Follicular helper T cells in rheumatoid arthritis

Yu, Mei; Cavero, Vanesssa; Liao, Qiao; Li, Hong

doi:10.1007/s10067-015-3028-5

Cited by 35 publications

(18 citation statements)

References 36 publications

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“…These TFh cells display CXCR5 + /PD1 high phenotype [67,68]. They have recently been observed in RA [69]. Both these markers were also modestly DM, and we previously reported high CXCR5 expression specifically on CD62L − naïve cells in RA [59].…”

Section: Discussionsupporting

confidence: 59%

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

et al. 2020

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Background: The genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis. Result: Monocytes, naïve and memory CD4 + T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4 + T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4 + T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in β values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4 + T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively. Conclusion: Our data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.

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Section: Discussionsupporting

confidence: 59%

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

et al. 2020

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“…Tfh cells secrete IL-21, a cytokine that has been found to not only promote naive T cell differentiation into potent B helper cells, but also to promote GC B cell responses through CD-40 L/CD-40 interaction [ 14 ]. Moreover, Tfh cells regulate B cell proliferation, differentiation, and antibody production via the secretion of IL-21 [ 13 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Circulating CXCR5 + T cells, which secrete high levels of IL-21 to promote B cell differentiation into plasma cells, are more capable of facilitating B cell maturation and humoral responses than CXCR5 − T cells [ 13 ]. Thus, circulating Tfh cells are crucial for the pathogenesis of autoimmune diseases [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis

Niu

Huang

et al. 2018

Arthritis Res Ther

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BackgroundFollicular helper T (Tfh) cells are specialized in helping B lymphocytes, which play a central role in autoimmune diseases that have a major B cell component, such as in rheumatoid arthritis (RA). Follicular regulatory T (Tfr) cells control the over-activation of Tfh and B cells in germinal centers. Dysregulation of Tfh cells and Tfr cells has been reported to be involved in the pathogenesis of some autoimmune diseases. However, the balance of Tfh and Tfr cells, and their roles in the development and progression of RA are still not clear.MethodsIn this study, we enrolled 44 patients with RA (20 patients with active RA and 24 patients with inactive RA) and 20 healthy controls, and analyzed the frequencies of circulating Tfh and Tfr cells, expression of programmed death-1 (PD-1), inducible co-stimulator (ICOS), intracellular IL-21, and pSTAT3 in Tfh cells, and serum levels of IL-6. The correlation among these parameters and that of Tfh or Tfr cells with disease activity were also analyzed.ResultsPatients with RA (especially active RA) had higher frequencies of Tfh cells, but lower percentages of Tfr cells, thereby resulting in elevated ratios of Tfh/Tfr. Expression levels of PD-1 and IL-21 in Tfh cells were higher in patients with RA than in healthy subjects, while no difference in ICOS expression was observed between patients and controls. Both pSTAT3 expression and serum IL-6 levels increased in patients with RA, and positive correlation between them was observed. Additionally, pSTAT3 expression was positively correlated with Tfh cell frequency. The Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP) was negatively correlated with Tfr cell frequency, but was positively correlated with both Tfh/Tfr ratio and PD-1 expression.ConclusionsResults demonstrated that enhanced IL-6/pSTAT3 signaling may contribute to promotion of Tfh cells, consequently skewing the ratio of Tfh to Tfr cells, which may be crucial for disease progression in RA.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1690-0) contains supplementary material, which is available to authorized users.

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“…Differential expression of CXCR3 and CCR6 within CD4 + CXCR5 + T cells defines three major subsets: CXCR3 + CCR6 − (Tfh1), CXCR3 − CCR6 − (Tfh2), and CXCR3 − CCR6 + (Tfh17) [ 30 ]. RA patients, both with active disease and in remission, demonstrate an increased frequency of Tfh and overrepresentation of Tfh subsets bearing a B cell helper phenotype [ 30 , 31 ]. There are few studies conducted in RA regarding the Th22 subpopulation; nevertheless, its characteristic cytokine, IL-22, which can also be produced by pathogenic Th17, has shown to have a pathogenic role associated with disease activity in RA, promoting osteoclastogenesis and bone destruction in RA [ 32 ].…”

Section: An Introduction To the Physiopathology Of Rheumatoid Arthmentioning

confidence: 99%

The Anti-Inflammatory Mediator, Vasoactive Intestinal Peptide, Modulates the Differentiation and Function of Th Subsets in Rheumatoid Arthritis

Villanueva‐Romero

Gutiérrez‐Cañas

Carrión

et al. 2018

Journal of Immunology Research

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Genetic background, epigenetic modifications, and environmental factors trigger autoimmune response in rheumatoid arthritis (RA). Several pathogenic infections have been related to the onset of RA and may cause an inadequate immunological tolerance towards critical self-antigens leading to chronic joint inflammation and an imbalance between different T helper (Th) subsets. Vasoactive intestinal peptide (VIP) is a mediator that modulates all the stages comprised between the arrival of pathogens and Th cell differentiation in RA through its known anti-inflammatory and immunomodulatory actions. This “neuroimmunopeptide” modulates the pathogenic activity of diverse cell subpopulations involved in RA as lymphocytes, fibroblast-like synoviocytes (FLS), or macrophages. In addition, VIP decreases the expression of pattern recognition receptor (PRR) such as toll-like receptors (TLRs) in FLS from RA patients. These receptors act as sensors of pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) connecting the innate and adaptive immune system. Moreover, VIP modulates the imbalance between Th subsets in RA, decreasing pathogenic Th1 and Th17 subsets and favoring Th2 or Treg profile during the differentiation/polarization of naïve or memory Th cells. Finally, VIP regulates the plasticity between theses subsets. In this review, we provide an overview of VIP effects on the aforementioned features of RA pathology.

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Follicular helper T cells in rheumatoid arthritis

Cited by 35 publications

References 36 publications

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis

The Anti-Inflammatory Mediator, Vasoactive Intestinal Peptide, Modulates the Differentiation and Function of Th Subsets in Rheumatoid Arthritis

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