Anti-dsDNA antibodies (Abs) are one of the diagnostic criteria of systemic lupus erythematosus (SLE). To understand how these autoAbs are regulated in healthy individuals and to identify the mechanisms underlying their expression in autoimmunity, we have used an immunoglobulin transgenic (Ig Tg) model. 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 (lpr/lpr) backgrounds. We present data showing that T cells play a determining role in the phenotype of anti-dsDNA B cells. Using Ab depletion to remove CD4 cells, we have demonstrated that the phenotypic changes in anti-dsDNA B cells in Fas-deficient mice - their follicular entry and maturation - are dependent on T cell help. Additionally, using a model system to provide T cell help, we can induce follicular entry, maturation, and Ab production from anti-dsDNA B cells in Fas-sufficient mice. Collectively, these results suggest that the availability of T cell help is responsible for determining whether anti-dsDNA B cells are functionally silent or become activated. Finally, we have identified unique attributes of the lpr/lpr dendritic cells (DCs) that we hypothesize play a central role in generating the (auto)reactive T cell help in vivo. Here, we propose to extend these preliminary findings to identify first, the nature of the CD4 T cell help in young Fas-deficient mice that promotes follicular entry but not terminal differentiation of anti-dsDNA B cells, and the requirements for T cell help in promoting autoAb production in 10-week-old animals. We will test the ability of distinct classes of T cells to provide T cell help to BALB/c anti-dsDNA B cells in Fas-sufficient mice and to alter the kinetics of autoAb production in lpr/lpr mice. Second, we will examine DC function in lpr/lpr mice, and determine the extent to which alterations in DC phenotype in lpr/lpr mice are involved in the initiation of autoimmunity or are secondary to the dysregulation of T and/or B cells. Defining the processes that release certain self-reactive B cells from their tolerant state is critical to the understanding and eventual treatment of autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR047913-04S1
Application #
6923350
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Gretz, Elizabeth
Project Start
2001-08-17
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$80,313
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
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
Hondowicz, Brian D; Alexander, Shawn T; Quinn 3rd, William J et al. (2007) The role of BLyS/BLyS receptors in anti-chromatin B cell regulation. Int Immunol 19:465-75
Pagan, Antonio J; Ramon, Hilda E; Hondowicz, Brian D et al. (2006) T cell-mediated activation and regulation of anti-chromatin B cells. Autoimmun Rev 5:373-6
Fields, Michele L; Metzgar, Michele H; Hondowicz, Brian D et al. (2006) Exogenous and endogenous TLR ligands activate anti-chromatin and polyreactive B cells. J Immunol 176:6491-502
Fields, Michele L; Hondowicz, Brian D; Wharton, Gina N et al. (2005) The regulation and activation of lupus-associated B cells. Immunol Rev 204:165-83
Fields, Michele L; Hondowicz, Brian D; Metzgar, Michele H et al. (2005) CD4+ CD25+ regulatory T cells inhibit the maturation but not the initiation of an autoantibody response. J Immunol 175:4255-64
Fields, Michele L; Nish, Simone A; Hondowicz, Brian D et al. (2005) The influence of effector T cells and Fas ligand on lupus-associated B cells. J Immunol 175:104-11

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