A hallmark of systemic lupus erythematosus (SLE), and murine models of lupus, is the presence of anti-double-stranded (ds) DNA Abs. Our goals are to understand how SLE-associated autoantibodies are regulated in healthy individuals and to identify the mechanisms underlying their expression in autoimmunity. The approach we have taken is to develop a transgenic (Tg) model using a heavy chain-only Tg (VH3H9) which can pair with endogenous light chains to generate a spectrum of anti-DNA and non-DNA antibodies (Abs). The advantage of this model is that the development of anti-dsDNA B cells can be tracked in the context of a diverse B cell repertoire in non- autoimmune and autoimmune-prone backgrounds.
Aim 1 of this competitive renewal is to compare the effects of distinct genetic mutations that are known to result in the production of SLE-associated autoantibodies on the phenotype and functional capacity of anti-dsDNA B cells. Specifically, lpr/lpr, gld/gld, and lyn-/- mice will be studied. Furthermore, the regulation of dsDNA B cells will also be investigated in induced models of SLE. Using the VH3H9 Tg in MRL-lpr/lpr mice, we have identified changes in the developmental status and tissue localization of anti-dsDNA B cells that precede autoantibody production.
Aim II is to understand the mechanisms behind these phenomena, with particular emphasis on identifying the role that defective Fas (lpr/lpr) plays in autoantibody expression.
Aim III is to characterize the nature and significance of the CD4 T cells that co-localize with anti-dsDNA B cells in MRL-lpr/lpr mice. The novel aspect of the proposed studies is that, in the context of the VH3H9 Tg, we can follow the fate of anti-dsDNA B cells under diverse circumstances to begin to identify steps that lead to autoantibody production. Knowledge of the parameters that influence the production of autoantibodies may inspire more targeted therapy for SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032137-11
Application #
6475677
Study Section
Special Emphasis Panel (ZRG1-ALY (01))
Program Officer
Johnson, David R
Project Start
1991-12-01
Project End
2004-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
11
Fiscal Year
2002
Total Cost
$365,608
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hondowicz, Brian D; Batheja, Amrita O; Metzgar, Michele H et al. (2010) ICOS expression by effector T cells influences the ability of regulatory T cells to inhibit anti-chromatin B cell responses in recipient mice. J Autoimmun 34:460-8
Hondowicz, Brian D; Batheja, Amrita O; Metzgar, Michele H et al. (2009) Efficient help for autoreactive B-cell activation requires CD4+ T-cell recognition of an agonist peptide at the effector stage. Eur J Immunol 39:2377-82
Mandik-Nayak, Laura; Ridge, Natalie; Fields, Michele et al. (2008) Role of B cells in systemic lupus erythematosus and rheumatoid arthritis. Curr Opin Immunol 20:639-45
Hondowicz, Brian D; Fields, Michele L; Nish, Simone A et al. (2008) Autoantibody production in lpr/lpr gld/gld mice reflects accumulation of CD4+ effector cells that are resistant to regulatory T cell activity. J Autoimmun 31:98-109
Fields, M L; Sokol, C L; Eaton-Bassiri, A et al. (2001) Fas/Fas ligand deficiency results in altered localization of anti-double-stranded DNA B cells and dendritic cells. J Immunol 167:2370-8
Mandik-Nayak, L; Nayak, S; Sokol, C et al. (2000) The origin of anti-nuclear antibodies in bcl-2 transgenic mice. Int Immunol 12:353-64
Mandik-Nayak, L; Seo, S j; Eaton-Bassiri, A et al. (2000) Functional consequences of the developmental arrest and follicular exclusion of anti-double-stranded DNA B cells. J Immunol 164:1161-8
Eaton-Bassiri, A S; Mandik-Nayak, L; Seo, S J et al. (2000) Alterations in splenic architecture and the localization of anti-double-stranded DNA B cells in aged mice. Int Immunol 12:915-26
Noorchashm, H; Bui, A; Li, H L et al. (1999) Characterization of anergic anti-DNA B cells: B cell anergy is a T cell-independent and potentially reversible process. Int Immunol 11:765-76
Choi, Y; Ramnath, V R; Eaton, A S et al. (1999) Expression in transgenic mice of dominant interfering Fas mutations: a model for human autoimmune lymphoproliferative syndrome. Clin Immunol 93:34-45

Showing the most recent 10 out of 15 publications