Background/Purpose: IL-33 is a pro-inflammatory cytokine that plays a role in asthma, COPD and autoimmune diseases. The role of IL-33 on B cell maturation and tolerance, however, is poorly understood.

Methods: The impact of systemic delivery of IL-33 via hydrodynamic DNA delivery was evaluated in mice, and in mouse immunization and lupus models. Changes in the cellular composition of various immune organs and levels of circulating cytokine, total immunoglobulin and autoantibody levels were characterized. Additional histological evaluation of the spleen was performed to further define changes to splenic architecture. Mechanistic insights were obtained using different systemic interventions to block individual pathways downstream of IL-33 delivery. The impact of IL-33 on the quality of T-dependent immunization responses was also evaluated, as was its impact on the progression and severity of lupus-like pathology in a lupus mouse model.

Results: We showed that IL-33 can induce the differentiation and accumulation of plasmablasts and plasma cells of all isotypes in the spleen leading to increased antibody production. Specifically, we showed that IL-33 leads to T-independent, IL-5 driven IgM/IgG2a production, and T-dependent production of IgG1 and IgE. This enhanced IL-33-driven antibody production was accompanied by disrupted splenic architecture and increased autoantibody production suggesting a break in peripheral B cell tolerance. In immunized mice, IL-33 disrupts germinal centers and generates antigen-specific antibodies of decreased affinity. In a mouse model of lupus, IL-33 exacerbates autoantibody production, kidney damage and decreases survival.

Conclusion: Taken together, these data demonstrate that IL-33 can promote plasma cell differentiation and autoantibody production at the expense of antigen-specific germinal center responses, with potential implications in autoimmunity. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-33-expands-plasma-cells-disrupts-germinal-centers-and-increases-autoantibody-production/