A preliminary study on the characterization of follicular helper T (Tfh) cells in rheumatoid arthritis synovium

2014 ◽  
Vol 116 (3) ◽  
pp. 539-543 ◽  
Author(s):  
Yang Chu ◽  
Fengming Wang ◽  
Meng Zhou ◽  
Lujun Chen ◽  
Yahua Lu
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatoid Arthritis Synovium ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Preliminary Study

scholarly journals Increased Frequency of Circulating Follicular Helper T Cells in Patients with Rheumatoid Arthritis

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jie Ma ◽  
Chenlu Zhu ◽  
Bin Ma ◽  
Jie Tian ◽  
Samuel Essien Baidoo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Activation ◽  
Critical Role ◽  
Cell Subset ◽  
Antibody Responses ◽  
Helper T Cells ◽  
B Cell Activation ◽  
Cell Frequency ◽  
Tfh Cells ◽  
Follicular Helper

Follicular helper T (Tfh) cells are recognized as a distinct CD4+helper T-cell subset, which provides for B-cell activation and production of specific antibody responses, and play a critical role in the development of autoimmune disease. So far, only one study investigated the circulating Tfh cells increased in a subset of SLE patients. Since relatively little is known about the Tfh cells in rheumatoid arthritis (RA) patients, in this study, Tfh-cell frequency, related cytokine IL-21, and transcription factor Bcl-6 were investigated in 53 patients with RA and 31 health controls. Firstly, we found that the frequency ofCD4+CXCR5+ICOShighTfh cells was increased significantly in the peripheral blood of RA patients, compared with that in healthy controls. It is known that Tfh cells are critical for directing the development of an antibody response by germinal centers B cells; secondly, we observed that the Tfh-cell frequency is accompanied by the level of anti-CCP antibody in RA patients. Furthermore, expression of Bcl-6 mRNA and plasma IL-21 concentrations in RA patients was increased. Taken together, these findings have shown that the increased frequency of circulating Tfh cells is correlated with elevated levels of anti-CCP antibody, indicating the possible involvement of Tfh cells in the disease progression of RA.

scholarly journals T helper cells in synovial fluid of patients with rheumatoid arthritis primarily have a Th1 and a CXCR3+Th2 phenotype

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Jonathan Aldridge ◽  
Anna-Karin H. Ekwall ◽  
Linda Mark ◽  
Beatrice Bergström ◽  
Kerstin Andersson ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Receptor Expression ◽  
Th2 Cells ◽  
T Helper ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Culture Supernatants ◽  
Bead Arrays ◽  
Fibroblast Like Synoviocytes

Abstract Background The majority of CD4+ T helper (Th) cells found in the synovial fluid (SF) of patients with rheumatoid arthritis (RA) express CXCR3, a receptor associated with Th1 cells. In blood, subsets of Th2 and Th17 cells also express CXCR3, but it is unknown if these cells are present in RA SF or how cytokines from these subsets affect cytokine/chemokine secretion by fibroblast-like synoviocytes (FLS) from patients with RA. Methods We examined the proportions of Th1, Th2, CXCR3+Th2, Th17, CXCR3+Th17, Th1Th17, peripheral T helper (TPh) and T follicular helper (TFh) cells in paired SF and blood, as well as the phenotype of TPh and TFh cells in RA SF (n = 8), by the use of flow cytometry. We also examined the cytokine/chemokine profile in paired SF and plasma (n = 8) and in culture supernatants of FLS from patients with chronic RA (n = 7) stimulated with Th-associated cytokines, by the use of cytometric bead arrays and ELISA. Cytokine receptor expression in FLS (n = 3) were assessed by the use of RNA sequencing and qPCR. Results The proportions of Th1 and CXCR3+Th2 cells were higher in SF than in blood (P < 0.05). TPh and PD-1highTFh in RA SF were primarily of a Th1 and a CXCR3+Th2 phenotype. Moreover, the levels of CXCL9, CXCL10, CCL20, CCL2, CXCL8, IL-6 and IL-10 were higher in SF than in plasma (P < 0.05). Lastly, IL-4, IL-13 and IL-17A induced RA FLS to secrete proinflammatory IL-6, CCL2, CXCL1 and CXCL8, while IFNγ mainly induced CXCL10. Conclusion These findings indicate that not only Th1 but also CXCR3+Th2 cells may have a pathogenic role in RA synovial inflammation.

Characterization of Human Follicular Helper T (TFH) Cells

2010 ◽  
Vol 135 ◽  
pp. S53
Author(s):  
Sang Taek Kim ◽  
Jin-Young Choi ◽  
Leah DiPlacido ◽  
Begona Lainez ◽  
Vivian Vlamakis ◽  
...  
Keyword(s):  
Tfh Cells ◽  
Follicular Helper

scholarly journals AB0044 ESTABLISHED RHEUMATOID ARTHRITIS PATIENTS HAVE INCREASED FREQUENCIES OF FOLLICULAR REGULATORY T CELLS IN PERIPHERAL BLOOD

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1325.3-1325
Author(s):  
C. Tomé ◽  
S. C. Barreira ◽  
P. Martins ◽  
A. Valido ◽  
R. Barros ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
T Cell Subsets ◽  
Peripheral Blood Mononuclear ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Healthy Donors ◽  
Cd69 Expression

Background:Several studies have demonstrated that an immune dysregulation affecting both B and T cells occurs in rheumatoid arthritis (RA). Follicular helper T (Tfh) cells are crucial for B cell maturation, activation and class-switching as well as for germinal center (GC) formation, whereas follicular regulatory T (Tfr) cells can modulate the GC reaction by suppressing Tfh and B cells.Objectives:The main goal of this study was to analyze the phenotype and frequency of circulating follicular T cell subsets in established RA patients.Methods:Blood samples were collected from established RA patients with active disease, treated with methotrexate (n=32) and from a group of age and sex-matched healthy donors (n=11). Peripheral blood mononuclear cells (PBMC) were isolated and Tfh (CD4+CXCR5+CD45RO+) and Tfr (CD4+ CXCR5+CD25+FoxP3+) cells, as well as their three major subsets [CXCR3+CCR6- (Th1-like), CXCR3-CCR6- (Th2-like) and CXCR3-CCR6+ (Th17-like)] were evaluated by flow cytometry.Results:The frequency of circulating Tfh cells was similar between established RA patients and controls. Nonetheless, RA patients had a decreased frequency of Th1-like Tfh cells, and an increased frequency of Th2-like Tfh cells when compared to controls. No significant differences were observed in the frequencies of Th17-like Tfh cells between both groups. The frequency of circulating Tfr cells was significantly increased in RA patients in comparison to controls. Furthermore, Tfr cells from RA patients had significantly increased CD69 median fluorescence intensity (MFI) values when compared to controls. No significant differences were found in the percentages and MFI values of PD-1, ICOS, CD28, CTLA-4, CD40-L and HLA-DR expressed by Tfh and Tfr cells in RA patients when compared to controls.Conclusion:Established RA patients have increased circulating frequencies of Tfr cells, with higher CD69 expression levels, when compared to healthy controls. These results suggest a pre-activation state of Tfr cells in RA and a potential role in the disease physiopathology.*RA Moura, JE Fonseca and L Graca are joint senior authors.Disclosure of Interests:None declared

scholarly journals Proportion of T Follicular Helper Cells in Peripheral Blood of Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Peyman Bemani ◽  
Kari K. Eklund ◽  
Mohammad Ali‐Hassanzadeh ◽  
Dieter Kabelitz ◽  
Reinhold E. Schmidt ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systematic Review ◽  
Meta Analysis ◽  
Geographical Location ◽  
Serum Markers ◽  
Disease Stage ◽  
Humoral Immune ◽  
Tfh Cells ◽  
Asian Populations ◽  
Follicular Helper

Abstract Objectives: Follicular helper T (Tfh) cells have critical roles in the development and promotion of humoral immune responses. Accumulating evidence points to alterations in the levels and activity of Tfh which may lead to impaired immune tolerance and development of antibody-mediated autoimmune diseases, such as rheumatoid arthritis (RA). To elucidate the status of Tfh cells in patients with RA, we conducted a systematic review and meta-analysis to assess the proportion and types of Tfh cells in the PB of RA patients.Method: We systematically searched databases of Embase, Pubmed, Web of sciences (WOS), and Scopus to identify the eligible articles. We performed meta-analysis to assess the proportion of Tfh cells in PB of RA patients compared to healthy controls (HCs). We also assessed the proportion of Tfh cells based on different parameters including Tfh definition markers, disease activity status, disease stage, treatment status, serum markers, and the geographical location of the included articles. Results: Regardless of definition markers, the proportion of Tfh cells in RA patients was significantly higher than that in HCs (SMD 0.75, [0.56, 0.93], p<0.0001). Based on subgroup analyses, the proportion of Tfh cells with the individual definitions were also significantly higher in PB of RA patients compared to HCs. Tfh cells proportion in untreated-RA and early-RA patients was markedly greater than HCs, when comparisons were made without considering the definition markers, and also when Tfh cells was defined by the specified definition markers. While the proportion of Tfh cells by all definitions was significantly higher in active- and remission-RA compared to HCs, individual analysis of two definitions, CD4+CXCR5+ and CD4+CXCR5+ICOS+, didn’t show significant differences. In addition, higher proportion of Tfh cells defined by all definitions as well as a specified definition (CD4+CXCR5+PD-1high) was observed when S+RA and S-RA patients were compared to the HCs. Higher Tfh cells proportion in RA patients compared with HCs was observed in the Asian populations (SMD 0.89, [0.68, 1.09], p<0.0001), while there was a trend toward significant in the proportion of Tfh between the two groups in non-Asians (SMD 0.29, [-0.003, 0.59], p=0.052).Conclusion: Altogether, our results demonstrate that circulating Tfh are highly elevated in RA patients and are also significantly increased in untreated-, early- and S+-RA patients, underscoring the potential pathogenic role of this cell population in RA and its potential use as a biomarker and a target for RA therapy.

scholarly journals Increased frequency of CD4+ and CD8+ follicular helper T cells in human lymph node biopsies during the earliest stages of rheumatoid arthritis

2021 ◽  
Author(s):  
Dornatien C Anang ◽  
Tamara H. Ramwadhdoebe ◽  
Janine Hahnlein ◽  
Bo van Kuijk ◽  
Noortje Smits ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Lymph Node ◽  
B Cells ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Helper T Cells ◽  
Healthy Controls ◽  
Tfh Cells ◽  
Follicular Helper

Objectives: Follicular helper T cells (Tfh cells) provide key B cell help, and are essential in germinal center (GC) formation and (auto) antibody generation. To gain more insight into their role during the earliest phase of rheumatoid arthritis (RA) we analyzed their frequencies, phenotype and cytokine profile in peripheral blood and lymphoid tissues. Methods: Using flow cytometry, we studied the frequency of Tfh and B cells in peripheral blood and lymph node (LN) needle biopsies. Three donor groups were included and compared: healthy controls (HCs), autoantibody positive individuals at risk for developing RA (RA-risk individuals), and early RA patients. Ex vivo stimulation of lymphocytes with PMA/ionomycin was performed to assess cytokine secretion by Tfh cells. Results: In blood, the frequency of circular Tfh cells (cTfh) did not differ between study groups. In lymphoid tissue, the frequency of Tfh cells correlated strongly with the frequency of CD19+ B cells. Compared to healthy controls, LN samples of RA patients and RA-risk individuals showed more CD19+ B cells and more CD4+CXCR5+ and CD8+CXCR5+ Tfh cells. These Tfh cells from LNs expressed less IL-21 upon ex vivo stimulation. Conclusion: LN tissue of early RA patients as well as part of RA-risk individuals exhibit increased frequencies of Tfh cells correlating with increased numbers of B cells. Interestingly, IL-21 production is already aberrant in the very early at risk phase of the disease. This suggests that Tfh cells may present a novel rationale for therapeutic targeting during the preclinical stage of the disease to prevent further disease progression.

scholarly journals THU0042 DIFFERENTIAL EFFECT OF ABATACEPT VS TNF BLOCKERS, ON THE FREQUENCY OF CIRCULATING FOLLICULAR HELPER (TFH) AND PERIPERAL HELPER (TPH) T CELLS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 234.1-234
Author(s):  
P. Fortea-Gordo ◽  
D. Peiteado ◽  
A. Villalba ◽  
M. J. Santos-Bornez ◽  
L. Nuño ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Peripheral Blood ◽  
Research Support ◽  
Cell Frequency ◽  
Cell Numbers ◽  
Tnf Blockers ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Treatment Escalation

Background:CXCR5+PD-1hifollicular helper (Tfh) and CXCR5-PD-1hiperipheral helper (Tph) T cells play an important role in the pathogenesis of Rheumatoid Arthritis (RA) by providing help to autoantibody secreting B cells. Whereas Tfh cells typically dwell in the germinal centers of lymphoid organs, Tph cells accumulate at inflamed tissues. An increased frequency of Tph cells and of circulating counterparts of Tfh cells have been described in the peripheral blood of patients with seropositive RA.Objectives:To examine the effect of treatment escalation using biological agents (TNF blockers or abatacept), on the frequency of circulating Tfh (cTfh) and Tph (cTph) cells in RA.Methods:Peripheral blood was drawn from seropositive RA patients with an incomplete response to csDMARDS (n=29) who initiated biological therapy with TNF blockers (TNFb) (n= 17) or abatacept (n= 12), prescribed based on routine clinical practice. cTfh and cTph cell frequencies were determined by flow cytometry of freshly isolated PBMCs at the basal visit and 6 months after starting treatment escalation. For each patient, an age and gender-matched healthy control (HC) was also studied at both time points (n=29).Results:As compared with HC, active RA patients receiving csDMARDs demonstrated a baseline increased frequency of both cTfh and cTph cells. A significant improvement of disease activity as determined by the DAS28 score (ΔDAS28>2.0) was apparent in all of the patients 6 months after initiating biologicals. At that time point, a significant reduction of the previously elevated cTph cell frequency was observed in both treatment groups. However, cTfh cells remained elevated in patients receiving TNFb notwithstanding a good therapeutic response, whereas subjects receiving abatacept experienced a significant abatement of their cTfh cell frequency. Experimental variation of the cTfh and cTph cell numbers in HC was minimal.Conclusion:Abatacept but not TNFb, are able to bring down cTfh cell numbers in RA. This indicates that costimulation blockade can help attain an immunological remission, whereas TNF neutralization may allow a persistent pathogenic germinal center overactivity. At the same time, treatment with both abatacept and TNF blockers results in a downmodulation of the previouly elevated cTph cell numbers, in parallel with the remitting local joint inflammation.References:[1]Simpson N et al, Arthritis Rheum 2010; Craft J, Nat Rev Rheumatol 2012; Arroyo-Villa I et al., Arthritis Res Ther 2014; Rao DA et al., Nature 2017.Disclosure of Interests:Paula Fortea-Gordo Grant/research support from: BMS, Diana Peiteado: None declared, Alejandro Villalba: None declared, Maria-Jose Santos-Bornez Grant/research support from: BMS, Laura Nuño: None declared, Irene Monjo: None declared, Alejandro Balsa Grant/research support from: BMS, Roche, Consultant of: AbbVie, Gilead, Lilly, Pfizer, UCB, Sanofi, Sandoz, Speakers bureau: AbbVie, Lilly, Sanofi, Novartis, Pfizer, UCB, Roche, Nordic, Sandoz, Maria-Eugenia Miranda-Carus Grant/research support from: BMS, Roche

scholarly journals In Situ Characterization of Follicular Helper CD4 T Cells Using Multiplexed Imaging

2021 ◽  
Vol 11 ◽  
Author(s):  
Kalliopi Ioannidou ◽  
Daba-Rokhya Ndiaye ◽  
Alessandra Noto ◽  
Craig Fenwick ◽  
Sotirios P. Fortis ◽  
...  
Keyword(s):  
Tissue Level ◽  
Phenotypic Characterization ◽  
Surface Receptors ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Nuclear Factors ◽  
Quantitative Manner ◽  
Spatial Positioning

Follicular helper CD4 T (Tfh) cells play an essential role in the formation of germinal centers (GCs), where mature B cells proliferate, differentiate, and provide long-term protective humoral responses. Despite the extensive phenotypic characterization and identification of human Tfh cell subsets, their spatial positioning at tissue level is not well understood. Here, we describe a quantitative multiplexed immunofluorescence approach allowing for the comprehensive in situ characterization of Tfh cells in human tonsils and lymph nodes (LNs) from individuals with angioimmunoblastic T-cell lymphoma (AITL). We have developed eight multiplexed panels comprising a spectrum of Tfh cell markers, like PD-1, CXCR5, and ICOS, along with transcription factors (Bcl6, Tbet, GATA3), to assess their expression, frequencies, spatial distribution and co-localization in a quantitative manner. Combined analysis of relevant markers revealed the presence of several Tfh cell subsets at tissue level based on the differential expression of surface receptors, nuclear factors as well as their distinct localization within the follicular areas. Interestingly, we found a considerable amount of tonsillar Tfh cells expressing high levels of the Th2 regulator GATA3. The co-expression of GATA3, CXCR5, and BCL6, points to an important role of GATA3 for the generation of effector human Tfh cells. Furthermore, our data revealed significantly different Tfh cell profile signatures between health and disease. Therefore, our imaging platform generates meaningful information for the in situ characterization of human Tfh cells and could provide the base for future studies aiming to a comprehensive understanding of Tfh cell tissue heterogeneity.

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