Accumulation of splenic plasma cells in lyn−/− mice is dependent on Bruton's tyrosine kinase but not IL‐6

Abstract

Deficiency of Lyn, a negative regulator of B and myeloid cell activation, results in B cell hyperresponsiveness, plasma cell accumulation, and production of autoantibodies in mice. Since accumulation of peripheral plasma cells is a common feature of both human and murine lupus, we have studied the mechanisms regulating this process in lyn−/− mice. Lyn‐deficient mice expressing reduced dosage of Btk (Btklo), a target of Lyn‐dependent inhibitory pathways, retain hypersensitivity to B cell receptor crosslinking but do not demonstrate increased plasma cell numbers or produce autoantibodies. Bone marrow‐derived macrophages from lyn−/− mice secrete more IL‐6, which promotes plasma cell differentiation and survival, than do wild type cells upon stimulation with LPS. Intracelluar staining for IL‐6 in splenic CD11b+ cells reveals that a greater frequency of lyn−/− myeloid cells produce IL‐6 upon LPS exposure than do wild type cells. Also, sera IL‐6 is significantly increased in aged lyn−/− mice. To determine if these effects are Btk‐mediated, we examined lyn−/−btklo mice and found that both production of IL‐6 in splenic CD11b+ cells and sera IL‐6 levels are normalized in lyn−/−btklo mice. However, lyn−/−IL‐6−/− mice continue to exhibit both plasma cell accumulation and production of anti‐DNA antibodies. Thus, plasma cell and autoimmune phenotypes in lyn−/− mice are mediated by Btk but not IL‐6.