Together, in this study, we demonstrated a novel function of AIM2 in B cells, described an IL-10-DNA demethylation-AIM2-Blimp-1/Bcl-6 pathway, and revealed the pathogenic role of AIM2 in antibody production, providing a potential therapeutic target for SLE treatment, and shedding light on the pathogenesis and therapy of humoral mediated autoimmune diseases. Here, AIM2 is linked to autoimmune disease.