There is an overlap between Vh segments encoding antibodies involved in secondary immune responses against exogenous antigens and those few that are expressed in fetal, autoreactive, and/or CD5 B cells. Consequently, the proposed functions for such 'core' antibodies might be related. This idea predicts that the origin of autoimmunity is linked to mechanisms that regulate primary Vh repertoire development. One such stage and tissue-restricted mechanism is the programmed recombination of targeted Vh genes. A proposed determinant of the targeting event is chromatin accessibility, potentially generated by prior germline transcription of the specified Vh. We propose to study this mechanism and its consequences for autoantibody production primarily in transgenic mice that contain human sequence IgH miniloci sufficient to direct VDJ recombination. Vh genes employed in the miniloci satisfy the above core criteria of expression in fetal B cells, autoreactive B cells and CD5 B cells. Our plan includes in vivo expression studies in normal and autoimmune strains and in vitro cell culture experiments aimed at dissecting cis/trans/acting regulators of germline transcription and chromatin accessibility.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
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
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
Girschick, Hermann J; Grammer, Amrie C; Nanki, Toshihiro et al. (2002) Expression of recombination activating genes 1 and 2 in peripheral B cells of patients with systemic lupus erythematosus. Arthritis Rheum 46:1255-63
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

Showing the most recent 10 out of 53 publications