Transgene‐mediated hyper‐expression of IL‐5 inhibits autoimmune disease but increases the risk of B cell chronic lymphocytic leukemia in a model of murine lupus

IL‐5 preferentially activates B1 cells to produce natural antibodies cross‐reactive to self antigens. To determine the role of IL‐5 in antibody‐mediated autoimmune disease, we generated systemic lupus erythematosus (SLE)‐prone (NZB×NZW)F1 mice congenic for IL‐5 transgene (TG‐F1). The transgene unexpectedly reduced the incidence of lupus nephritis. Anti‐DNA antibodies in sera and those produced by splenic B cells in vitro were markedly decreased in TG‐F1 mice, while total polyclonal Ig levels were comparable to those in IL‐5 transgene‐negative (NZB×NZW)F1 (non‐TG‐F1) littermates. Flow cytometry‐sorted splenic B1 cells showed a significant reduction of anti‐DNA antibody synthesis in response to IL‐5, while proliferative responses to IL‐5 did not significantly differ between TG‐F1 and non‐TG‐F1 mice. As TG‐F1 mice aged, frequencies of peripheral B1 cells progressively increased, and the mice frequently developed B cell chronic lymphocytic leukemia (B‐CLL). Our results suggest that dysregulated, continuous high expression of IL‐5 in SLE‐prone mice may directly or indirectly mediate a skewed signaling of proliferation/differentiation of self‐antigen‐activated B1 cells, leading to suppression of autoimmune disease, but instead to aberrant expansion of B1 cells, giving rise to B‐CLL. Thus, this model may provide a clue to the pathogenesis of both SLE and B‐CLL.