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 #
1R01DE017568-01
Application #
7126206
Study Section
Special Emphasis Panel (ZDE1-YL (33))
Program Officer
Shum, Lillian
Project Start
2006-07-01
Project End
2011-04-30
Budget Start
2006-07-01
Budget End
2007-04-30
Support Year
1
Fiscal Year
2006
Total Cost
$353,210
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