In the proposed studies, we will test the hypothesis that IL-17 enhances autoreactive germinal center (GC) formation via upregulation of regulators of G-protein signaling (RGS) proteins, the enhanced GC T- and B-cell interactions lead to upregulation of activation-induced cytidine deaminase (AID) and the production of highly pathogenic autoantibodies. The significance of these studies lies in the identification of a mechanistic link between IL-17 and autoantibody production and the ability to distinguish the roles of autoantibodies and inflammatory responses in the development of rheumatoid arthritis. BXD2 mice develop spontaneous erosive arthritis and generalized autoimmune disease. A unique immune feature of these mice is the high numbers of Th17 CD4+ T cells, which are spontaneously activated in the spleen. Our data suggest that IL-17 promotes the interaction of B cells and CD4+ T cells in the spleen and the formation of spontaneous GCs. This action of IL-17 is mediated by upregulation of RGS13 and RGS16. Upregulation of these genes decrease, rather than increase, the signaling to the CXCR4 and CXCR5 chemokine receptors expressed on GC B and T cells. In this application, we will address the following questions. (1) Does IL-17 induce the formation and function of autoreactive GCs? The effects of IL- 17 will be determined in terms of its regulation of B-cell migration between the marginal and follicular B- cell zones, B-cell expression of AID, and the production of pathogenic autoantibodies. GC formation will be analyzed by confocal microscopy and FACS analysis. (2) Does IL-17 regulate GC formation by up- regulation of RGS proteins? The ability of IL-17 to regulate chemotaxis will be determined in vitro using a Transwell chamber, Flow chamber live imaging analysis, and in vivo by analysis of homing in BXD2 mice of GFP+ B cells in which the IL-17R or Rgs genes have been modulated using shRNA technology, or B cells obtained from targeted knockout mice. (3) Does IL-17-driven formation of autoreactive GCs contribute to the development of CII arthritis independently of IL-17-driven inflammatory responses? The IL-17 signaling mechanisms in B cells will be identified and similarities to the NF-:B pro-inflammatory pathways will be determined. In parallel, the effects of IL-17 modulation of autoantibody production in B cells vs. peripheral chronic inflammation in the development of erosive arthritis will be determined using a newly established CII arthritis model in BXD2 mice. The feasibility of these studies is ensured by the team of experts that has been assembled and the immediate availability of the reagents and mice that will be used. The potential identification of the events that drive pathogenic autoantibody formation in mouse models of arthritis and the definition of the relative roles of IL-17-driven autoimmunity and inflammation would both suggest novel therapeutic targets for arthritis and other autoimmune diseases and indicate unrecognized effects of therapies currently under development.Short Narrative Arthritis or nephritis-inducing autoantibodies can either initiate or worsen inflammation in patients with rheumatoid arthritis or systemic lupus erythematosus. It is difficult to eliminate these autoantibodies once they are formed. Thus, blocking the formation of germinal centers, which is the biologic factory that these autoantibodies are generated, can be an important and novel therapy for these patients. This proposal will analyze specific molecular pathways that interact in lymphocytes leading to the formation of germinal centers. Understanding of the specific factors produced by these lymphocytes that lead to pathogenic autoantibodies production will provide new targets for intervention of this process.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Johnson, David R
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Ding, Yanna; Li, Jun; Yang, PingAr et al. (2014) Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice. Arthritis Rheumatol 66:2601-12
Li, Hao; Hsu, Hui-Chen; Wu, Qi et al. (2014) IL-23 promotes TCR-mediated negative selection of thymocytes through the upregulation of IL-23 receptor and ROR?t. Nat Commun 5:4259
Li, Jun; Hsu, Hui-Chen; Ding, Yana et al. (2014) Inhibition of fucosylation reshapes inflammatory macrophages and suppresses type II collagen-induced arthritis. Arthritis Rheumatol 66:2368-79
Wang, John H; New, James S; Xie, Shutao et al. (2013) Extension of the germinal center stage of B cell development promotes autoantibodies in BXD2 mice. Arthritis Rheum 65:2703-12
Li, Jun; Yang, PingAr; Wu, Qi et al. (2013) Death receptor 5-targeted depletion of interleukin-23-producing macrophages, Th17, and Th1/17 associated with defective tyrosine phosphatase in mice and patients with rheumatoid arthritis. Arthritis Rheum 65:2594-605
Ding, Yanna; Li, Jun; Wu, Qi et al. (2013) IL-17RA is essential for optimal localization of follicular Th cells in the germinal center light zone to promote autoantibody-producing B cells. J Immunol 191:1614-24
Li, Hao; Wu, Qi; Li, Jun et al. (2013) Cutting Edge: defective follicular exclusion of apoptotic antigens due to marginal zone macrophage defects in autoimmune BXD2 mice. J Immunol 190:4465-9
Mountz, John D; Li, Jun; Hsu, Hui-Chen (2012) Systemic autoimmunity caused by fas deficiency in macrophages: a new perspective on the first identified autoimmunity gene. Arthritis Rheum 64:609-12
Li, Jun; Hsu, Hui-Chen; Yang, PingAr et al. (2012) Treatment of arthritis by macrophage depletion and immunomodulation: testing an apoptosis-mediated therapy in a humanized death receptor mouse model. Arthritis Rheum 64:1098-109
Wang, John H; Wu, Qi; Yang, Pingar et al. (2011) Type I interferon-dependent CD86(high) marginal zone precursor B cells are potent T cell costimulators in mice. Arthritis Rheum 63:1054-64

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