Background/Purpose: Targeting IL-23 to treat autoimmune disease and chronic inflammation is currently in development based on its pro-inflammatory function via regulating the activation of Th17 cells. IL-23 was previously shown to be important for promoting pathogenic autoantibody production in Fas deficient B6-Fas^lpr/lpr mice, suggesting the positive role of IL-23 in mediating Fas-independent germinal center (GC) responses. In contrast, the lack of IL-23 did not influence conventional GC formation and IgG anti-CII autoantibodies in type II collagen immunized DBA/1 mice. We determined if IL-23 could regulate development of GCs and pathogenic autoantibody production in BXD2 mice.

Methods: The BXD2-IL-23 p19^–⁄– mice were generated by 10 generation crossing the B6-p19^–⁄– with the BXD2 mice. Serum autoantibodies were determined by ELISA. GC development was measured by FACS (GL-7 and Fas) and confocal imaging analyses. Autoantibody class switching was enumerated by the percentage of (IgM^–IgD^–) in GL-7⁺ B cells. Immune complex deposition (IgM and IgG) in kidney was detected by confocal imaging.

Results: There was lower induction of Il17a in subpopulations of spleen cells from BXD2-p19^–⁄– mice compared to WT BXD2 mice. However, unlike BXD2-Il17ra^–⁄– mice, which developed lower levels of both IgM and IgG autoantibodies, BXD2-p19^–⁄– mice exhibited significantly elevated titer of total IgM and IgM anti-DNA and RF autoantibodies but significantly lower levels of total IgG and IgG anti-histone, compared to WT BXD2 mice. Despite the lower circulating IgG autoantibodies, IgG staining was significantly increased in the glomerulus of BXD2-p19^–⁄– mice compared to BXD2 and normal B6 mice with both an immune complex and linear staining pattern. The number and size of PNA⁺ GCs and the percent of GL-7⁺Fas⁺ GC B cells were increased in BXD2-p19^–⁄– mice comparable to WT BXD2 mice. Abnormal GC development kinetics was confirmed by increased conventional isotype switched IgM^–IgD^– GL7⁺Fas⁺ B cells in BXD2-p19^–⁄– mice compared to BXD2 WT mice.

Conclusion: The present findings provide a potential link to consolidate previous findings on the importance of IL-23 in mediating IgG autoantibody development in B6-Fas^lpr/lpr mice and the lack of effects in development of IgG anti-CII antibody in CII immunized IL-23 deficient mice. These results extend the paradigm of IL-23 disease beyond the classical IL23-Th17 axis and suggest IL-23 exhibits a negative effect on development of classical GC B cells that produce highly pathogenic autoAbs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-23-regulates-development-of-spontaneous-germinal-centers-and-pathogenic-autoantibody-production-in-bxd2-mice/