Regulatory mechanisms for self-reactive B cells with somatic mutations in the immunoglobulin genes

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Autoantibodies characteristic for autoimmune diseases have been shown to undergo affinity maturation by somatic hypermutations in their variable regions. Whether self-reactive B cells that have undergone affinity maturation are regulated differently from those without somatic mutations has not yet been elucidated. We have demonstrated that CD40 signaling blocks antigen-mediated apoptosis of B cells, resulting in rescuing self-reactive B cells from clonal deletion. Indeed, patients with systemic lupus erythematosus (SLE) and SLE-prone BXSB mice have been reported to overexpress CD40 ligand (CD40L) on T cells and express CD40L ectopically on B cells. To assess the role of CD40L in generation of self-reactive B cells, we established transgenic mice expressing CD40L on B cells. CD40L-trasgenic mice produce autoantibodies and develop SLE-like glomerulonephritis. Transgenic mice expressing both CD40L and low affinity anti-DNA antibodies show do defects in B cell tolerance. However, those expressing both CD40L and high affinity anti-DNA antibodies show defects in clonal deletion of self-reactive B cells and produce autoantibodies. These results indicate that CD40-mediated breakdown of B cell tolerance requires B cells with high affinity to self-antigens. Self-reactive B cells that acquire somatic mutations in immunoglobulin may be differently regulated from those without somatic mutations at tolerance breakdown.