Elevated Th22 Cells Correlated with Th17 Cells in Patients with Rheumatoid Arthritis

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.

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AB0031 T HELPER 17 CELLS WERE SIGNIFICANTLY DECREASED BY MITOCHONDRIAL ELECTRON TRANSPORT CHAIN COMPLEX INHIBITOR IN PATIENTS WITH RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3441 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1318.2-1318

Author(s):

H. R. Lee ◽

S. J. Yoo ◽

J. Kim ◽

I. S. Yoo ◽

C. K. Park ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Electron Transport ◽

Disease Activity ◽

Th17 Cells ◽

Electron Transport Chain ◽

Chain Complex ◽

Complex Iii ◽

Mitochondrial Electron Transport Chain ◽

Transport Chain ◽

Healthy Control

Background:Reactive oxygen species (ROS) and T helper 17 (TH17) cells have been known to play an important role in the pathogenesis of rheumatoid arthritis (RA). However, the interrelationship between ROS and TH17 remains unclear in RAObjectives:To explore whether ROS affect TH17 cells in peripheral blood mononuclear cells (PBMC) of RA patients, we analyzed ROS expressions among T cell subsets following treatment with mitochondrial electron transport chain complex inhibitors.Methods:Blood samples were collected from 40 RA patients and 10 healthy adult volunteers. RA activity was divided according to clinical parameter DAS28. PBMC cells were obtained from the whole blood using lymphocyte separation medium density gradient centrifugation. Following PBMC was stained with Live/Dead stain dye, cells were incubated with antibodies for CD3, CD4, CD8, and CD25. After fixation and permeabilization, samples were stained with antibodies for FoxP3 and IL-17A. MitoSox were used for mitochondrial specific staining.Results:The frequency of TH17 cells was increased by 4.83 folds in moderate disease activity group (5.1>DAS28≥3.2) of RA patients compared to healthy control. Moderate RA activity patients also showed higher ratio of TH17/Treg than healthy control (3.57 folds). All RA patients had elevated expression of mitochondrial specific ROS than healthy control. When PBMC cells were treated with 2.5uM of antimycin A (mitochondrial electron transport chain complex III inhibitor) for 16 h, the frequency of TH17 cells was significantly decreased.Conclusion:The mitochondrial electron transport chain complex III inhibitor markedly downregulated the frequency of TH17 cells in moderate disease activity patients with RA. These findings provide a novel approach to regulate TH17 function in RA through mitochondrial metabolism related ROS production.References:[1]Szekanecz, Z., et al., New insights in synovial angiogenesis. Joint Bone Spine, 2010. 77(1): p. 13-9.[2]Prevoo, M.L., et al., Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum, 1995. 38(1): p. 44-8.Disclosure of Interests:None declared

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Increased IL-6 expression on THP-1 by IL-34 stimulation up-regulated rheumatoid arthritis Th17 cells

Clinical Rheumatology ◽

10.1007/s10067-017-3746-y ◽

2017 ◽

Vol 37 (1) ◽

pp. 127-137 ◽

Cited By ~ 6

Author(s):

Bing Wang ◽

Yawei Tang ◽

Xiaotong Sun ◽

Xunli Ouyang ◽

Han Li ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Th17 Cells

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Elevated Th22 cells correlated with Th17 cells in patients with high liver stiffness in nonalcoholic fatty liver disease

European Journal of Inflammation ◽

10.1177/2058739218802678 ◽

2018 ◽

Vol 16 ◽

pp. 205873921880267 ◽

Cited By ~ 2

Author(s):

Si-Biao Su ◽

Wen Chen ◽

Fei-Fei Huang ◽

Jian-Feng Zhang

Keyword(s):

Flow Cytometry ◽

Liver Disease ◽

Plasma Level ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Th17 Cells ◽

Liver Stiffness ◽

Nonalcoholic Fatty Liver ◽

Th22 Cells

The aims of this article are to investigate the effects of Th22 and Th17 cells and plasma cytokines in patients with nonalcoholic fatty liver disease (NAFLD) and to examine the correlation between Th22 and Th17 cells levels and disease progression. Blood samples from 70 patients with NAFLD and 26 healthy controls (HCs) were collected. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) analysis were performed. ELISA revealed interleukin (IL)-22 plasma level in FibroScan subgroup patients was 2.2-fold higher than that in the HCs ( P < 0.01), body mass index (BMI) subgroup patients were 2.3-fold higher than HCs ( P < 0.01), IL-17A plasma level was 5.6-fold higher in FibroScan subgroup patients than that in the HCs ( P < 0.01), and 5.8-fold higher in BMI subgroup than HCs ( P < 0.01). Flow cytometry revealed median proportions of Th22 cells in FibroScan group was greater than that in the HCs (3.85% vs 0.86%; P < 0.001). Similar results were obtained for Th17 cells (6.36% vs 0.9%; P < 0.001). The liver stiffness measurement value was highly correlated with the proportion of Th17 and Th22 cells and moderately correlated with the plasma level of IL-17A, IL-22, and the BMI value. In conclusion, the elevated proportions of Th17 and Th22 cells were significantly correlated with the degree of liver cirrhosis in NAFLD patients. They may play an inflammatory and immune response role in progression from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) or fibrosis.

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Essentials of Th17 cell commitment and plasticity

Blood ◽

10.1182/blood-2012-09-378653 ◽

2013 ◽

Vol 121 (13) ◽

pp. 2402-2414 ◽

Cited By ~ 219

Author(s):

Pawel Muranski ◽

Nicholas P. Restifo

Keyword(s):

Th17 Cells ◽

T Regulatory Cells ◽

Adoptive Cell Transfer ◽

Orphan Receptor ◽

Immune Memory ◽

Th22 Cells ◽

Follicular Helper ◽

New Findings ◽

Cell Commitment

Abstract CD4+ T helper (Th) cells exist in a variety of epigenetic states that determine their function, phenotype, and capacity for persistence. These polarization states include Th1, Th2, Th17, and Foxp3+ T regulatory cells, as well as the more recently described T follicular helper, Th9, and Th22 cells. Th17 cells express the master transcriptional regulator retinoic acid–related orphan receptor γ thymus and produce canonical interleukin (IL)-17A and IL-17F cytokines. Th17 cells display a great degree of context-dependent plasticity, as they are capable of acquiring functional characteristics of Th1 cells. This late plasticity may contribute to the protection against microbes, plays a role in the development of autoimmunity, and is necessary for antitumor activity of Th17 cells in adoptive cell transfer therapy models. Moreover, plasticity of this subset is associated with higher in vivo survival and self-renewal capacity and less senescence than Th1 polarized cells, which have less plasticity and more phenotypic stability. New findings indicate that subset polarization of CD4+ T cells not only induces characteristic patterns of surface markers and cytokine production but also has a maturational aspect that affects a cell’s ability to survive, respond to secondary stimulation, and form long-term immune memory.

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The relationship of blood CDC42 level with Th1 cells, Th17 cells, inflammation markers, disease risk/activity, and treatment efficacy of rheumatoid arthritis

Irish Journal of Medical Science (1971 -) ◽

10.1007/s11845-021-02858-y ◽

2021 ◽

Author(s):

Yongji Li ◽

Wendi Yang ◽

Feng Wang

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Treatment Response ◽

Treatment Efficacy ◽

Th17 Cells ◽

Immune Cell ◽

Disease Risk ◽

Th1 Cells ◽

Clinical Role ◽

Reactive Protein

Abstract Background Cell division control protein 42 (CDC42) is reported to be involved in multiple inflammation processes by regulating T cell differentiation, maintaining immune cell homeostasis, and altering their function, while no relevant studies explored its clinical role in patients with rheumatoid arthritis (RA). Therefore, this study aimed to explore the correlation of CDC42 with Th1 and Th17 cells and its association with disease risk, activity, and treatment outcomes of RA. Methods After the enrollment of 95 active RA patients and 50 healthy subjects (HC), their CDC42, Th1 cells, and Th17 cells were assayed by RT-qPCR and flow cytometry, accordingly. For RA patients only, CDC42 was also detected at W6, and W12 after treatment. The treatment response and remission status were evaluated at W12. Results Compared to HC, CDC42 was reduced (P < 0.001), while Th1 cells (P = 0.021) and Th17 cells (P < 0.001) were increased in RA patients. Besides, CDC42 was negatively correlated with Th17 cells (P < 0.001), erythrocyte sedimentation rate (ESR) (P = 0.012), C-reactive protein (P = 0.002), and disease activity score in 28 joints (DAS28) (P = 0.007), but did not relate to Th1 cells or other disease features (all P > 0.05) in RA patients. Furthermore, CDC42 was elevated during treatment in RA patients (P < 0.001). Moreover, CDC42 increment at W12 correlated with treatment response (P = 0.004). Besides, CDC42 elevation at W0 (P = 0.038), W6 (P = 0.001), and W12 (P < 0.001) also linked with treatment remission. Conclusion CDC42 has the potential to serve as a biomarker to monitor disease activity and treatment efficacy in patients with RA.

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Circulating Th22 cells, as well as Th17 cells, are elevated in patients with renal cell carcinoma

International Journal of Medical Sciences ◽

10.7150/ijms.47384 ◽

2021 ◽

Vol 18 (1) ◽

pp. 99-108

Author(s):

Zhiguo Peng ◽

Yu Hu ◽

Juchao Ren ◽

Nengwang Yu ◽

Zeyan Li ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Th17 Cells ◽

Th22 Cells

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Therapeutic Potential of a Novel Bifidobacterium Identified Through Microbiome Profiling of RA Patients With Different RF Levels

Frontiers in Immunology ◽

10.3389/fimmu.2021.736196 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yunju Jeong ◽

JooYeon Jhun ◽

Seon-Yeong Lee ◽

Hyun Sik Na ◽

JeongWon Choi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Relative Abundance ◽

Th17 Cells ◽

Mononuclear Cells ◽

Therapeutic Potential ◽

Human Peripheral Blood ◽

Cartilage Damage ◽

Therapeutic Effects ◽

Bioinformatics Analyses ◽

Proinflammatory Mediators

The potential therapeutic effects of probiotic bacteria in rheumatoid arthritis (RA) remain controversial. Thus, this study aimed to discover potential therapeutic bacteria based on the relationship between the gut microbiome and rheumatoid factor (RF) in RA. Bacterial genomic DNA was extracted from the fecal samples of 93 RA patients and 16 healthy subjects. Microbiota profiling was conducted through 16S rRNA sequencing and bioinformatics analyses. The effects of Bifidobacterium strains on human peripheral blood mononuclear cells and collagen-induced arthritis (CIA) mice were assessed. Significant differences in gut microbiota composition were observed in patients with different RF levels. The relative abundance of Bifidobacterium and Collinsella was lower in RF-high than in RF-low and RF-negative RA patients, while the relative abundance of Clostridium of Ruminococcaceae family was higher in RF-high than in RF-low and RF-negative patients. Among 10 differentially abundant Bifidobacterium, B. longum RAPO exhibited the strongest ability to inhibit IL-17 secretion. Oral administration of B. longum RAPO in CIA mice, obese CIA, and humanized avatar model significantly reduced RA incidence, arthritis score, inflammation, bone damage, cartilage damage, Th17 cells, and inflammatory cytokine secretion. Additionally, B. longum RAPO significantly inhibited Th17 cells and Th17-related genes—IL-17A, IRF4, RORC, IL-21, and IL-23R—in the PBMCs of rheumatoid arthritis patients. Our findings suggest that B. longum RAPO may alleviate RA by inhibiting the production of IL-17 and other proinflammatory mediators. The safety and efficacy of B. longum RAPO in patients with RA and other autoimmune disorders merit further investigation.

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