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Abstract Number: 2795

IL-23 Acts through IL-23R+ Tfh cells to Promote Pathogenic IgG Autoantibody Formation in Lupus

Huixian Hong1, Qi Wu2, PingAr Yang2, Bao Luo3, Jun Li4, Hao Li5, Daniel Cua6, Hui-Chen Hsu2 and John D. Mountz7, 1University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, Department of Medicine, Birmingham, AL, 2Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, Department of Medicine, Birmingham, AL, 3DIvision of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, Department of Medicine, Birmingham, AL, 4Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, Department of Medicine, Birmingham, AL, 5Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 6Discovery Research, Merck Research Laboratory, Palo Alto, CA, 7University of Alabama at Birmingham, Devision of Clinical Immunology and Rheumatology; University of Alabama at Birmingham and Birmingham VA Medical Center, Birmingham, AL

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: auto-immunity and autoantibodies, B cells, T cells

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Session Information

Date: Tuesday, October 23, 2018

Title: 5T085 ACR Abstract: B Cell Biology & Targets in Autoimmune & Inflammatory Disease (2791–2796)

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.


Disclosure: H. Hong, None; Q. Wu, None; P. Yang, None; B. Luo, None; J. Li, None; H. Li, None; D. Cua, None; H. C. Hsu, None; J. D. Mountz, None.

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 9). https://acrabstracts.org/abstract/il-23-acts-through-il-23r-tfh-cells-to-promote-pathogenic-igg-autoantibody-formation-in-lupus/. Accessed .
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