scholarly journals Ratio of Circulating IFNγ+“Th17 Cells” in Memory Th Cells Is Inversely Correlated with the Titer of Anti-CCP Antibodies in Early-Onset Rheumatoid Arthritis Patients Based on Flow Cytometry Methods of the Human Immunology Project

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Shigeru Kotake ◽  
Yuki Nanke ◽  
Toru Yago ◽  
Manabu Kawamoto ◽  
Tsuyoshi Kobashigawa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Early Onset ◽  
Early Phase ◽  
Th17 Cells ◽  
Joint Inflammation ◽  
Helper T Cells ◽  
Systemic Autoimmune Disease ◽  
Activated T Cells ◽  
Human Immunology

Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic joint inflammation characterized by activated T cells. IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. However, it remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we validated the methods of the Human Immunology Project using only the cell-surface marker through measuring the actual expression of IL-17 and IFNγ. We also evaluated the expression of CD161 in human Th17 cells. We then tried to identify Th17 cells, IL-17+Th17 cells, and IFNγ+Th17 cells in the peripheral blood of early-onset RA patients using the standardized method of the Human Immunology Project. Our findings validated the method and the expression of CD161. The ratio of IFNγ+Th17 cells in memory T cells was inversely correlated to the titers of anti-CCP antibodies in the early-onset RA patients. These findings suggest that Th17 cells play important roles in the early phase of RA and that anti-IL-17 antibodies should be administered to patients with early phase RA, especially those with high titers of CCP antibodies.

scholarly journals Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161+Th1 Cells) to CD161+Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Shigeru Kotake ◽  
Yuki Nanke ◽  
Toru Yago ◽  
Manabu Kawamoto ◽  
Tsuyoshi Kobashigawa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Cartilage ◽  
Peripheral Blood ◽  
Early Onset ◽  
Early Phase ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Chronic Inflammatory Disease ◽  
Helper T Cells ◽  
Th1 Cells

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161+Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161+Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase.

scholarly journals TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

2019 ◽  
Author(s):  
Xu Jiang ◽  
Shi-yu Wang ◽  
Chen Zhou ◽  
Jing-hua Wu ◽  
Yu-hao Jiao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Th17 Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Systemic Autoimmune Disease ◽  
Autoreactive T Cell

AbstractThe pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells, with highly similar TCR repertoires between them. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Moreover, TCR diversity in subsets including Th17 was negatively correlated with RA disease activity indices such as C-reactive protein and erythrocyte sedimentation rate. Thus, shared and abnormally expanded EMT and Th17 TCR repertoires might be pivotal for RA pathogenesis.

scholarly journals The Phenotype of Circulating Follicular-Helper T Cells in Patients with Rheumatoid Arthritis Defines CD200 as a Potential Therapeutic Target

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Aron Chakera ◽  
Sophia C. Bennett ◽  
Olivier Morteau ◽  
Paul Bowness ◽  
Raashid A. Luqmani ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Therapeutic Target ◽  
Patient Characteristics ◽  
Helper T Cells ◽  
Immunoglobulin Superfamily ◽  
Systemic Autoimmune Disease ◽  
Follicular Helper T Cells ◽  
Potential Therapeutic Target ◽  
Follicular Helper

Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting synovial joints in which the development of autoantibodies represents a failure of normal tolerance mechanisms, suggesting a role for follicular helper T cells (TFH) in the genesis of autoimmunity. To determine whether quantitative or qualitative abnormalities in the circulatingTFHcell population exist, we analysed by flow cytometry the number and profile of these cells in 35 patients with RA and 15 matched controls. Results were correlated with patient characteristics, including the presence of autoantibodies, disease activity, and treatment with biologic agents. CirculatingTFHcells from patients with RA show significantly increased expression of the immunoglobulin superfamily receptor CD200, with highest levels seen in seropositive patients (P=0.0045) and patients treated with anti-TNFαagents (P=0.0008). This occurs in the absence of any change inTFHnumbers or overt bias towards Th1, Th2, or Th17 phenotypes. CD200 levels did not correlate with DAS28 scores (P=0.887). Although the number of circulatingTFHcells is not altered in the blood of patients with RA, theTFHcells have a distinct phenotype. These differences associateTFHcells with the pathogenesis of RA and support the relevance of the CD200/CD200R signalling pathway as a potential therapeutic target.

scholarly journals Exosomes derived from synovial fibroblasts under hypoxia aggravate rheumatoid arthritis by regulating Treg/Th17 balance

2020 ◽  
Vol 245 (14) ◽  
pp. 1177-1186
Author(s):  
Yanjie Ding ◽  
Laifang Wang ◽  
Huiqiang Wu ◽  
Qing Zhao ◽  
Shufang Wu
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Therapeutic Target ◽  
Th17 Cells ◽  
Synovial Fibroblasts ◽  
Treg Cells ◽  
Joint Disease ◽  
Systemic Autoimmune Disease ◽  
Potential Therapeutic Target ◽  
Hypoxic Environment

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic destructive joint disease. To date, the etiology and pathogenesis of RA have not been fully elucidated, but a large number of studies have indicated that hypoxia is an important feature of RA. Our study was designed to probe how hypoxia-induced exosome (exo) derived from synovial fibroblasts (SFs) affect RA. In this study, we found that hypoxic environment existed in synovial tissue of RA, and miR-424 expression was increased in RA, and exosome derived from synovial fibroblasts (SFs-exo) could significantly induce T cells differentiation, which Th17 cells increased and Treg cells decreased. Besides, SFs-exo affected the expression of related inflammatory cytokines. And, we also found that FOXP3 was a target gene of miR-424 and exo-miR-424 KD inhibited RA worsening. These results suggested that SFs-exo in hypoxia aggravates rheumatoid arthritis by regulating Treg/Th17 balance and thus may be a potential therapeutic target for RA. Impact statement A comparative study of osteoarthritis (OA) and RA mice was implemented to suggest that miR-424 expression was increased in RA, and exosome-miR-424 derived from synovial fibroblasts (SFs-exo) could significantly induce T cells differentiation in which Th17 cells increased and Treg cells decreased via targeting FOXP3. And thus, miR-424 may be a potential therapeutic target for RA.

scholarly journals Induction of IL-9 in Peripheral Lymphocytes of Rheumatoid Arthritis Patients and Healthy Donors by Th17-Inducing Cytokine Conditions

2021 ◽  
Vol 12 ◽  
Author(s):  
Jana Heim ◽  
Giovanni Almanzar ◽  
Marc Schmalzing ◽  
Michael Gernert ◽  
Hans-Peter Tony ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Th17 Cells ◽  
Helper T Cells ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Autoimmune Inflammation ◽  
Healthy Donors ◽  
Th9 Cells ◽  
Driving Conditions

IL-9-producing Th9 cells display a group of helper T cells with similarities to Th17 and Th2 T cells and have been shown to be involved in synovial inflammation in rheumatoid arthritis (RA) patients. So far, it is unclear which parameters drive Th9 differentiation in lymphocytes derived from RA patients compared to immunologically healthy individuals and whether autocrine mechanisms are able to enhance Th9 polarization. Further, parallel pathways of induction of IL-17-producing cells with Th9 phenotype have to be distinguished from exclusively Th9-inductive mechanisms. Thus, the present study aimed to determine the parameters of Th9 induction by simulation in a standardized inflammatory cytokine milieu.Peripheral naive and non-naive T cells of RA patients and healthy donors (HD) were cultured under Th9 and Th17-driving conditions and phenotypically analyzed by flow cytometry and molecular analysis.Our findings indicate a similar differentiation pathway of Th9 and Th17 cells and similar distributions of IL-9+ T cells in RA and HD regardless of Th9- or Th17-promoting cytokine milieus. Whereas the magnitude and direction of Th9- or Th17-polarization was about the same in RA and HD, IL-17+ CD4+ T cells were significantly stimulated by Th17-inducing conditions in HD. In conclusion, the results indicate that Th9- and Th17-inducing cytokine conditions mimicking autoimmune inflammation in RA may have similar stimulatory effects regarding polarization of peripheral naive and non-naive T cells into Th9 or Th17 cells. The results suggest that the differentiation of Th9 cells may be also induced by Th17-driving conditions.

scholarly journals Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells

2020 ◽  
Vol 117 (48) ◽  
pp. 30639-30648
Author(s):  
Dan Hu ◽  
Emily C. Tjon ◽  
Karin M. Andersson ◽  
Gabriela M. Molica ◽  
Minh C. Pham ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
Proinflammatory Cytokines ◽  
Th17 Cells ◽  
Gene Set Enrichment Analysis ◽  
Aberrant Expression ◽  
Signature Genes ◽  
The Impact

IL-17–producing Th17 cells are implicated in the pathogenesis of rheumatoid arthritis (RA) and TNF-α, a proinflammatory cytokine in the rheumatoid joint, facilitates Th17 differentiation. Anti-TNF therapy ameliorates disease in many patients with rheumatoid arthritis (RA). However, a significant proportion of patients do not respond to this therapy. The impact of anti-TNF therapy on Th17 responses in RA is not well understood. We conducted high-throughput gene expression analysis of Th17-enriched CCR6+CXCR3−CD45RA−CD4+T (CCR6+T) cells isolated from anti-TNF–treated RA patients classified as responders or nonresponders to therapy. CCR6+T cells from responders and nonresponders had distinct gene expression profiles. Proinflammatory signaling was elevated in the CCR6+T cells of nonresponders, and pathogenic Th17 signature genes were up-regulated in these cells. Gene set enrichment analysis on these signature genes identified transcription factor USF2 as their upstream regulator, which was also increased in nonresponders. Importantly, short hairpin RNA targetingUSF2in pathogenic Th17 cells led to reduced expression of proinflammatory cytokines IL-17A, IFN-γ, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as transcription factor T-bet. Together, our results revealed inadequate suppression of Th17 responses by anti-TNF in nonresponders, and direct targeting of the USF2-signaling pathway may be a potential therapeutic approach in the anti-TNF refractory RA.

scholarly journals BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation

2018 ◽  
Vol 215 (9) ◽  
pp. 2413-2428 ◽  
Author(s):  
Krystin Deason ◽  
Ty Dale Troutman ◽  
Aakanksha Jain ◽  
Dilip K. Challa ◽  
Rajakumar Mandraju ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Activated T Cells ◽  
Th1 Cell ◽  
Th17 Cell Differentiation ◽  
Th 17 ◽  
Phosphoinositide 3 Kinase

The toll-like receptor (TLR) and interleukin (IL)–1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll–IL-1 receptor homology domain–containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R–induced phosphoinositide 3-kinase–Akt–mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β–induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.

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