The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases (original) (raw)
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Interleukin-17-producing T helper cells in autoimmunity
Autoimmunity Reviews, 2010
With all the incredible progress in scientific research over the past two decades, the trigger of the majority of autoimmune disorders remains largely elusive. Research on the biology of T helper type 17 (T H 17) cells over the last decade not only clarified previous observations of immune regulations and disease manifestations, but also provided considerable information on the signaling pathways mediating the effects of this lineage and its seemingly dual role in fighting the invading pathogens on one hand, and in frightening the host by inducing chronic inflammation and autoimmunity on the other hand. In this context, recent reports have implicated T H 17 cells in mediating host defense as well as a growing list of autoimmune diseases in genetically-susceptible individuals. Herein, we summarize the current knowledge on T H 17 in autoimmunity with emphasis on its differentiation factors and some mechanisms involved in initiating pathological events of autoimmunity.
A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders
Molecular Immunology, 2019
The T helper 17 (Th17) cells contain a dynamic subset of CD4+ T-cells that are able to develop into other different lineage subsets, including the Th1-like Th17 cells. These cells co-express retinoic acid-related orphan receptor gamma t (RORγt) and transcription factor T-box-expressed-in-T-cells (T-bet) and produce both interleukin (IL)-17 and interferon (IFN)-γ. Recent reports have shown that Th1-like Th17 cells play crucial roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, as well as, some primary immunodeficiency with autoimmune features. Here, the actual mechanisms for Th17 cells plasticity to Th1-like Th17 cells are discussed and reviewed in association to the role that Th1-like Th17 cells have on inflammatory and autoimmune disorders.
Immunological Reviews, 2008
Our understanding of the role of T cells in human disease is undergoing revision as a result of the discovery of T-helper 17 (Th17) cells, a unique CD4 1 T-cell subset characterized by production of interleukin-17 (IL-17). IL-17 is a highly inflammatory cytokine with robust effects on stromal cells in many tissues. Recent data in humans and mice suggest that Th17 cells play an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma. Initial reports also propose a role for Th17 cells in tumorigenesis and transplant rejection. Important differences, as well as many similarities, are emerging when the biology of Th17 cells in the mouse is compared with corresponding phenomena in humans. As our understanding of human Th17 biology grows, the mechanisms underlying many diseases are becoming more apparent, resulting in a new appreciation for both previously known and more recently discovered cytokines, chemokines, and feedback mechanisms. Given the strong association between excessive Th17 activity and human disease, new therapeutic approaches targeting Th17 cells are highly promising, but the potential safety of such treatments may be limited by the role of these cells in normal host defenses against infection.
Autoimmune diseases in the TH17 era
Brazilian Journal of Medical and Biological Research, 2009
A new subtype of CD4 + T lymphocytes characterized by the production of interleukin 17, i.e., TH17 cells, has been recently described. This novel T cell subset is distinct from type 1 and type 2 T helper cells. The major feature of this subpopulation is to generate significant amounts of pro-inflammatory cytokines, therefore appearing to be critically involved in protection against infection caused by extracellular microorganisms, and in the pathogenesis of autoimmune diseases and allergy. The dynamic balance among subsets of T cells is important for the modulation of several steps of the immune response. Disturbances in this balance may cause a shift from normal immunologic physiology to the development of immune-mediated disorders. In autoimmune diseases, the fine balance between the proportion and degree of activation of the various T lymphocyte subsets can contribute to persistent undesirable inflammatory responses and tissue replacement by fibrosis. This review highlights the importance of TH17 cells in this process by providing an update on the biology of these cells and focusing on their biology and differentiation processes in the context of immune-mediated chronic inflammatory diseases.
International Immunology, 2008
T helper 17 (T h 17) cells represent a new subset of CD41 effector T cells which have been described in both mice and humans. However, some differences seem to exist between murine and human T h 17 cells with regard to their features, origin and role in immunopathology. Murine T h 17 cells share their developmental origin with Foxp31 Treg cells, indeed naive T-cell precursors can be differentiated to regulatory T (Treg) cells by transforming growth factor-b (TGF-b) alone, whereas the contemporaneous presence of TGF-b and IL-6 gives origin to T h 17 cells. Human T h 17 cells which consistently express the CC chemokine receptor 6 and the equivalent of the murine NK1.1, CD161, appear to exclusively originate in response to IL-1b and IL-23 from a small subset of CD1611CD41 T-cell precursors detectable in the thymus and in umbilical cord blood. These cells constitutively express the T h 17-driving transcription factor retinoic acid-related orphan receptor (ROR)gt and the IL-23R and can also give origin to T h 1 cells or T h 2 cells under the appropriate polarizing conditions. By contrast, human CD161-naive T cells only give rise to T h 1 and T h 2 cells, but not T h 17 cells. TGF-b may not exert a direct critical role in human T h 17 cell differentiation, but indirectly favours their development by inhibiting the development of T h 1 cells, which are much more susceptible than T h 17 cells to its suppressive activity on cell proliferation. Moreover, while murine T h 17 are pathogenic in some murine models of autoimmunity where T h 1 cells seem to play a protective role, both T h 17 and T h 1 certainly contribute to the pathogenesis of human autoimmune and other chronic inflammatory disorders.
Distinct regulation of interleukin-17 in human T helper lymphocytes
Arthritis & Rheumatism, 2007
Objective-IL-17 producing helper T cells have been proposed to represent a separate lineage of CD4 + cells, designated Th17 cells, which are regulated by the transcription factor RORγt. However, despite advances in understanding murine Th17 differentiation, a systematic assessment of factors that promote the differentiation of naïve human T cells to Th17 cells has not been reported. This present study was undertaken to assess the effects of cytokines known to promote murine Th17 cells on naïve human CD4 + T cells.
Role of TH-17 Cells in Rheumatic and Other Autoimmune Diseases
Rheumatology : Current Research, 2011
In humans multiple pathways can induce TH-17 cell differentiation, whereas in mice this process is mostly modulated by IL-6 and TGF-β. IL-17 produced by TH-17 cells has been associated with a number of inflammatory autoimmune diseases including psoriasis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. In this review, we have primarily focused on the role of TH-17 cells/IL-17 in the pathogenesis of rheumatoid arthritis and experimental arthritis. The potential role of TH-17 cells in rheumatoid arthritis progression has been demonstrated by correlating the percent TH-17 cells or levels of IL-17 with rheumatoid arthritis disease activity score and C-reactive protein levels. Further, previous studies suggest that IL-17 mediated vascularization may lay the foundation for rheumatoid arthritis joint neutrophil and monocyte recruitment as well as cartilage and bone destruction. The profound role of IL-17 in the pathogenesis of experimental arthritis may be due to its synergistic effect with TNF-α and IL-1β. Although the initial clinical trial employing anti-IL-17 antibody has been promising for rheumatoid arthritis, future studies in humans will shed more light on how anti-IL-17 therapy affects rheumatoid arthritis and other autoimmune disease pathogenesis.
Reasons for rarity of Th17 cells in inflammatory sites of human disorders
Seminars in Immunology, 2013
T helper 17 (Th17) cells have been reported to be responsible for several chronic inflammatory diseases. However, a peculiar feature of human Th17 cells is that they are very rare in the inflammatory sites in comparison with Th1 cells. The first reason for this rarity is the existence of some self-regulatory mechanisms that limit their expansion. The limited expansion of human Th17 cells is related to the retinoic acid orphan (ROR)C-dependent up-regulation of the interleukin (IL)-4 induced gene 1 (IL4I1), which encodes for a l-phenylalanine oxidase, that has been shown to down-regulate CD3 expression in T cells. This results in abnormalities of the molecular pathway which is responsible for the impairment of IL-2 production and therefore for the lack of cell proliferation in response to T-cell receptor (TCR) signalling. IL4I1 up-regulation also associates with the increased expression of Tob1, a member of the Tob/BTG anti-proliferative protein family, which is involved in cell cycle arrest. A second reason for the rarity of human Th17 cells in the inflammatory sites is their rapid shifting into the Th1 phenotype, which is mainly related to the activity of IL-12 and TNF-␣. We have named these Th17-derived Th1 cells as non-classic because they differ from classic Th1 cells for the expression of molecules specific for Th17 cells, such as RORC, CD161, CCR6, IL4I1, and IL-17 receptor E. This distinction may be important for defining the respective pathogenic role of Th17, non-classic Th1 and classic Th1 cells in many human inflammatory disorders.
Arthritis Research & Therapy, 2008
The discovery in mice of a new lineage of CD4 + effector T helper (Th) cells that selectively produce IL-17 has provided exciting new insights into immune regulation, host defence, and the pathogenesis of autoimmune and other chronic inflammatory disorders. This population of CD4 + Th cells, which has been termed 'Th17', indeed plays an apparently critical role in the pathogenesis of some murine models of autoimmunity. Interestingly, murine Th17 cells share a common origin with Foxp3 + T regulatory cells, because both populations are produced in response to transforming growth factor-β, but they develop into Th17 cells only when IL-6 is simultaneously produced. Initial studies in humans have confirmed the existence of Th17 cells, but they have shown that the origin of these cells in humans differs from that in mice, with IL-1β and IL-23 being the major cytokines responsible for their development. Moreover, the presence in the circulation and in various tissues of Th cells that can produce both IL-17 and interferon-γ, as well as the flexibility of human Th17 clones to produce interferon-γ in addition to IL-17 in response to IL-12, suggests that there may be a developmental relationship between Th17 and Th1 cells, at least in humans. Resolving this issue has great implications in tems of establishing the respective pathogenic roles of Th1 and Th17 cells in autoimmune disorders. In contrast, it is unlikely that Th17 cells contribute to the pathogenesis of human allergic IgE-mediated disorders, because IL-4 and IL-25 (a powerful inducer of IL-4) are both potent inhibitors of Th17 cell development.