Regulation of the B cell receptor repertoire and self reactivity by BAFF. Mus musculus

The TNF-family cytokine BAFF (TNFSF13B, BLyS) promotes B lymphocyte survival and is overexpressed in individuals with systemic lupus erythematosus and Sjögren's Syndrome. BAFF can rescue anergic autoreactive B cells from death, but only when competition from nonautoreactive B cells is lacking. Yet high BAFF levels promote autoantibody formation in individuals possessing diverse B cells. To better understand how excess BAFF promotes autoimmunity in a polyclonal immune system, immunoglobulin light (L)-chain usage was analyzed in 3H9 site-directed IgH-chain transgenic mice, whose B cells recognize DNA and chromatin when they express certain endogenous L-chains. BAFF levels were manipulated in 3H9 mice by introducing transgenes expressing either BAFF or its natural inhibitor DBAFF. B cells in BAFF/3H9 mice were elevated in number, used a broad L-chain repertoire, including L-chains generating high affinity autoreactivity, and produced abundant autoantibodies. Comparison of spleen and lymph node B cells suggested that highly autoreactive B cells were expanded. By contrast, DBAFF/3H9 mice had reduced B cell numbers with a repertoire similar to that of 3H9 mice, but lacking usage of a subset of Vk genes. The results show that limiting BAFF signaling only slightly selects against higher affinity autoreactive B cells, whereas its overexpression leads to broad tolerance escape and positive selection of autoreactive cells. The results have positive implications for the clinical use of BAFF-depleting therapy.