Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is driven in part by chronic B and T lymphocyte hyperresponsiveness to self antigens. A deficiency of interleukin‐21 (IL‐21) or IL‐21 receptor (IL‐21R) in mice dramatically reduces inflammation and B and T cell activation in models of autoimmunity, including SLE. However, whether IL‐21 is essential for the maintenance and amplification of preestablished inflammation has not been widely examined in various animal models. The purpose of this study was to examine the impact of novel mouse IL‐21R neutralizing antibodies on recall responses to antigen challenge and on disease progression in the (NZB × NZW)F1 (NZB/NZW) mouse model of SLE.

Humoral and cellular immune responses to immunization with sheep red blood cells (SRBCs) were measured in mice dosed with IL‐21R blocking antibodies. Progression of nephritis and markers of immune activation was monitored in NZB/NZW mice following different anti–IL‐21R treatment regimens.

IL‐21R blockade specifically inhibited secondary IgG responses to SRBC immunization. In NZB/NZW mice, IL‐21R blockade completely inhibited the onset of nephritis, which was associated with dramatic reductions in splenomegaly and in B cell and T cell activation. When administered to mice with preexisting disease, anti–IL‐21R antibody halted the disease progression and mortality and reversed the nephritis in a subset of mice. Furthermore, treatment cessation was not followed by rapid reemergence of disease.

Our results highlight the importance of IL‐21 in promoting humoral recall responses and in sustaining autoimmune inflammation.