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. ? ? ?
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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 |
