A novel mechanism for IL-23 to up-regulate AICDA and promote pathogenic autoantibodies in lupus

Abstract

Abstract Targeting IL-23 to treat autoimmune disease and chronic inflammation is under development based on its proinflammatory function and pro-Th17 cell effects. IL-23 was previously shown to be important for promoting pathogenic autoantibody production in B6-Faslpr/lpr mice. In contrast, the lack of IL-23 did not influence germinal center (GC) formation and IgG anti-CII autoantibodies in type II collagen immunized DBA/1 mice. We determined if IL-23 regulated development of spontaneous GCs and autoantibody production in lupus-prone BXD2 mice by generating IL-23 deficient BXD2-p19−/− mice. There was significantly decreased total IgG, but increased total IgM and IgM anti-DNA and RF autoantibodies in BXD2-p19−/− mice compared to BXD2 mice. Flow cytometry and confocal imaging analyses showed that both the size and number of GL-7+Fas+ GC B cells were increased, yet there was a decreased development of GC dark zone (DZ) (CD86−CXCR4+) B cells in BXD2-p19−/− mice. Interestingly, the expression of activation-induced cytidine deaminase (AICDA or Aicda) was significantly decreased in GC B cells in BXD2-p19−/− mice. However, the expression of GC program genes (Bach2, Pax5) was increased except Bcl6. In contrast, the expression of key plasma cell program genes Prdm1 in GC B cells was diminished in the absence of IL-23. Our data suggest a novel pathway for IL-23 to promote IgG autoantibody production by upregulation of AICDA in the GC DZ. Importantly, such pathway is independent of the canonical GC program genes that have been implicated for the induction of AICDA. These results suggest a potential novel action of anti-IL-23 therapies to inhibit adaptive immune responses in addition to its known inhibitory role of innate response in autoimmune diseases.