CD40L is excessively produced in both human and murine lupus and plays a role in lupus pathogenesis. To address how excess CD40L induces autoantibody production, we crossed CD40L-transgenic mice with the anti-DNA H-chain transgenic mouse lines 3H9 and 56R, well-characterized models for studying B-cell tolerance to nuclear antigens. Excess CD40L did not induce autoantibody production in 3H9 mice in which anergy maintains self-tolerance, nor did it perturb central tolerance, including deletion and receptor editing, of anti-DNA B cells in 56R mice. In contrast, CD40L/ 56R mice restored a large number of marginal zone (MZ) B cells reactive to Sm/ribonucleoprotein (RNP) and produced autoantibody, whereas these B cells were deleted by apoptosis in MZ of 56R mice. Thus, excess CD40L efficiently blocked tolerance of Sm/RNP-reactive MZ B cells, leading to production of anti-Sm/RNP antibody implicated in the pathogenesis of lupus. These results suggest that self-reactive B cells such as anti-Sm/RNP B cells, which somehow escape tolerance in the bone marrow and migrate to MZ, are tolerized by apoptotic deletion in MZ and that a break in this tolerance may play a role in the pathogenesis of lupus.peripheral tolerance | lupus-related autoantibody | marginal zone B cells M aintenance of B-cell tolerance occurs at various checkpoints throughout B-cell development and maturation and involves multiple mechanisms. Self-reactive immature B cells are subjected to central tolerance mechanisms in the bone marrow, including deletion by apoptosis (clonal deletion), functional inactivation (clonal anergy), or Ig V gene replacement (receptor editing) (1-4). B-cell tolerance can also occur after B cells leave the bone marrow and home to peripheral lymphoid organs. This peripheral tolerance involves mechanisms such as anergy, ignorance, and maturation arrest (5-7). Moreover, how tolerance is maintained in self-reactive B cells, which are anergized in bone marrow and migrate to the peripheral lymphoid tissues, has been extensively studied. These B cells are excluded from the follicle or marginal zone (MZ) and show reduced longevity (2, 8-10) attributable to increased dependence on B cell-activating factor belonging to the tumor necrosis factor family (BAFF) for survival (11, 12). However, it is not fully understood how peripheral tolerance mechanisms are broken in autoimmunity.B-cell self-tolerance has been addressed using antibodytransgenic (Tg) mice in which most of the B cells are reactive to a particular self-antigen. The anti-DNA H-chain Tg mice 3H9 and 56R are well-characterized models for studying B-cell tolerance to nuclear antigens (1, 10, 13-16), to which autoantibodies are characteristically produced in various autoimmune diseases including systemic lupus erythematosus (SLE). The 56R H chain was generated by introducing an arginine residue to the 3H9 VH region to increase affinity of the transgene-encoded antibodies for DNA. When paired with almost any of the mouse endogenous Ig L chains, both the 3H9 and the 56R H chains form an...

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