The current concept of T (h) 17 cells and their expanding role in systemic lupus erythematosus (original) (raw)
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IL-17 and the Th17 lineage in systemic lupus erythematosus
Current Opinion in Rheumatology, 2008
Revising the Th1/Th2 paradigm: Th17 cells and their signature cytokines For over 20 years, the dominant paradigm in T-cellmediated disease, whether infectious or autoimmune, stated that immune responses are controlled by Th1 or Th2 cells [1 ]. Th1 cells secrete interferon gamma (IFNg) and are induced to differentiate by cues from IL-12, whereas Th2 cells secrete IL-4, IL-5 and IL-13 and are triggered to develop by IL-4. Development of each T-helper lineage is self-reinforcing and mutually antagonistic, and all diseases have traditionally been viewed in the confines of this model. A major revolution in T-cell biology occurred with the discovery of a new subset of CD4 þ T cells, termed 'Th17' after their signature cytokine, IL-17 [2,3 ]. The implications for understanding-and ultimately treatingautoimmunity are profound. For years, it was considered that Th1 cells were the major mediators of inflammation in autoimmune syndromes, particularly in rheumatoid arthritis (RA), Crohn's disease and multiple sclerosis, but it is now evident that Th17 cells are the primary drivers of these autoimmune diseases. This discovery emerged from reports comparing IL-12 and IL-23, het-erodimeric cytokines that share a common subunit, 'IL-12p40'. Mice with a targeted deletion in IL-12p40 are resistant to many autoimmune diseases. However, in many instances, IFNgÀ/À mice do not phenocopy IL-12p40 mice, but rather show unchanged or enhanced susceptibility to disease [1 ]. When mice lacking the unique IL-12p35 subunit of IL-12 were created, they failed to induce Th1 cells as expected, but remained susceptible to induction of mouse models of RA and multiple sclerosis [4,5]. Conversely, mice deficient in the IL-23-specific subunit p19 still developed Th1 cells, but were resistant to autoimmune disease [6,7]. Additional studies implicating IL-23 came from the observation that this cytokine could stimulate T cells to secrete IL-17 in vitro [8]. Two reports in 2005 demonstrated convincingly that the Th17 cell population arises independently of Th1 and Th2, as the key cytokines and transcription factors involved in differentiating classic T-helper subsets were dispensable for Th17 development [9,10]. Moreover, Th1 and Th2 cells suppress Th17, explaining in part why this lineage was overlooked. Although these early studies presumed that IL-23 was the inductive cytokine for the Th17 lineage, a flurry of reports demonstrated
Clinical Rheumatology, 2011
This study was designed to investigate the functional heterogeneity of human Th17 and how their plasticity shapes the nature of immune cell responses to inflammation and autoimmune diseases, such as systemic lupus erythematosus (SLE). We evaluated functional Th17 cell subsets based on the profile of cytokine production in peripheral blood (PB), bone marrow aspirates (BM) and lymph node biopsies (LN) from healthy individuals (n=35) and PB from SLE patients (n=34). Data were analysed by an automated method for merging and calculation of flow cytometric data, allowing us to identify eight Th17 subpopulations. Normal BM presented lower frequencies of Th17 (p=0.006 and p=0.05) and lower amount of IL-17 per cell (p=0.03 and p=0.02), compared to normal PB and LN biopsies. In the latter tissues were found increased proportions of Th17 producing TNF-α or TNF-α/IL-2 or IFN-γ/TNF-α/IL-2, while in BM, Th17 producing other cytokines than IL-17 was clearly decreased. In SLE patients, the frequency of Th17 was higher than in control, but the levels of IL-17 per cell were significantly reduced (p<0.05). Among the eight generated subpopulations, despite the great functional heterogeneity of Th17 in SLE, a significant low proportion of Th17 producing TNF-α was found in inactive SLE, while active SLE showed a high proportion producing only IL-17. Our findings support the idea that the functional heterogeneity of Th17 cells could depend on the cytokine microenvironment, which is distinct in normal BM as well as in active SLE, probably due to a Th1/Th2 imbalance previously reported by our group.
Balance between Regulatory T and Th17 Cells in Systemic Lupus Erythematosus: The Old and the New
Clinical and Developmental Immunology, 2012
Pathogenic mechanisms underlying the development of systemic lupus erythematosus (SLE) are very complex and not yet entirely clarified. However, the pivotal role of T lymphocytes in the induction and perpetuation of aberrant immune response is well established. Among T cells, IL-17 producing T helper (Th17) cells and regulatory T (Treg) cells represent an intriguing issue to be addressed in SLE pathogenesis, since an imbalance between the two subsets has been observed in the course of the disease. Treg cells appear to be impaired and therefore unable to counteract autoreactive T lymphocytes. Conversely, Th17 cells accumulate in target organs contributing to local IL-17 production and eventually tissue damage. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent an intriguing and useful tool for SLE treatment in the next future. In this paper, the current knowledge about Treg and Th17 cells interplay in SLE will be discussed.
Clinical Immunology, 2008
IL-23-dependent IL-17-producing T helper (Th) lymphocytes are associated with autoimmunity. We investigated the immunopathological mechanisms for activation of Th17 cells of patients with systemic lupus erythematosus (SLE). Concentration of cytokines/chemokine in plasma and culture supernatant from SLE patients and healthy controls were measured by ELISA or flow cytometry. Plasma IL-12, IL-17, IL-23 and CXCL10 concentrations and the number of Th17 cells were significantly elevated in SLE patients than control subjects (both p b 0.05). Elevated IL-12, IL-17 and CXCL10 concentrations correlated positively and significantly with SLEDAI (all p b 0.05). Plasma IL-12 and IL-17 showed significant and positive correlation with plasma Th1 chemokine CXCL10 concentration in SLE patients (all p b 0.05). Ex vivo inductions of IL-17 by IL-23 or IL-18 from co-stimulated lymphocytes were significantly higher in SLE patients than controls (all p b 0.05). The activated IL-23/IL-17 axis is important for the inflammatory immunity in SLE.
Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells
Nature Communications, 2020
Mature double negative (DN) T cells are a population of αβ T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8 + T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.
T-helper 17 cell cytokines and interferon type I: partners in crime in systemic lupus erythematosus?
Arthritis Research & Therapy, 2014
Introduction: 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.
Aims: To determine the role of IL-17 cytokine in systemic lupus erythematosus (SLE) patients and its association with clinical presentation of the disease and disease activity. Methods: 72 SLE patients and 70 healthy age and sex matched controls were included in the study. SLE disease activity was assessed in all patients with SLE disease activity index (SLEDAI-2K) scores. Plasma levels of IL-6, and IL-17 were measured by enzyme-linked immunosorbent assay and correlated their levels with clinical manifestations of the disease and SLEDAI-2K. Results: Plasma levels of IL-6 and IL-17 were significantly elevated in SLE patients than in control subjects (13.98 6.95 versus 7.47 1.23 pg/mL) and (19.47 10.21 versus 9.93 1.89 pg/mL), respectively. IL-6 and IL-17 were positively correlated with SLEDAI-2K scores (r = 0.684 at P < 0.001, r = 0.322 at P = 0.006), and lupus nephritis (r = 0.364 at P = 0.002, r = 0.474 at P < 0.001) respectively; similarly, the IL-17/IL-6 ratio was positively correlated with SLEDAI-2K (r = 0.243 at P = 0.039). Also, the level of both cytokines was positively correlated to each other during periods of disease activity (r = 0.755, P < 0.001) as well as during remission (r = 0.384, P = 0.040). Conclusion: Over-expression of IL-17 correlates with disease activity of SLE. A longitudinal study in a larger cohort of SLE patients can help validate the results.
IL-17 is Aberrantly Overexpressed Among Under-treatment Systemic Lupus Erythematosus Patients
Systemic lupus erythematosus, IL-17, glucocorticoids, pathogenesis, organ damage, treatment Scan to discover online Background & Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic inflammatory immune response. Current therapies mostly rely on glucocorticoids which are accompanied by side-effects and mostly fail to achieve a favorable remission. Th17 subpopulation of T cells is increased in exacerbated SLE as IL-17 cytokine is overexpressed. However, IL-17 is reported to be resistant to glucocorticoids in various disorders. Here, we evaluated the plasma level of IL-17 among newly diagnosed and under-treatment SLE patients to understand the effect of glucocorticoids on Th17 response.
Rheumatology, 2009
Objective. We studied the role of type 17 Th cells (TH17) in the pathogenesis of SLE. Methods. We quantified the mRNA expression of IL-17,-23,-27 and retinoic-acid-related orphan receptor (ROR)-, the regulator for the development and function of TH17, in the urinary sediment of 23 subjects with active lupus nephritis, 25 subjects with a history of lupus nephritis in remission, 30 SLE patients with no history of renal involvement and 8 healthy subjects. Results. All three groups of lupus patients had a higher urinary expression of TH17-related cytokines than the controls. However, urinary expression of IL-17 and-27 was found to be inversely correlated with the SLEDAI score (r ¼ À0.252 and À0.258, respectively; P < 0.05 for both). For patients with active lupus nephritis, the histological activity index of kidney biopsy was also found to be inversely correlated with the urinary expression of ROR-(r ¼ À0.447; P ¼ 0.032), IL-17 (r ¼ À0.454; P ¼ 0.029) and IL-23 (r ¼ À0.455; P ¼ 0.029). Urinary expression of IL-17,-23,-27 and ROR was also found to be inversely correlated with the urinary expression of IFN-and T-bet, the key transcription factor of type 1 Th cells. After 6 months of treatment, urinary IL-27 expression rose significantly in patients with complete response (from 2.07 AE 1.62 to 3.70 AE 1.69; P ¼ 0.028) but remained unchanged in those with partial or no response (from 2.60 AE 1.87 to 2.52 AE 1.94; P ¼ 0.9). Conclusions. The urinary expression of TH17-related genes is increased in SLE patients. The degree of up-regulation, however, is inversely related to systemic and renal lupus activity, as well as urinary expression of TH1-related genes. Urinary expression of TH17-related genes increased again after successful immunosuppressive treatment of active disease. Our findings suggest a regulatory role of TH17-related cytokines in pathogenesis of lupus nephritis.