The role of Tfh cells, Th17 cells, and the gut microbiota in autoimmune arthritis /

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Bibliographic Details
Author / Creator:Block, Katharine Emma, author.
Ann Arbor : ProQuest Dissertations & Theses, 2015
Description:1 electronic resource (121 pages)
Format: E-Resource Dissertations
Local Note:School code: 0330
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Other authors / contributors:University of Chicago. degree granting institution.
Notes:Advisors: Haochu Huang Committee members: Maria-Luisa Alegre; Albert Bendelac; Bana Jabri; Cathryn R. Nagler.
Dissertation Abstracts International, Volume: 77-05(E), Section: B.
Summary:Autoimmune arthritis in the K/BxN mouse model is driven by autoreactive T cells and autoantibodies. Two helper T cell subsets, Tfh and Th17 cells, have been suggested to be able to provide help to B cells. We investigated the contribution of Tfh and Th17 cells, as well as the T cell cytokines IL-21 and IL-17, to disease pathogenesis. Using genetic approaches, we found that IL-21 production from autoreactive T cells was required by B cells for the formation of germinal centers and autoantibodies. IL-21R expression on T cells was not required for Tfh cell differentiation and arthritis suggesting that IL-21 was not an autocrine factor for Tfh cells. T cells deficient in the transcription factor RORgammat and incapable of Th17 cell differentiation induced disease normally. IL-17 deficient mice developed arthritis and had a normal Tfh cell population, germinal centers, and autoantibody levels.
The gut microbiota is known to promote disease in this model, and we investigated the effect of gut bacteria on T cell differentiation. Because Th17 cell differentiation is promoted by gut bacteria, Th17 cells has been suggested to mediate the effect of gut bacteria on arthritis. However, we showed that gut microbiota regulates autoimmune development independent of IL-17. In contrast, Tfh cell differentiation was defective in antibiotic treated mice. Furthermore, Bcl6 deficient T cells incapable of Tfh cell differentiation did not induce disease. We conclude that the Th17 axis is not required for K/BxN arthritis. Our studies highlight the role Tfh cells and IL-21 plays in autoantibody formation and their relationship to gut microbiota. These results have implications in treatment of human autoimmune arthritis.