Sjogren's Syndrome (SS) is a systemic autoimmune disease associated with chronic inflammation of salivary and lacrimal glands that is characterized by autoantibody formation and B cell hyperactivity. Elevated levels of the B cell survival cytokine BAFF are associated with lupus and SS in both humans and experimental animals. The absence of BAFF, by contrast, leads to a severe deficiency in B cells. The applicant's laboratory recently discovered an inhibitory BAFF splice isoform, deltaBAFF, that has not been taken into account in most studies, but which may be a key regulator modulating the potential extreme effects of too much or too little BAFF activity. Studies from autoantibody transgenic mice have indicated that autoreactive B cells are more dependent on BAFF for survival than are non-autoreactive B cells. However, this differential dependence can only be revealed in situations in which autoreactive B cells make up a large fraction of all B cells, i.e., in the absence of cell: cell competition. Therefore, it is not clear how excess BAFF promotes autoimmunity in a polyclonal immune system. As BAFF has effects on T cells as well as B cells, it is not excluded that excess BAFF breaks B cell tolerance indirectly, through T cell dysregulation. Alternatively, BAFF may rescue only those autoantibodies of relatively low affinity. These hypotheses will be tested in the following Specific Aims: 1) To determine in a polyclonal immune system whether or not BAFF over-expression selectively rescues low affinity self-reactive clones. 2) To determine if reduction in BAFF levels by deltaBAFF over-expression leads to subnormal levels of basal autoantibody activity and more stringent self-tolerance. 3) To assess autoantibody formation and B cell tolerance in BAFF over-expressing mice lacking T cells. The long-term goal of these studies is to understand how BAFF promotes Sjogren's Syndrome and to determine the basic parameters regulating immune tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017568-05
Application #
7816742
Study Section
Special Emphasis Panel (ZDE1-YL (33))
Program Officer
Burgoon, Penny W
Project Start
2006-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$342,305
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Ota, Miyo; Duong, Bao H; Torkamani, Ali et al. (2010) Regulation of the B cell receptor repertoire and self-reactivity by BAFF. J Immunol 185:4128-36