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Key Points The IL-23–IL-17 axis is critically involved in the development of autoimmunity Tissue-specific IL-17A expression exacerbates tissue damage and disease chronicity The roles of IL-23 and IL-17 at different stages in the development and progression of rheumatoid arthrits (RA) and spondyloarthritis needs further investigation Greater understanding of the role of the IL-23–IL-17 axis in RA as opposed to psoriatic arthritis and psoriasis is needed Early combination therapy neutralizing both TNF activity and the IL-17/T H 17 pathway might be a successful approach to achieving stable remission in patients with autoimmune disease and might even prevent disease development This article reviews what is known about the role of the IL 23–IL 17 immune pathway at different stages in the development and progression of chronic immune-mediated inflammatory diseases, in particular rheumatoid arthritis and spondyloarthritis. The author draws on findings from disease-specific animal models and human ex vivo studies as well as data from clinical trials of therapies targeting the IL 23–IL 17 axis. The discovery that the IL-23–IL-17 immune pathway is involved in many models of autoimmune disease has changed the concept of the role of T-helper cell subsets in the development of autoimmunity. In addition to T H 17 cells, IL-17 is also produced by other T cell subsets and innate immune cells; which of these IL-17-producing cells have a role in tissue inflammation, and the timing, location and nature of their role(s), is incompletely understood. The current view is that innate and adaptive immune cells expressing the IL-23 receptor become pathogenic after exposure to IL-23, but further investigation into the role of IL-23 and IL-17 at different stages in the development and progression of chronic (destructive) inflammatory diseases is needed. Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the two most common forms of chronic immune-mediated inflammatory arthritis, and the IL-23–IL-17 axis is thought to have a critical role in both. This Review discusses the basic mechanisms of these cytokines in RA and SpA on the basis of findings from disease-specific animal models as well as human ex vivo studies. Promising therapeutic applications to modulate this immune pathway are in development or have already been approved. Blockade of IL-17 and/or T H 17-cell activity in combination with anti-TNF therapy might be a successful approach to achieving stable remission or even prevention of chronic immune-mediated inflammatory diseases.

Interleukin-17 has been implicated in the pathogenesis of inflammatory arthritis. Evidence from animal models and preliminary results from trials in human disease highlight the emergence of this proinflammatory cytokine as a target for RA therapy. The discovery of interleukin (IL)-17 and its major cell source, the type 17 T-helper (T H 17) lymphocyte, has been a major step in the understanding of erosive arthritis. This Review summarizes current knowledge of the role of IL-17 in this context derived from both animal models and studies in patients with rheumatoid arthritis. Evidence shows that IL-17 is present at sites of inflammatory arthritis and that, in synergistic interactions, it amplifies the inflammation induced by other cytokines, primarily tumor necrosis factor. In several animal models of arthritis, inhibition of IL-17 limits inflammation and joint erosion. Initial observations from phase I trials show that signs and symptoms of RA are significantly suppressed following treatment with anti-IL-17 antibodies, without notable adverse effects. The emergence of IL-17 blockade as a future therapy in rheumatoid arthritis is highlighted, along with the potential goals and limitations of this therapeutic approach. Key Points Interleukin 17 (IL-17) is present at sites of inflammatory arthritis In synergistic interactions, IL-17 amplifies the inflammation induced by other cytokines, mostly tumor necrosis factor Inhibition of IL-17 in several animal models of arthritis controls inflammation and joint destruction IL-17 has a role in inflammatory arthritis phenotypes with a destructive disease course In clinical trials, anti-IL-17 antibodies show efficacy in ameliorating the signs and symptoms of human rheumatoid arthritis, in line with preclinical results

Background: The authors of this research study intended to verify whether there are any changes in gene expression in depressed patients without coexisting inflammatory diseases for selected immune-inflammatory factors that are particularly important in autoimmune disease pathogenesis (IL-17, IL-21, IL-23, IL-35, Foxp3). Methods: The study was carried out on a group of 190 patients with depression and 100 healthy volunteers. The severity of depressive symptoms was assessed using the Hamilton Depression Scale. RT-PCR was used to evaluate mRNA expression and ELISA was used to measure protein expression of these genes. Results: The level of gene expression for IL-17, IL-21, IL-23, and IL-35 was substantially higher in the group of patients with depression compared to the control group. The mean mRNA expression of Foxp3 was considerably reduced in patients suffering from depressive disorders. There was a statistically significant correlation between the number of hospitalizations and the expression of specific inflammatory factors. Conclusions: Expression of specific inflammatory genes may be a factor in the etiopathogenesis of depressive disorders. The duration of the disease seems to be more important for the expression of the genes in question than the severity of depression. These cytokines may affect the metabolism of neurotransmitters and neuroendocrine functions in the brain as well as be a marker and a new potential therapeutic target for recurrent depressive disorders.

Interleukin (IL)‐17 is a major contributor to the pathogenesis of allergic asthma. Developmental endothelial locus‐1 (Del‐1) is an endothelial cell‐secreted protein known to inhibit IL‐17 expression. However, little is known about the association between Del‐1 and IL‐17 in the pathogenesis of allergic asthma. Using bronchoalveolar lavage fluid (BALF) and peripheral blood samples collected from allergic asthmatic patients and controls, we explored the role of Del‐1 in relation to IL‐17 in allergic asthma. We found that the negative correlation between Del‐1 and IL‐17 was significant in BALF of allergic asthmatics. Del‐1 treatment inhibited the expression of IL‐17, the differentiation of IL‐17‐secreting leukocytes and associated cytokines. Contrarily, IL‐17 levels were increased after treatment with anti‐Del‐1 mAb. Consistent with this, Del‐1 treatment led to downregulation of IL‐5, CCL5 and IL‐4, thus reducing secretion of eosinophil cationic protein. Furthermore, Del‐1 significantly downregulated the expression of ICAM‐1 and may have the potential to reduce leukocyte transendothelial migration. Our data demonstrate that Del‐1 can negatively regulate IL‐17 and its proinflammatory function, thereby limiting airway inflammation in allergic asthmatics, and suggest Del‐1 as a potential candidate for prevention and treatment of allergic asthma. We demonstrated that Del‐1 reduces IL‐17‐mediated inflammation and may inhibit eosinophilia. A lack of Del‐1 correlated with the pathophysiology of asthma may provide new clues to the development of allergic asthmatic inhibitors as a novel strategy in the treatment of allergic diseases. In addition, since Del‐1 is an endogenous anti‐inflammatory factor, Del‐1 may be a safe and promising approach for the treatment of allergic asthma.

Background: Platelet “Microvesicles” (MVs) are studied for their role in blood coagulation and inflammation. The study aimed to establish if MVs are related to age, plasma levels of inflammation, coagulation, and fibrinolysis markers in healthy individuals. Methods: We prospectively enrolled volunteers aged over 18 years. MVs, plasma levels of C-reactive protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10), Interleukin 17 (IL-17), and transforming growth factor β (TGF-β), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, factor VII (FVII), thrombin activatable fibrinolysis inhibitor (TAFI), and Protein S were tested. Results: A total of 246 individuals (median age 65 years (“IQR”54–72)) were evaluated. Both univariate analysis and logistic regression models showed that MVs positively correlate with age, CRP, IL-6, IL-10, IL-17, TGF-β, fibrinogen, PAI-1, VWF, FVII, and homocysteine, while inversely correlating with TAFI and Protein S. The ROC curve analysis performed to identify a cut off for MV values (700 kMP) showed a good accuracy with over-range cytokines fibrinolysis factor and coagulation markers. Conclusions: To the best of our knowledge, this study is the first to correlate MVs with an entire panel of cardiovascular risk factors in healthy individuals. A future possible role of MVs in screening exams is suggested.

In juvenile idiopathic arthritis (JIA) inflammatory T cells and their produced cytokines are drug targets and play a role in disease pathogenesis. Despite their clinical importance, the sources and types of inflammatory T cells involved remain unclear. T cells respond to polarizing factors to initiate types of immunity to fight infections, which include immunity types 1 (T1), 2 (T2), and 3 (T17). Polarizing factors drive CD4 + T cells towards T helper (Th) cell subtypes and CD8 + T cells towards cytotoxic T cell (Tc) subtypes. T1 and T17 polarization are associated with autoimmunity and production of the cytokines IFNγ and IL-17 respectively. We show that JIA and child healthy control (HC) peripheral blood mononuclear cells are remarkably similar, with the same frequencies of CD4 + and CD8 + naïve and memory T cell subsets, T cell proliferation, and CD4 + and CD8 + T cell subsets upon T1, T2, and T17 polarization. Yet, under T1 polarizing conditions JIA cells produced increased IFNγ and inappropriately produced IL-17. Under T17 polarizing conditions JIA T cells produced increased IL-17. Gene expression of IFNγ, IL-17, Tbet, and RORγT by quantitative PCR and RNA sequencing revealed activation of immune responses and inappropriate activation of IL-17 signaling pathways in JIA polarized T1 cells. The polarized JIA T1 cells were comprised of Th and Tc cells, with Th cells producing IFNγ (Th1), IL-17 (Th17), and both IFNγ-IL-17 (Th1.17) and Tc cells producing IFNγ (Tc1). The JIA polarized CD4 + T1 cells expressed both Tbet and RORγT, with higher expression of the transcription factors associated with higher frequency of IL-17 producing cells. T1 polarized naïve CD4 + cells from JIA also produced more IFNγ and more IL-17 than HC. We show that in JIA T1 polarization inappropriately generates Th1, Th17, and Th1.17 cells. Our data provides a tool for studying the development of heterogeneous inflammatory T cells in JIA under T1 polarizing conditions and for identifying pathogenic immune cells that are important as drug targets and diagnostic markers.

Background/Objectives: Psoriasis is currently treated with biologics targeting the IL-17A signaling, which plays a major role in immune response and keratinocyte hyperproliferation. These include inhibitors of IL-17A and/or its heterodimer with IL-17F (Secukinumab, Ixekinumab and Bimekizumab) and the receptor IL17-RA (Brodalumab). Although these drugs are safe and highly effective, there is significant variability in response among patients. This can be partly attributed to the patients’ genetic background, thus pointing to the need to identify pharmacogenetic markers for treatment response. Methods: The study involved 88 Greek patients who were treated with inhibitors of the IL-17A signaling for at least 6 months. Patients were classified as responders and non-responders according to the change in Psoriasis Area Severity Index. A total of 730,000 variants were genotyped and analyzed for association with the 3-month and 6-month responses to treatment. Results: The analysis identified 21 variants which were associated with the response, showing statistical significance after Bonferroni correction. These include variants located in protein coding genes (TP63, NRG1, SCN8A, TAF9, TMEM9, SMIM36, SYT14, BPIFC, SEZ6L2, PCARE), as well as intergenic and long non-coding RNA intronic variants. The functional significance of the variants was assessed using in silico analysis and for several variants, a link with immune processes was proposed. Notably, rs11649499 status, which was associated with complete clinical remission at 3 months, may influence key lipid mediators involved in psoriasis. Conclusions: This GWAS identified novel variants that could be utilized upon validation in larger populations as predictive markers regarding patient response to drugs targeting the IL-17A pathway.

BackgroundGenetic association studies have elucidated the link of variants in the interleukin 17 ( IL-17 ) family genes with susceptibility to human diseases, yet have obtained controversial outcomes. Therefore, we sought to update comprehensive synopsis of variants in the IL-17 family genes with susceptibility to human diseases.MethodsOur study screened the Pubmed and Web of Science to enroll eligible articles and performed a meta-analysis, then graded the cumulative evidence of significant association using Venice criteria and false-positive report probability test, and finally assessed the function of variants with strong evidence.ResultsSeven variants in IL-17 family genes had significant relationships with susceptibility to 18 human diseases identified by meta-analyses. Strong evidence was assigned to 4 variants ( IL-17A rs2275913, IL-17A rs8193037, IL-17F rs1889570, IL-17F rs763780) with susceptibility to 6 human diseases (lung and cervical cancer, spondyloarthritis, asthma, multiple sclerosis, rheumatoid arthritis), moderate to 2 variants with risk of 5 diseases, weak to 5 variants with risk of 10 diseases. Bioinformatics analysis suggested that the variants with strong evidence might fall in putative functional regions. Additionally, positive relationships for 5 variants with risk of 4 diseases (based on two datasets) and 14 variants with risk of 21 diseases (based on one dataset) were considered noteworthy.ConclusionsThis study offers updated and comprehensive clues that variants in the IL-17 family genes are significantly linked with susceptibility to cervical, lung cancer, asthma, multiple sclerosis, rheumatoid arthritis and spondyloarthritis, and elucidates the crucial role of the IL-17 regions in the genetic predisposition to cancer or noncancerous diseases.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune cell abnormalities which lead to the production of autoantibodies and the deposition of immune complexes. Interleukin (IL)-17-producing cells play an important role in the pathogenesis of the disease, making them an attractive therapeutic target. Studies in lupus-prone mice and of ex vivo cells from patients with SLE humans have shown that IL-17 represents a promising therapeutic target. Here we review molecular mechanisms involved in IL-17 production and Th17 cell differentiation and function and an update on the role of IL-17 in autoimmune diseases and the expected usefulness for targeting IL-17 therapeutically.

Mounting evidence suggests that aberrations in immune-inflammatory pathways contribute to the pathophysiology of major depressive disorder (MDD), and individuals with MDD may have elevated levels of predominantly pro-inflammatory cytokines and C-reactive protein. In addition, previous meta-analyses suggest that antidepressant drug treatment may decrease peripheral levels of interleukin-1 beta (IL-1β) and IL-6. Recently, several new studies examining the effect of antidepressants on these cytokines have been published, and so we performed an updated meta-analysis of studies that measured peripheral levels of cytokines and chemokines during antidepressant treatment in patients with MDD. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from inception through March 9, 2017. Forty-five studies met inclusion criteria (N = 1517). Peripheral levels of IL-6, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-10, IL-2, IL-4, interferon-γ, IL-8, the C-C motif ligand 2 chemokine (CCL-2), CCL-3, IL-1 receptor antagonist, IL-13, IL-17, IL-5, IL-7, and the soluble IL-2 receptor were measured in at least three datasets and thus were meta-analyzed. Antidepressant treatment significantly decreased peripheral levels of IL-6 (Hedges g = −0.454, P <0.001), TNF-α (g = −0.202, P = 0.015), IL-10 (g = −0.566, P = 0.012), and CCL-2 (g = −1.502, P = 0.006). These findings indicate that antidepressants decrease several markers of peripheral inflammation. However, this meta-analysis did not provide evidence that reductions in peripheral inflammation are associated with antidepressant treatment response although few studies provided separate data for treatment responders and non-responders.