Treatment of BXSB-Yaa mice with IL-21R-Fc fusion protein minimally attenuates systemic lupus erythematosus.

Interleukin-21 (IL-21) is a pleiotropic cytokine whose function is only now being unraveled. Abundant evidence indicates that activated CD4 T cells are the primary, if not the only, source of IL-21. While it is clear that IL-21 is actively transcribed by naïve activated T cells, recent studies have shown that IL-21 potentially promotes a developmental shift of naïve T cells toward the Th2 phenotype. BXSB-Yaa mice develop an autoimmune syndrome similar to systemic lupus erythematosus (SLE), affecting males earlier than females on account of the presence of the Yaa (Y-linked autoimmune acceleration) locus. Previous results indicate the elevation of IL-21 expression by BXSB-Yaa mice at an age when the early characteristics of autoimmune processes first become evident. We set out to determine whether IL-21 was necessary for disease progression in BXSB-Yaa mice. Mice were treated for 24 weeks with soluble IL-21R-Fc in order to therapeutically neutralize the IL-21 present. The results overall suggest a biphasic effect of IL-21, negatively influencing survival early on and positively influencing survival at later stages. We propose that IL-21 exerts a pleiotropic effect in which it promotes the protective effects of CD8+ suppressor cells in the early disease phase and then promotes the humoral components of SLE in the later disease stages. This experiment provides preliminary evidence for a role of IL-21 in modulating the severity of SLE in BXSB-Yaa mice.