IL-33 expands plasma cells, disrupts germinal centers, and increases autoantibody production in mice.

Abstract

IL-33 is an inflammatory cytokine contributing to asthma, Chronic Obstructive Pulmonary Disease (COPD), and autoimmune diseases. Although recent studies suggest that IL-33 can induce the generation of autoantibodies, the role of IL-33 on B cell maturation and tolerance is poorly understood. Here, by inducing systemic overexpression of IL-33 in mice, we show that this cytokine induces the IL-5 and CD4 T cell-dependent accumulation of plasmablasts and plasma cells of all isotypes in the spleen, and leads to an increased antibody production. IL-33 also disrupts splenic architecture and elevates autoantibody production, indicating a break in peripheral tolerance. Consistently, elevated levels of IL-33 exacerbate autoantibody production, kidney damage, and decrease survival in a mouse model of lupus. Additionally, intranasal delivery of IL-33 in mice or exposure to house dust mite extract (HDM) increases autoantibodies in the lung. Notably, blocking IL-33 reduced the autoantibodies generated during HDM exposure, indicating that HDM-induced autoantibody production is IL-33 dependent. Thus, our findings implicate IL-33 in the break of peripheral B cell tolerance, opening new therapeutic avenues for the treatment of infection, COPD and autoimmune conditions.