The inflammatory cytokine IL-18 induces self-reactive innate antibody responses regulated by natural killer T cells

Abstract

Inflammatory responses initiate rapid production of IL-1 family cytokines, including IL-18. This cytokine is produced at high levels in inflammatory diseases, including allergy and autoimmunity, and is known to induce IgE production in mice. Here we provide evidence that IL-18 is directly coupled to induction of self-reactive IgM and IgG antibody responses and recruitment of innate B2 B cells residing in the marginal zone of the spleen. Moreover, the data suggest that the B-cell activation occurs predominantly in splenic extrafollicular plasma cell foci and is regulated by natural killer T (NKT) cells that prevent formation of mature germinal centers. We also find evidence that NKT cells control this type of B-cell activation via cytotoxicity mediated by both the perforin and CD95/CD178 pathways. Thus, NKT cells regulate innate antibody responses initiated by an inflammatory stimulus, suggesting a general mechanism that regulates B-cell behavior in inflammation and autoreactivity.

B Cell–Intrinsic MyD88 Signaling Is Essential for IgE Responses in Lungs Exposed to Pollen Allergens

“…Although the contribution of IL-1a/b and IL-18 in lung Th2 responses has been interpreted as an adjuvant effect through epithelial cells and APCs or a direct effect on CD4 + T cells, the role of these cytokines in B cells was previously unknown. However, recapitulating our results from this study and the fact that functional IL-1R and IL-18R are expressed on B cells (54)(55)(56), IL-1a/b and IL-18 also stimulate B cells to promote GC responses and IgE/IgG1 production during the airway instillation of pollen allergens. The results demonstrated in this study are not contradictive to the roles for IL-1 family cytokines on epithelia, myeloid APCs, or T cells that were described previously (37)(38)(39)(40).…”

“…Furthermore, the administration of IL-18 induced strong GC responses and the production of IgE (54). In humans, IL-18Ra is expressed on GC and memory B cells at higher levels than on naive B cells (55), suggesting involvement of IL-18 in GC Ab production.…”

“…Exogenous administration of IL-18 into mice stimulates innate type B cells, such as B-1 B cells and marginal zone B cells, in vivo (54). Furthermore, the administration of IL-18 induced strong GC responses and the production of IgE (54).…”

A Genetic Defect in Mice That Impairs Missing Self Recognition Despite Evidence for Normal Maturation and MHC Class I–Dependent Education of NK Cells

“…The mice had normal proportions of other hematopoietic cells (T cells, dendritic cells, monocytes, and neutrophils) (17,48). However, they had a reduced splenic cellularity and were reported to have a profound defect in the maturation of marginal zone B cells (48). Comparison with other gene-deficient strains revealed that the defect is not due to the absence of CD1 per se, nor to the absence of NKT cells.…”

“…Studies of mixed bone marrow chimeras were consistent with a defect being intrinsic to the IMSR NK cells. The mice had normal proportions of other hematopoietic cells (T cells, dendritic cells, monocytes, and neutrophils) (17,48). However, they had a reduced splenic cellularity and were reported to have a profound defect in the maturation of marginal zone B cells (48).…”