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 exposed 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. Elevated levels of IL-33 induce the production of autoantibodies through an unknown mechanism. Here, the authors show that IL-33 disrupts splenic architecture and germinal center organization, causing an expansion of antibody-secreting plasmablasts and plasma cells. In multiple mouse models of inflammation, administration of IL-33 exacerbates the pathology, increasing the production of autoantibodies, whereas IL-33 blockade reverses autoantibody production in a model of lung inflammation.

Background: During chronic inflammation, lymphoid aggregates (LAs) composed of a large aggregate of B cells are formed at mucosal sites. The presence of LAs has also been reported in the lungs of patients with asthma and severe COPD. However, the functional relevance of LAs in airway inflammation remains unclear. Methods: We exposed mice to HDM extract or saline intranasally three times per week for up to 15 weeks. Localization of LAs and B/PCs within lung tissue was assessed by immunofluorescence microscopy. Transcriptional profiling of lung B/PCs was performed using single-cell RNA-seq. IgG1, IgA, and IgE production was measured in lung tissue by ELISA and ELISPOT. Gene expression of Ighg1, Igha, and Ighe was assessed by TaqMan. Results: B cells accumulated in the lung tissue after HDM exposure, with a subset expressing Fas, Gl7, Aicda, Ki67, and Bcl6 (GC-like markers) and the immunoglobulin transcripts Ighg1, Igha, and Ighe, suggesting the occurrence of local class-switching at mucosal sites. A second subset expressed genes associated with PC differentiation, including Prdm1, Xbp1, Sdc1, and Tnfrsf17. Histological analysis revealed that upon short-term (4 weeks) allergen exposure, B cells formed aggregates together with T cells mainly around the airway epithelial wall. Surprisingly, we found that PCs localized outside of the LAs and produced Der p1-specific antibodies, suggesting that allergen-specific antibodies are produced in the lung outside of LAs. In contrast, long-term allergen exposure (15 weeks) led to the dissemination of these LAs to distal parts of the lung with a different cellular composition compared to acute exposure. Finally, systemic depletion of B cells abolished lung LAs and resulted in changes in airway inflammation and remodeling. Conclusions: These data demonstrate that the lung can serve as a source of B cell class-switching, PC differentiation, and local antibody production during repeated intranasal allergen exposure.

Understanding the phenotypic and transcriptional signature of immunoglobulin E (IgE)-producing cells is fundamental to plasma cell (PC) biology and development of therapeutic interventions for allergy. Here, using a mouse model of intranasal house dust mite (HDM) exposure, we showed that short-lived IgE PCs emerge in lung draining lymph nodes (dLNs) during early exposure (<3 weeks) and long-lived IgE PCs accumulate in the bone marrow (BM) with prolonged exposure (>7 weeks). IgE PCs had distinct surface and gene expression profiles in these different tissues compared with other Ig isotypes. IgE BMPCs up-regulated genes associated with prosurvival and BM homing, whereas IgE dLN PCs expressed genes associated with recent class switching and differentiation. IgE PCs also exhibited higher expression of endoplasmic reticulum (ER) stress and protein coding genes and higher antibody secretion rate when compared with IgG1. Overall, this study highlights the unique developmental path and transcriptional signature of short-lived and long-lived IgE PCs.

Food allergy affects a growing number of infants, children, and adults worldwide. Food allergen specific oral immunotherapy (OIT) has been demonstrated to clinically desensitize individuals however is accompanied by a risk of moderate to severe adverse events including life-threatening anaphylaxis. Biologics targeting type 2 inflammation and the reduction of IgE are currently under investigation as an adjunct to OIT to enhance safety and efficacy. Herein, we utilize murine models of anaphylaxis and food allergy diagnosis and treatment to evaluate the benefit of Interleukin-4 Receptor alpha (IL-4Ra) blockade as an adjunct to OIT.