Background: 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.

Objectives: To define the role of IL-33 in regulating B cell responses and how this impacts disease pathology.

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. The role of IL-33 in lung autoantibody production was also investigated in mouse models of lung inflammation.

Results: We show 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 demonstrate that IL-33 induces IL-5 driven production of IgM and IgG2a, as well as CD4+ T cell driven production of IgG1 and IgE. This IL-33 induced antibody production is accompanied by disrupted splenic architecture and elevated autoantibody production, indicating a break in peripheral tolerance. Consistent with this, overexpression of IL-33 exacerbated autoantibody production, kidney damage and decreased survival in a mouse model of lupus. Additionally, either intranasal delivery of IL-33 or exposure to house dust mite extract (HDM) increased 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.

Conclusion: Taken together, our data demonstrate that IL-33 expands plasma cells, disrupts germinal centers and promotes autoantibody production that may exacerbate disease pathologies.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Andre Limnander is a current employee of Regeneron, may hold Regeneron stock or stock options, Eva Conde is a current employee of Regeneron, may hold Regeneron stock or stock options, Seblewongel Asrat is a current employee of Regeneron, may hold Regeneron stock or stock options, Andrea Vecchione is a current employee of Regeneron, may hold Regeneron stock or stock options, Kaitlyn Gayvert is a current employee of Regeneron, may hold Regeneron stock or stock options, Paulina Pedraza is a current employee of Regeneron, may hold Regeneron stock or stock options, Carley Tasker is a current employee of Regeneron, may hold Regeneron stock or stock options, Sharon Huang is a current employee of Regeneron, may hold Regeneron stock or stock options, Dmitry Yarilin is a current employee of Regeneron, may hold Regeneron stock or stock options, Dylan Birchard is a current employee of Regeneron, may hold Regeneron stock or stock options, Li-Hong Ben is a current employee of Regeneron, may hold Regeneron stock or stock options, Wei Keat Lim is a current employee of Regeneron, may hold Regeneron stock or stock options, Andrew Murphy is a current employee and officer of Regeneron, may hold Regeneron stock or stock options, Matthew Sleeman is a former employee of Regeneron, may hold Regeneron stock or stock options, Jamie Orengo is a current employee and officer of Regeneron, may hold Regeneron stock or stock options.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.