Hsu HC, Yang P, Wang J et al.Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9:166-175

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Nature Immunology (Impact Factor: 20). 03/2008; 9(2):166-75. DOI: 10.1038/ni1552
Source: PubMed


Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4+ T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

Download full-text


Available from: Robin G Lorenz
  • Source
    • "Likewise, patients with SLE have increased numbers of IL-17-producing cells and an elevated level of IL-17 in the serum, and IL-17-producing cells in affected kidneys (17, 24). It is possible that IL-17-producing cells, as opposed to other T-cell subsets, are early participants in mounting the immune response in peripheral lymphoid tissues (25, 26) and target organs in these patients. Recently, it has been shown that increased Th17 cells correlates with IFN type 1-inducible signature in SLE patients (27). "
    [Show abstract] [Hide abstract]
    ABSTRACT: SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.
    Full-text · Article · May 2014 · Frontiers in Immunology
  • Source
    • "IL-23 inducing mucosal antibody responses is a novel observation and clearly further work is required to address the mechanism. Based on previous reports of IL-17 influencing B cell activation [31] and germinal center development [32], the IL-23 bearing CYT-IVAC could be modulating Th17 responses. Recently, activation of lung Th17 cells were also found to induce the development of polymeric Ig receptor and elevate mucosal secretion of IgA antibodies [33]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Potent and safe adjuvants are needed to improve the efficacy of parenteral and mucosal vaccines. Cytokines, chemokines and growth factors have all proven to be effective immunomodulatory adjuvants when administered with a variety of antigens. We have previously evaluated the efficacy of membrane-anchored interleukins (IL) such as IL-2 and IL-4 co-presented as Cytokine-bearing Influenza Vaccines (CYT-IVACs) using a mouse model of influenza challenge. Findings Here, we describe studies evaluating the parenteral and mucosal adjuvanticity of membrane-bound IL-12 and IL-23 CYT-IVACs in young adult mice. Mucosal immunization using IL-12 and IL-23 bearing whole influenza virus vaccine (WIV) was more effective at eliciting virus-specific nasal IgA and reducing viral lung burden following challenge compared to control WIV vaccinated animals. Both IL-12 and IL-23 bearing WIV elicited the highest anti-viral IgA levels in serum and nasal washes. Conclusions This study highlights for the first time the mucosal adjuvant potential of IL-12 and IL-23 CYT-IVAC formulations in eliciting mucosal immune responses and reducing viral lung burden. The co-presentation of immunomodulators in direct context with viral antigen in whole inactivated viral vaccines may provide a means to significantly lower the dose of vaccine required for protection.
    Full-text · Article · May 2014 · Virology Journal
  • Source
    • "Interestingly, IL-21, a cytokine produced by Th17 cells, in combination with BAFF, has been reported to induce synergistically the differentiation of human memory B cells into antibody-producing plasma cells in the absence of further co-stimulation [25]. BAFF is known to be involved in germinal center formation [26], a process in which IL-17 is also involved [27]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A hallmark of systemic autoimmune diseases like systemic lupus erythematosus (SLE) is the increased expression of interferon (IFN) type I inducible genes, so-called IFN type I signature. Recently, T helper 17 subset (Th17 cells), which produces IL-17A, IL-17F, IL-21 and IL-22, has been implicated in SLE. As CCR6 enriches for Th17 cells, we used this approach to investigate whether CCR6+ memory T helper cells producing IL-17A, IL-17F, IL-21 and/or IL-22 are increased in SLE patients and whether this increase is related to the presence of IFN type I signature. In total, 25 SLE patients and 15 healthy controls (HC) were included. SLE patients were divided into IFN type I signature positive (IFN+) (n = 16) and negative (IFN-) (n = 9) patients as assessed by mRNA expression of IFN inducible genes (IFIGs) in monocytes. Expression of IL-17A, IL-17F, IL-21 and IL-22 by CD4+CD45RO+CCR6+ T cells (CCR6+ cells) was measured by flow cytometry and compared between IFN+, IFN- patients and HC. Increased percentages of IL-17A and IL-17A/IL-17F double producing CCR6+ cells were observed in IFN+ patients compared with IFN- patients and HC. IL-17A and IL-17F expression within CCR6+ cells correlated significantly with IFIG expression. In addition, we found significant correlation between B cell activating factor of the tumour necrosis family (BAFF) - a factor strongly correlating with IFN type I - and IL-21 producing CCR6+ cells. We show for the first time higher percentages of IL-17A and IL-17A/IL-17F double producing CCR6+ memory T helper cells in IFN+ SLE patients, supporting the hypothesis that IFN type I co-acts with Th17 cytokines in SLE pathogenesis.
    Full-text · Article · Mar 2014 · Arthritis research & therapy
Show more