Our long-term goal is to define the fundamental mechanism of the systemic autoimmune disease (SLE) and malignant B cell lymphomas that develop spontaneously in the crosses between NZB and the normal SWR mouse strains. The etiologic mechanism of Systemic lupus erythematosus (SLE) remains elusive because the primary antigen that triggers the pathogenic autoimmune response in this disease is unknown. In spite of this obstacle, we have cloned the select T and B cells that are pathogenic in SLE. Analyses of the structure and specificities of the receptors expressed by these particular T and B cells that are representative of the disease and studies of their regulation may lead to an understanding of the etiologic mechanism of lupus. The major goals of this application involve: 1) Pathogenic B Cells: (a) Define the structural basis of cationic charge, antigenic specificities, idiotypic cross reactions and clonal relationships among pathogenic anti-DNA autoantibodies. b) Study the germline V gene repertoire that generates the pathogenic autoantibodies, define the natural specificities of antibodies encoded by these germ line V genes and determine the degree of somatic mutations required to generate the pathogenic autoantibodies. c) Determine if the lupus-prone mice have an intrinsic B cell defect in tolerance induction or in Ig somatic mutation mechanisms using transgenic mice carrying autoantibody V genes. 2) Pathogenic T Cells: (a) Determine the V region sequences of the receptors (TCRs) expressed by the pathogenic autoantibody-inducing T cells to detect any clonal restriction/recurrent usage or any special feature in their junctional region (CDR3) sequences that would provide clues for their antigenic specificities. b) Determine the specificities of these T helper cells that preferentially interact with the pathogenic autoantibody-producing B cells, using synthetic peptides and B-B hybridomas. c) Attempt to block the pathogenic autoimmune response in vivo by rendering the autoimmune T helper cells anergic. These studies will help us to design specific therapies that could intervene in the basic steps leading to systematic autoimmune disease in lupus and may direct similar approaches for other rheumatic diseases where the inciting antigen is unknown. Furthermore, understanding the nature of the intrinsic B cell abnormally in these NZB crosses could help elucidate the mechanism of B cell lymphoma development in these mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA031789-15
Application #
3169909
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1979-07-01
Project End
1997-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
15
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Datta, S K; Kaliyaperumal, A; Mohan, C et al. (1997) T helper cells driving pathogenic anti-DNA autoantibody production in lupus: nucleosomal epitopes and CD40 ligand signals. Lupus 6:333-6
Datta, S K; Kaliyaperumal, A; Desai-Mehta, A (1997) T cells of lupus and molecular targets for immunotherapy. J Clin Immunol 17:11-20
Desai-Mehta, A; Lu, L; Ramsey-Goldman, R et al. (1996) Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 97:2063-73
Kaliyaperumal, A; Mohan, C; Wu, W et al. (1996) Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J Exp Med 183:2459-69
Mohan, C; Datta, S K (1995) Lupus: key pathogenic mechanisms and contributing factors. Clin Immunol Immunopathol 77:209-20
Datta, S K; Mohan, C; Desai-Mehta, A (1995) Mechanisms of the pathogenic autoimmune response in lupus: prospects for specific immunotherapy. Immunol Res 14:132-47
Mohan, C; Shi, Y; Laman, J D et al. (1995) Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol 154:1470-80
Mao, C; Osman, G E; Adams, S et al. (1994) T cell receptor alpha-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice. J Immunol 152:1462-70
Mohan, C; Adams, S; Stanik, V et al. (1993) Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 177:1367-81
O'Keefe, T L; Datta, S K; Imanishi-Kari, T (1992) Cationic residues in pathogenic anti-DNA autoantibodies arise by mutations of a germ-line gene that belongs to a large VH gene subfamily. Eur J Immunol 22:619-24

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