB x NZW) F1 mice. The applicant's research efforts since the last competitive review of this project have continued to support the hypothesis that autoimmunity to DNA is both initiated and sustained as a clonally selective, antigenic-specific immune response to DNA most likely in the form of DNA-protein complexes. The research has continued to focus on experiments to understand how the specificity and specificity maturation of the autoimmune anti-DNA antibody response within individual (NZB x NZW) F1 mice and the DNA-peptide induced immune anti-DNA antibody response in normal mice proceed. The results have provided new information about B cell selection in the autoimmune response to DNA and the V region structures necessary for that selection to occur. In the applicant's continuing research efforts to understand how autoimmunity to DNA is initiated, they will test the hypothesis that autoimmunity to DNA is initiated by antigen-specific B cell stimulation in the absence of peripheral B cell tolerance induced by extracellular DNA or nucleosomes. The specific experimental aims to be pursued in the research proposed will be to determine what role, if any, germinal centers play in the specificity maturation that generates high avidity autoantibodies to native DNA. Proposed experiments will also determine the role of soluble DNA or nucleosomes in maintaining immunological tolerance to DNA. The experimental systems designed to complete the proposed research will include the use of (NZB x NZW) F1 mice transgenic for expression of anti-DNA antibodies. These mice have an interesting autoimmune phenotype that make them highly suited for experiments to test the hypothesis that autoimmunity to DNA in (NZB x NZW) F1 mice derives from antigen-selective B cell stimulation in the absence of effective peripheral tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026833-13
Application #
6651523
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Johnson, David R
Project Start
1988-07-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
13
Fiscal Year
2003
Total Cost
$209,654
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Marion, Tony N; Postlethwaite, Arnold E (2014) Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus. Semin Immunopathol 36:495-517
Radic, Marko; Marion, Tony N (2013) Neutrophil extracellular chromatin traps connect innate immune response to autoimmunity. Semin Immunopathol 35:465-80
Krishnan, Meera R; Wang, Congmiao; Marion, Tony N (2012) Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice. Kidney Int 82:184-92
Steeves, Meredith A; Marion, Tony N (2004) Tolerance to DNA in (NZB x NZW)F1 mice that inherit an anti-DNA V(H) as a conventional micro H chain transgene but not as a V(H) knock-in transgene. J Immunol 172:6568-77
Marion, Tony N; Krishnan, Meera R; Steeves, Meredith A et al. (2003) Affinity maturation and autoimmunity to DNA. Curr Dir Autoimmun 6:123-53
Desai, D D; Marion, T N (2000) Induction of anti-DNA antibody with DNA-peptide complexes. Int Immunol 12:1569-78
Krishnan, M R; Marion, T N (1998) Comparison of the frequencies of arginines in heavy chain CDR3 of antibodies expressed in the primary B-cell repertoires of autoimmune-prone and normal mice. Scand J Immunol 48:223-32
Ash-Lerner, A; Ginsberg-Strauss, M; Pewzner-Jung, Y et al. (1997) Expression of an anti-DNA-associated VH gene in immunized and autoimmune mice. J Immunol 159:1508-19
Marion, T N; Krishnan, M R; Desai, D D et al. (1997) Monoclonal anti-DNA antibodies: structure, specificity, and biology. Methods 11:3-11
Krishnan, M R; Jou, N T; Marion, T N (1996) Correlation between the amino acid position of arginine in VH-CDR3 and specificity for native DNA among autoimmune antibodies. J Immunol 157:2430-9

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