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 Pivotal role for αVintegrins in sustained Tfh support of the germinal center response for long-lived plasma cell generation

2019 ◽  
Vol 116 (10) ◽  
pp. 4462-4470
Author(s):  
Dillon C. Schrock ◽  
Scott A. Leddon ◽  
Angela Hughson ◽  
Jim Miller ◽  
Adam Lacy-Hulbert ◽  
...  
Keyword(s):  
T Cell ◽  
Germinal Center ◽  
Influenza A ◽  
Cell Activation ◽  
Plasma Cells ◽  
Helper T Cells ◽  
Cell Recognition ◽  
B Cell Activation ◽  
T Cell Recognition ◽  
Follicular Helper

CD4+ follicular helper T cells (Tfh) are essential for germinal center (GC) reactions in the lymph node that generate high-affinity, long-lived plasma cells (LLPCs). Temporal GC analysis suggests B memory cells (Bmem) are generated early, while LLPCs are generated late in the GC reaction. Distinct roles for Tfh at these temporally different stages are not yet clear. Tfh entry into the GC is highly dynamic and the signals that maintain Tfh within the GC for support of late LLPC production are poorly understood. The GC is marked by inflammation-induced presentation of specific ECM components. To determine if T cell recognition of these ECM components played a role in Tfh support of the GC, we immunized mice with a T cell-restricted deletion of the ECM-binding integrin αV(αV-CD4 cKO). T cell integrin αVdeletion led to a striking defect in the number and size of the GCs following immunization with OVA protein in complete Freund’s adjuvant. The GC defect was not due to integrin αVdeficiency impeding Tfh generation or follicle entry or the ability of αV-CD4 cKO Tfh to contact and support B cell activation. Instead, integrin αVwas essential for T cell-intrinsic accumulation within the GC. Altered Tfh positioning resulted in lower-affinity antibodies and a dramatic loss of LLPCs. Influenza A infection revealed that αVintegrin was not required for Tfh support of Bmem but was essential for Tfh support of LLPCs. We highlight an αVintegrin–ECM-guided mechanism of Tfh GC accumulation that selectively impacts GC output of LLPCs but not Bmem.

scholarly journals Regulatory B Cell Imbalance Correlates With TFH Expansion in Systemic Sclerosis.

2020 ◽  
Author(s):  
arsene mekinian ◽  
Laure Ricard ◽  
Florent Malard ◽  
Sébastien Riviere ◽  
Charlotte Laurent ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
B Cell ◽  
Cell Activation ◽  
Cell Subset ◽  
Healthy Controls ◽  
B Cell Activation ◽  
Autoantibody Production ◽  
Regulatory B Cell ◽  
Follicular Helper ◽  
Pulmonary Arterial

Abstract Objective.Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis, microangiopathy and immune dysfunction. B cell abnormalities characterized by autoantibody production and polyclonal B cell activation play an important role in the pathogenesis of SSc. We previously identified an expansion of functional and activated circulating T follicular helper (cTfh) cells in SSc patients. The aim of this study was to analyze the frequency of regulatory B (Breg) cell subsets and the correlation with Tfh in SSc patients.Methods.Circulating Breg cells CD24hiCD38hi and CD27+CD24hilevels and cTfh cells CD4+CXCR5+PD1+were determined by cytometry in 50SSc patients and 32 healthy subjects.Results.The frequency of Breg cells CD24hiCD38hi and CD24hiCD27+ was significantly reduced in patients with SSc as compared to controls (p=0.02 and p<0.001, respectively). In contrast, when examining the CD21low B cell subset, the frequency was significantly increased in SSc patients compared to healthy controls, (p<0.001). There was no difference in Bregcell levels in patients with diffuse SSc and limited SSc. However, CD24hiCD27+Breg cell frequency was significantly decreased in SSc patients with pulmonary arterial hypertension (p=0.014), but not in patients with interstitial lung disease (p=0.058).Furthermore, we observed a negative correlation between cTfh and CD24hiCD27+ Breg cell levels in SSc patients but not in healthy controls (p=0.02). Conclusions: These results suggest that Breg cell subsets may participate in the regulation of cTfh and disease severity. Decreased CD24hiCD27+ Breg cell frequencymay contribute to the development of SSc.

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 Altered T Follicular Helper Cell Subsets and Function in Chronic Lymphocytic Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Xun Wu ◽  
J. Ernesto Fajardo-Despaigne ◽  
Christine Zhang ◽  
Vishala Neppalli ◽  
Versha Banerji ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activation ◽  
Cell Clone ◽  
Cell Subset ◽  
Lymphocytic Leukemia ◽  
Functional Markers ◽  
B Cell Activation ◽  
Follicular Helper

Follicular helper T cells (TFH) have specialized properties in promoting normal B cell activation but their role in chronic lymphocytic leukemia (CLL) is unknown. We find that TFH cells are elevated in CLL patients and are phenotypically abnormal, expressing higher levels of PD-1, TIGIT, CD40L, IFNγ and IL-21, and exhibiting abnormal composition of TFH1, TFH2 and TFH17 subsets. Frequencies of CD4-positive T cells expressing TFH1 markers and IL-21 were positively correlated with patient lymphocyte counts and RAI stage, suggesting that accumulation of abnormal TFH cells is concomitant with expansion of the leukemic B cell clone. Treatment with ibrutinib led to normalization of TFH frequencies and phenotype. TFH cells identified in CLL bone marrow display elevated expression of several functional markers compared to blood TFH cells. CLL T cell-B cell co-culture experiments revealed a correlation of patient TFH frequencies with functional ability of their CD4-positive T cells to promote CLL proliferation. Conversely, CLL cells can preferentially activate the TFH cell subset in co-culture. Together our results indicate that CLL development is associated with expansion of abnormal TFH populations that produce elevated levels of cytokines and costimulatory molecules which may help support CLL proliferation.

scholarly journals Hyaluronate-CD44 Interactions Can Induce Murine B-Cell Activation

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2901-2908 ◽  
Author(s):  
Asimah Rafi ◽  
Mitzi Nagarkatti ◽  
Prakash S. Nagarkatti
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Surface Glycoprotein ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Cell Surface Glycoprotein ◽  
Immunodeficient Mice

Abstract CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.

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