Abstract
CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L-transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig λ1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig λ1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break.
Highlights
Antibodies to nuclear antigens such as DNA and the RNA-related Sm/RNP antigen are characteristically produced in patients with systemic lupus erythematosus (SLE), a prototype of systemic autoimmune diseases, and play a role in the development of this autoimmune disease[1,2,3]
Using CD40L/56R double transgenic mice expressing both the anti-DNA H chain 56R and CD40L in B cells, we previously demonstrated that anti-Sm/RNP B cells are regulated by a novel tolerance mechanism in peripheral lymphoid tissue, i.e., deletion in splenic marginal zone (MZ), and that the MZ deletion is perturbed by excess CD40L19
Excess CD40L fails to expand anergized anti-DNA B cells To address whether excess CD40L perturbs clonal anergy of anti-DNA B cells, we crossed CD40L Tg mice with 3H9 mice, because B cells expressing Ig λ1 L chain and 3H9 H chain are reactive to DNA and show characteristics for anergy including follicular exclusion, shortened life span and failure of antibody production[23]
Summary
Antibodies to nuclear antigens such as DNA and the RNA-related Sm/RNP antigen are characteristically produced in patients with systemic lupus erythematosus (SLE), a prototype of systemic autoimmune diseases, and play a role in the development of this autoimmune disease[1,2,3]. How B cells reactive to nuclear antigens are regulated has been extensively studied using transgenic (Tg) mice expressing auto-antibodies against DNA and RNA components, especially the anti-DNA H chain-Tg mouse lines 3H9 and 56R4–9 Studies using these auto-antibody-Tg mice demonstrated that self-reactive B cells that produce autoantibodies to nuclear antigens are deleted by apoptosis (clonal deletion)[10], are functionally inactivated (clonal anergy)[11] or change antigen specificity by immunoglobulin (Ig) V gene replacement (receptor editing)[8,12], in the bone marrow before they migrate to the peripheral lymphoid organs. In both patients with SLE and in SLE mouse models, CD40L is overexpressed by T cells and ectopically expressed in B cells[15,16,17], and this excess CD40L expression appears to play a role in development of SLE, as treatment with antagonistic anti-CD40L antibody markedly reduces the severity of the disease in both humans and mice[18]
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