scholarly journals Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses

2007 ◽  
Vol 204 (13) ◽  
pp. 3183-3194 ◽  
Author(s):  
Lisa C. Zaba ◽  
Irma Cardinale ◽  
Patricia Gilleaudeau ◽  
Mary Sullivan-Whalen ◽  
Mayte Suárez-Fariñas ◽  
...  
Keyword(s):  
Th17 Cell ◽  
Th17 Cells ◽  
Treatment Options ◽  
Interferon Γ ◽  
Th1 Cells ◽  
Inhibitory Effects ◽  
Effector Molecules ◽  
Downstream Effector ◽  
Chemokine Ligand ◽  
Lymphotoxin Α

Biological agents have dramatically improved treatment options for patients with severe psoriasis. Etanercept (tumor necrosis factor [TNF] receptor–immunoglobulin fusion protein) is an effective treatment for many psoriasis patients, and blockade of TNF is considered to be its primary action. However, in this clinical trial, we show that etanercept has early inhibitory effects on a newly appreciated type of T cells: T helper type 17 (Th17) cells. Etanercept reduced the inflammatory dendritic cell products that drive Th17 cell proliferation (interleukin [IL] 23), as well as Th17 cell products and downstream effector molecules (IL-17, IL-22, CC chemokine ligand 20, and β-defensin 4). In contrast, Th1 cellular products and effector molecules (interferon γ, lymphotoxin α, and myxovirus resistance 1) were reduced late in disease resolution. This study suggests a role for Th17 in addition to Th1 cells in the pathogenesis of psoriasis. Th17 cells may be particularly important in driving epidermal activation in psoriatic plaques, whereas Th1 cells must also be eliminated for final disease resolution.

scholarly journals Plasma Levels of Eicosapentaenoic Acid Are Associated with Anti-TNF Responsiveness in Rheumatoid Arthritis and Inhibit the Etanercept-driven Rise in Th17 Cell Differentiationin Vitro

2017 ◽  
Vol 44 (6) ◽  
pp. 748-756 ◽  
Author(s):  
Louisa Jeffery ◽  
Helena L. Fisk ◽  
Philip C. Calder ◽  
Andrew Filer ◽  
Karim Raza ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Fatty Acid ◽  
Eicosapentaenoic Acid ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Differentiationin Vitro

Objective.To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF–driven Th17 cell differentiation.Methods.Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25− T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry.Results.Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (−0.51, p = 0.007 and −0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequenciesin vitro. Physiological concentrations of EPA, but not LA, prevented this.Conclusion.EPA status was associated with clinical improvements to anti-TNF therapyin vivoand prevented the effect of ETN on Th17 cellsin vitro. EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.

scholarly journals Th1/17 Cells Infiltrate Murine Cytomegalovirus-Infected Renal Allografts via Virus-Induced CCL20 and Promote Th1 Cells through IL-17A.

2021 ◽  
Author(s):  
Ravi Dhital ◽  
Shashi Anand ◽  
Qiang Zeng ◽  
Victoria M Velazquez ◽  
Srinivasa R Boddeda ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Acute Rejection ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activity ◽  
Murine Cytomegalovirus ◽  
Th1 Cells ◽  
Cmv Infection ◽  
Th1 Cell ◽  
Cmv Dnaemia

Cytomegalovirus (CMV) infection is associated with renal allograft failure by unknown mechanisms. In a murine renal transplant model, murine CMV (MCMV) induces intragraft infiltration of Th17 cells co-expressing Th1 cytokines, IFN-γ and TNF-α, but only a minority of intragraft Th17 cells are specific for MCMV antigens. Instead, MCMV promotes viral antigen-independent Th17 cell recruitment via CCL20-CCR6 and CXCL10-CXCR3 interactions. Th17 cells correlate directly with Th1 cell frequencies and inversely with Tregs in MCMV infected grafts. Pharmacologic inhibition of IL-17A reduces intragraft Th17 cells and neutrophils, increases Tregs, and reduces total but not MCMV-specific Th1 cells. Among a clinical renal transplant cohort with acute rejection, patients with CMV DNAemia had significantly higher serum IL-17A quantities compared to those without CMV DNAemia. Together, these findings indicate that CMV infection upregulates Th17 cell activity during acute rejection and suggests that inhibition of IL-17A may ameliorate CMV-associated allograft injury without impairing antiviral Th1 cells.

Preferential Accumulation of Activated Th1 Cells Not Only in Rheumatoid Arthritis But Also in Osteoarthritis Joints

2011 ◽  
Vol 38 (8) ◽  
pp. 1569-1575 ◽  
Author(s):  
HISAKATA YAMADA ◽  
YASUHARU NAKASHIMA ◽  
KEN OKAZAKI ◽  
TARO MAWATARI ◽  
JUN-ICHI FUKUSHI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Qualitative Difference ◽  
Flow Cytometric Analysis ◽  
Interferon Γ ◽  
Th1 Cells ◽  
Activation Markers

Objective.It was previously found that Th1 but not Th17 cells were predominant in the joints of rheumatoid arthritis (RA). To verify whether this is a unique feature of CD4 T cells in RA joints, we performed comparative flow cytometric analysis of CD4 T cells in RA and osteoarthritis (OA) joints.Methods.Mononuclear cells were isolated from peripheral blood (PB), synovial membrane (SM), and synovial fluid (SF) from a total of 18 RA and 12 OA patients. The expression of surface molecules and cytokine production of CD4 T cells was examined by a flow cytometer.Results.Most CD4 T cells in RA joints expressed memory/activation markers, such as CD45RO, HLA-DR, and CD69. CCR5 was highly expressed on CD4 T cells in SF but not in PB or SM. With regard to Th17-related molecules, CD4 T cells expressing CCR6 were not enriched in either SF or SM. In contrast, CD161-positive cells were abundant in the joint, many of which, however, produced interferon-γ but not interleukin 17A. Virtually all T cells in OA joints, although much less numerous than in RA joints, expressed activation markers. Th1 cells were predominant in both OA and RA joints, while there were a few Th17 cells. The frequency of Th17 cells in the joint tended to be lower in OA than RA.Conclusion.There was a quantitative but not qualitative difference in CD4 T cells, including the expression of activation markers and cytokine profiles, between RA and OA joints.

scholarly journals Induction of a colitogenic phenotype in Th1 cells depends on IL-23R signaling

2021 ◽  
Author(s):  
Mathias Pawlak ◽  
David DeTomaso ◽  
Gerd Meyer zu Horste ◽  
Youjin Lee ◽  
Jackson Nyman ◽  
...  
Keyword(s):  
T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cytokine Receptor ◽  
Specific Factor ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Tissue Inflammation

SummaryThe cytokine receptor IL-23R plays a fundamental role in inflammation and autoimmunity. However, several observations have been difficult to reconcile under the assumption that only Th17 cells critically depend on IL-23 to acquire a pathogenic phenotype. Here, we report that Th1 cells differentiated in vitro with IL-12 + IL-21 show similar levels of IL-23R expression as in pathogenic Th17 cells. We demonstrate that IL-23R is required for Th1 cells to acquire a highly colitogenic phenotype. scRNAseq analysis of intestinal T cells enabled us to identify novel regulators induced by IL-23R-signaling in Th1 cells which differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1 cells inhibited induction of colitis. In this process, we were able to uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver of Th1 cell-mediated tissue inflammation and disease.

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 Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis

2015 ◽  
Vol 112 (22) ◽  
pp. 7061-7066 ◽  
Author(s):  
Stacey N. Harbour ◽  
Craig L. Maynard ◽  
Carlene L. Zindl ◽  
Trenton R. Schoeb ◽  
Casey T. Weaver
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Developmental Plasticity ◽  
Transfer Model ◽  
Th1 Cells ◽  
Inflammatory Bowel ◽  
Ifn Γ

Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A+ phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-γ, giving rise to “Th1-like” cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-γ–deficient Th17 cells retained an IL-17A+ phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-γ receptors. Moreover, Th17 cells could provide “help” for the development of pathogenic Th1 cells from naïve precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells.

scholarly journals Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Jennifer M. Monk ◽  
Harmony F. Turk ◽  
Yang-Yi Fan ◽  
Evelyn Callaway ◽  
Brad Weeks ◽  
...  
Keyword(s):  
Th17 Cell ◽  
Th17 Cells ◽  
De Novo ◽  
Inflammatory Responses ◽  
T Cell Subsets ◽  
Prostaglandin E ◽  
Trinitrobenzene Sulfonic Acid ◽  
Th1 Cells ◽  
Desaturase Gene ◽  
Th1 Cell

During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA-) derived eicosanoids, such as prostaglandin E2(PGE2), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2levels. We utilized two genetic mouse models, which differentially antagonize PGE2levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS-) induced colitis.Fat-1mice contain theω3 desaturase gene fromC. elegansand synthesize n-3 PUFAde novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast,Fads1Null mice contain a disruptedΔ5desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates,Fat-1andFads1Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression of Th17 cell markers (IL-17A,RORγτ, and IL-23), decreased percentages of Th17 cells and, improved colon injury scores (P≤0.05). Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE2levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

scholarly journals T-bet is essential for encephalitogenicity of both Th1 and Th17 cells

2009 ◽  
Vol 206 (7) ◽  
pp. 1549-1564 ◽  
Author(s):  
Yuhong Yang ◽  
Jeffrey Weiner ◽  
Yue Liu ◽  
Alan J. Smith ◽  
David J. Huss ◽  
...  
Keyword(s):  
T Cells ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Th1 Cells ◽  
Autoimmune Encephalomyelitis ◽  
End Products ◽  
Experimental Autoimmune

The extent to which myelin-specific Th1 and Th17 cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis (EAE) is controversial. Combinations of interleukin (IL)-1β, IL-6, and IL-23 with transforming growth factor β were used to differentiate myelin-specific T cell receptor transgenic T cells into Th17 cells, none of which could induce EAE, whereas Th1 cells consistently transferred disease. However, IL-6 was found to promote the differentiation of encephalitogenic Th17 cells. Further analysis of myelin-specific T cells that were encephalitogenic in spontaneous EAE and actively induced EAE demonstrated that T-bet expression was critical for pathogenicity, regardless of cytokine expression by the encephalitogenic T cells. These data suggest that encephalitogenicity of myelin-specific T cells appears to be mediated by a pathway dependent on T-bet and not necessarily pathway-specific end products, such as interferon γ and IL-17.

Evidence for Associations Between Th1/Th17 “Hybrid” Phenotype and Altered Lipometabolism in Very Severe Graves Orbitopathy

2020 ◽  
Vol 105 (6) ◽  
pp. 1851-1867 ◽  
Author(s):  
Sijie Fang ◽  
Shuo Zhang ◽  
Yazhuo Huang ◽  
Yu Wu ◽  
Yi Lu ◽  
...  
Keyword(s):  
T Cell ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Cell Subsets ◽  
Th1 Cell ◽  
Effector T Cell ◽  
Cell Lineages ◽  
Graves Orbitopathy ◽  
Ifn Γ

Abstract Purpose The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. Methods Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. Results In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ–producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ–producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. Conclusions Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.

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