IL‐21 promotes the production of anti‐DNA IgG but is dispensable for kidney damage in lyn−/− mice

The autoimmune disease systemic lupus erythematosus is characterized by loss of tolerance to nuclear Ags and a heightened inflammatory environment, which together result in end organ damage. Lyn‐deficient mice, a model of systemic lupus erythematosus, lack an inhibitor of B‐cell and myeloid cell activation. This results in B‐cell hyper‐responsiveness, plasma cell accumulation, autoantibodies, and glomerulonephritis (GN). IL‐21 is associated with autoimmunity in mice and humans and promotes B‐cell differentiation and class switching. Here, we explore the role of IL‐21 in the autoimmune phenotypes of lyn^–/– mice. We find that IL‐21 mRNA is reduced in the spleens of lyn^–/–IL‐6^–/– and lyn^–/–Btk^lo mice, neither of which produce pathogenic autoantibodies or develop significant GN. While IL‐21 is dispensable for plasma cell accumulation and IgM autoantibodies in lyn^–/– mice, it is required for anti‐DNA IgG antibodies and some aspects of T‐cell activation. Surprisingly, GN still develops in lyn^–/–IL‐21^–/– mice. This likely results from the presence of IgG autoantibodies against a limited set of non‐DNA Ags. These studies identify a specific role for IL‐21 in the class switching of anti‐DNA B cells and demonstrate that neither IL‐21 nor anti‐DNA IgG is required for kidney damage in lyn^–/– mice.