Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: IL-23 is currently a target for several forms of autoimmune diseases, yet its role in promoting pathogenic autoantibody development is less clear. IL-23 was required for pathogenic autoantibody production in Fas deficient B6-Faslpr/lpr mice. In contrast, in the type II collagen immunized DBA/1 mice, IL-23 did not promote germinal center (GC) formation and IgG anti-CII autoantibody generation. The purposes of this study are to: (i) determine if IL-23 is required for GC and pathogenic autoantibody development; and (ii) determine if IL-23 acts on follicular T-helper cells (Tfh) or GC B cells to induce autoantibody formation in BXD2 mice.
Methods: Sera autoantibody levels were assessed by ELISA in B6, BXD2, and BXD2-p19-/-mice. GC development was determined by FACS (GL-7+ Fas+) and immunostaining and confocal imaging (PNA+). IL-23R expression was measured by FACS and quantitative real-time PCR. GC program genes and plasma cell program genes expression were measured by quantitative real-time PCR. Exogenous IL-23 was administered to mice using an IL-23 expressing adenovirus (AdIL-23, 2×109 pfu).
Results: There was significantly increased total IgM and IgM anti-DNA and RF but decreased total IgG autoantibodies in BXD2-p19-/- mice compared to BXD2 mice. Surprisingly, the size and number of GC were increased in BXD2-p19-/- mice, compared to IL-23 competent BXD2 mice. Il23r expression was higher in Tfh cells compared to non Tfh cells and Il23r was undetectable in GC B cells. Moreover, administration of AdIL-23 into B6 mice induced significantly increased expression of IL-23R in Tfh cells but not in GC B cells. Despite the lack of IL-23R expression in GC B cells, the low titers of autoantibodies in BXD2-p19-/- mice was associated with a significantly diminished expression of activation-induced cytidine deaminase (AID or Aicda) in GC B cells of BXD2-p19-/- mice compared to BXD2 mice. However, p19 deficiency did not suppressed the expression of other cannonical GC program genes, Bach2 and Pax5.
Conclusion: Our data suggest that IL-23 is required for GC B-cell AID induction and thereby pathogenic autoantibody class-switch recombination. Furthermore, IL-23 acts through a novel population of IL-23R+ responding Tfh cells to promote IgG pathogenic autoantibody production in the BXD2 mouse model of lupus.
This work was supported by grants from R01-AI-071110, R01 AI134023, I01BX004049, 1I01BX000600 and Lupus Research Alliance Distinguished Innovator Award to J.D.M, R01-AI-083705 and the LRA Novel Research Award to H-C.H., and the P30-AR-048311 and the P30-AI-027767 to support flow cytometry analysis.
To cite this abstract in AMA style:Hong H, Wu Q, Yang P, Luo B, Li J, Li H, Cua D, Hsu HC, Mountz JD. IL-23 Acts through IL-23R+ Tfh cells to Promote Pathogenic IgG Autoantibody Formation in Lupus [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/il-23-acts-through-il-23r-tfh-cells-to-promote-pathogenic-igg-autoantibody-formation-in-lupus/. Accessed January 19, 2020.
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