Circulating Tfh Cells Research Articles

Abundance and specificity of influenza reactive circulating memory follicular helper and non-follicular helper CD4 T cells in healthy adults.

CD4 T-cell responses are functionally complex and regulate many aspects of innate and adaptive immunity. Follicular helper (Tfh) cells are CD4 T cells specialized to support B-cell production of isotype-switched, high-affinity antibody. So far, studies of Tfh cells in humans have focused on their differentiation requirements, with little research devoted to their antigen specificity. Here, after separating circulating human memory CD4 T cells based on expression of CXCR5, a signature marker of Tfh, we have quantified and assayed the influenza protein antigen specificity of blood Tfh cells and CD4 T cells lacking this marker. Through the use of peptide pools derived from nucleoprotein (NP) or haemagglutinin (HA) and a panel of human donors, we have discovered that circulating Tfh cells preferentially recognize peptide epitopes from HA while cells lacking CXCR5 are enriched for specificity toward NP. These studies suggest that reactive CD4 T cells specific for distinct viral antigens may have generalized differences in their functional potential due to their previous stimulation history.

Identification of follicular helper T cells as a novel cell population potentially involved in the pathogenesis of Rheumatoid Arthritis (HUM3P.251)

Abstract Background. RA is an autoimmune disease characterized by chronic inflammation of the synovium, causing progressive joint destruction. The treatment for RA is largely based on the clinic manifestations, which are remote from the fundamental pathophysiologic defects. Identification of cellular subsets or biomarkers is a necessary first step toward more accurate prognosis and better therapeutic decisions. Here, we identified a novel T cell subset, follicular helper T cells (Tfh) in RA patients, and examined the hypothesis that Tfh cells may account for RA pathogenesis by providing a fostering environment for self-reactive B cells, resulting in autoantibody production. Methods. Peripheral blood was collected from 26 RA patients and healthy donors. Synovial fluid from actively inflamed joints of RA patients was also collected. Clinical disease activity (DAS-28) and serum laboratory results were obtained. Tfh cells were defined by their signature surface markers via flow cytometry. IL-21 expression and plasmablasts were measured by intracellular staining. Results. A novel T cell subset with Tfh cell signature molecule and cytokine was expanded in the peripheral blood of active RA patients. The percentage of Tfh cells correlated positively with the level of pathogenic auto-antibody (anti-CCP) and disease activity. Conclusions. Circulating Tfh cells may serve as a biomarker of pathogenesis in RA patients. Targeting RA-Tfh cells may provide earlier and precise treatment strategies.

Elevated circulating Th17 and follicular helper CD4(+) T cells in patients with rheumatoid arthritis.

It remains not fully elucidated the potential functions of Th17 cells and follicular helper T (Tfh) cells and secreting cytokines in the pathogenesis of rheumatoid arthritis (RA) and their association with disease activity. In this study, the frequencies of Th17 and Tfh cells were determined by flow cytometry, and the levels of interleukin (IL)-17, IL-21, and IL-22 were measured by ELISA in RA patients with different disease activities. The dynamic changes of cell subsets were also detected in response to disease-modify antirheumatic drugs (DMARDs) therapy. The percentages of CD3(+) CD4(+) IL-17A(+) (Th17) cells and CD3(+) CD4(+) CXCR5(+) ICOS(high) (Tfh) cells, as well as the concentrations of IL-17, IL-21, and IL-22 were significantly elevated in RA patients than those in healthy individuals. Furthermore, Tfh cells, IL-21, and IL-22 in the serum was positively correlated with the values of disease activity score. Concentrations of IL-21 and IL-22 in the serum were remarkably reduced following the DMARDs therapies. Our data suggested that Th17 cells, Tfh cells as well as the secreting cytokines may be involved in the pathogenesis of RA. The frequency of circulating Tfh cells and the productions of IL-21 and IL-22 were associated with the disease activity of RA patients, and might be potential therapeutic targets for treatment of RA.

Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production.

B cells require CD4+ T follicular helper (Tfh) cells to progress through the germinal center and provide protective Ab responses. In this article, we reveal a reciprocal interaction whereby circulating human plasmablasts are potent inducers of the Tfh cell–differentiation program, including the expression of their key transcription factor Bcl-6. The markedly increased propensity of plasmablasts, compared with naive B cells, to induce Tfh cell differentiation was due to their increased production of IL-6. Specific targeting of IL-6 using tocilizumab therapy in patients with rheumatoid arthritis led to a significant reduction in circulating Tfh cell numbers and IL-21 production, which was correlated with reduced plasmablast formation. Our data uncover a positive-feedback loop between circulating plasmablasts and Tfh cells that could sustain autoimmunity and spread Ab-driven inflammation to unaffected sites; this represents an important therapeutic target, as well as reveals a novel mechanism of action for tocilizumab.

Increased frequency of circulating follicular helper T cells in lupus patients is associated with autoantibody production in a CD40L-dependent manner

This study was to determine the frequency of circulating follicular helper T (Tfh) cells in patients with systemic lupus erythematosus (SLE) and investigate the relationship between Tfh cells and autoantibody production. An increased frequency of circulating Tfh cells was found in SLE patients, and there were positive co-relationship between Tfh cells and SLEDAI, serum IgG, Anti-nuclear antibody titers and anti-dsDNA (P=0.0004, 0.0006, 0.0237, 0.0000, respectively). B cells sorted from SLE patients produced more IgG than healthy controls in the presence of autologous CD4+ T cells. CD4+ T cells were further sorted into CXCR5+ and CXCR5− cells, and CD4+CXCR5+ T cells helped B cells producing more IgG than CD4+CXCR5− T cells. Blocking the interaction of T cells and B cells by anti-CD40L but not anti-ICOSL dramatically decreased antibody production in the co-culture system. This study suggests that increased frequency of circulating Tfh cells in SLE patients is associated with excess B-cell help and autoantibody production in a CD40L dependent manner.

IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients.

Aims/hypothesisType 1 diabetes results from the autoimmune destruction of insulin-secreting pancreatic beta cells by T cells. Despite the established role of T cells in the pathogenesis of the disease, to date, with the exception of the identification of islet-specific T effector (Teff) cells, studies have mostly failed to identify reproducible alterations in the frequency or function of T cell subsets in peripheral blood from patients with type 1 diabetes.MethodsWe assessed the production of the proinflammatory cytokines IL-21, IFN-γ and IL-17 in peripheral blood mononuclear cells from 69 patients with type 1 diabetes and 61 healthy donors. In an additional cohort of 30 patients with type 1 diabetes and 32 healthy donors, we assessed the frequency of circulating T follicular helper (Tfh) cells in whole blood. IL-21 and IL-17 production was also measured in peripheral blood mononuclear cells (PBMCs) from a subset of 46 of the 62 donors immunophenotyped for Tfh.ResultsWe found a 21.9% (95% CI 5.8, 40.2; p = 3.9 × 10−3) higher frequency of IL-21+ CD45RA− memory CD4+ Teffs in patients with type 1 diabetes (geometric mean 5.92% [95% CI 5.44, 6.44]) compared with healthy donors (geometric mean 4.88% [95% CI 4.33, 5.50]). Consistent with this finding, we found a 14.9% increase in circulating Tfh cells in the patients (95% CI 2.9, 26.9; p = 0.016).Conclusions/interpretationThese results indicate that increased IL-21 production is likely to be an aetiological factor in the pathogenesis of type 1 diabetes that could be considered as a potential therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3509-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis.

There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5(+) CD4(+) Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P < 0.05) and HC (P < 0.01). Second, the function of circulating Tfh cells from PBC patients, including interleukin (IL)-21 production (P < 0.05), the ability to promote B-cell maturation, and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in ursodeoxycholic acid (UDCA) responders compared to UDCA-treated nonresponders, in both cross-sectional (P = 0.023) and longitudinal studies (P = 0.036), respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. These results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches.

Higher Frequency of Circulating PD-1(high) CXCR5(+)CD4(+) Tfh Cells in Patients with Chronic Schistosomiasis.

The current knowledge of immunological responses to schistosomiasis is insufficient for the development of vaccine and therapies. The role of T follicular helper (Tfh) cells in schistosome infections is not fully defined. The frequency of circulating Tfh cells and serum cytokine levels were analyzed in 11 patients with chronic schistosomiasis and 10 healthy controls (HC), who reside in an endemic area for Schistosomiasis japonicum. Significantly higher frequencies of circulating CXCR5+ CD4+ Tfh cells and higher expression levels of ICOS and PD-1 in CXCR5+ CD4+ Tfh cells were observed in patients with chronic schistosomiasis compared to HC. The levels of IL-21 in serum and the expression of IL-21 mRNA were higher in chronic schistosomiasis patients than in HC. Moreover, the frequency of circulating PD-1high CXCR5+ CD4+ Tfh cells positively correlated with the levels of IL-21 in serum from patients with chronic schistosomiasis. A positive correlation was also found between the frequency of PD-1high CXCR5+ CD4+ Tfh cells and the levels of soluble egg antigen (SEA)-specific antibodies in serum samples from the patient group. Our study is the first regarding Tfh cells in chronic human schistosomiasis and the finding indicate that PD-1high CXCR5+ CD4+Tfh cells might play an important role in the production of specific antibodies in schistosomiasis. This study contributes to the understanding of immune response to schistosomiasis and may provide helpful support in vaccine development.

Decreased frequencies of circulating CD4⁺ T follicular helper cells associated with diminished plasma IL-21 in active pulmonary tuberculosis.

BackgroundCirculating T follicular helper (Tfh) cells represent a distinct subset of CD4+ T cells and are important in immunity to infections. Although they have been shown to play a role in experimental models of tuberculosis infection, their role in human tuberculosis remains unexplored.Aims/MethodologyTo determine the distribution of circulating Tfh cells in human TB, we measured the frequencies of Tfh cells ex vivo and following TB - antigen or polyclonal stimulation in pulmonary TB (PTB; n = 30) and latent TB (LTB; n = 20) individuals, using the markers CXCR5, PD-1 and ICOS.ResultsWe found that both ex vivo and TB - antigen induced frequencies of Tfh cell subsets was significantly lower in PTB compared to LTB individuals. Similarly, antigen induced frequencies of Tfh cells expressing IL-21 was also significantly lower in PTB individuals and this was reflected in diminished circulating levels of IL-21 and IFNγ. This was not accompanied by diminished frequencies of activated or memory B cell subsets. Finally, the diminution in frequency of Tfh cells in PTB individuals was dependent on IL-10, CTLA-4 and PD-L1 in vitro.ConclusionsThus, PTB is characterized by adiminution in the frequency of Tfh cell subsets.

Alterations in Peripheral Blood Follicular Helper T Cell (TFH) Subsets and TREG in Kidney Transplant Recipients With DSA.

Donor-specific anti-HLA antibodies (DSA) represent a key risk factor for acute and chronic rejection, and are a major cause of long-term graft failure after kidney transplantation (KTx). The immunological mechanisms that lead to the development of DSA are not entirely understood. We postulated that an imbalance between TFH (CD4+CD45RO+CXCR5+), which provide key help for antibody production by B cells, and TREG (CD4+CD25highFoxP3+CD127-) correlates with the development of DSA after Tx. Twenty-six thymoglobulin-induced KTx patients participating in an ongoing prospective study were monitored for DSA occurrence in the first year after Tx. During this period, 7 patients were identified as DSA positive by Luminex Single Antigen Bead Assay (cut-off 1000 MFI). Three patients developed DSA by day 30 post-Tx, while 3 presented DSA after day 180. Moreover, one patient had DSA pre-Tx that showed a 4 fold increase by day 30 post-Tx. In addition, 6 healthy control (HC) subjects and 5 DSA negative KTx recipients were included as controls. Whole blood was obtained at regular intervals before and after Tx, and analyzed by flow cytometry.We observed that the overall frequency of circulating TFH cells was not significantly different among the three groups: KTx recipients with DSA, KTx recipients with no DSA, and HC. However, the % of circulating Th1-TFH (CD4+CD45RO+CXCR3+CXCR5+) cells was significantly increased and the % of circulating TREG was decreased in KTx patients with DSA, as compared to their own pre-Tx values and to HC, resulting in a significantly increased Th1-TFH:TREG ratio. In addition, KTx patients with no DSA displayed comparable levels of Th1-TFH and TREG to those of HC, but significantly lower % of Th1-TFH compared to DSA positive patients.In conclusion, patients who develop DSA display a significant skewing of TFH cell subsets toward a Th1-TFH phenotype, accompanied by a concomitant decrease in TREG that results in elevated Th1-TFH:TREG ratio. This finding suggests that an altered balance of TFH cell subsets and TREG is associated with DSA generation after KTx.

Increased frequency of circulating follicular helper T cells in patients with ankylosing spondylitis

Objective. The relationship between circulating follicular helper T (Tfh) cells and ankylosing spondylitis (AS) remains unclear. The aims of our study were to measure the levels of circulating Tfh cells and several related parameters in patients with AS, and examine the correlation of these factors with disease activity.Methods. We designated CD4 + CXCR5 + ICOS+ T cells as circulating Tfh cells. The percentage of circulating Tfh cells was detected using flow cytometry. Plasma IL-21 and immunoglobulin (IgA, IgM, and IgG) levels were quantified using enzyme-linked immunosorbent assay in 60 AS patients and 60 healthy controls (HC).Results. The percentage of circulating Tfh cells was increased in AS patients compared with that in HC. As AS patients were divided into active and inactive groups, the percentage of circulating Tfh cells was significantly increased in active group compared with both inactive group and HC. Plasma IL-21 and immunoglobulin levels were elevated in AS patients, and the differences were significant except IgG. In addition, the percentage of circulating Tfh cells was positively correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and plasma IL-21 levels were positively correlated with plasma immunoglobulin levels. But neither circulating Tfh cells nor BASDAI was significantly correlated with plasma IL-21 and immunoglobulin levels in AS patients, with the exception of significant correlation between BASDAI and plasma IgM levels in active AS patients.Conclusion. Our study has shown the increased percentage of circulating Tfh cells correlated with disease activity, and the high plasma IL-21 levels were associated with high plasma immunoglobulin levels in patients with AS, indicating that the circulating Tfh cells may be associated with the development of AS.

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

Rheumatoid arthritis (RA) is a chronic and systematic autoimmune inflammatory disease. Recently, a novel T cell subset, follicular helper CD4 T cell (Tfh cells) was found in relation to the pathogenesis and progression of RA, and increased numbers of circulating Tfh cells were found in RA patients. However, there is little evidence regarding the localization of Tfh cells in synovium tissues from RA patients, owing to the lack of an available method to characterize their localization in tissue. The aim of our present study was to characterize the Tfh cells in rheumatoid synovium tissues from RA patients by using immunohistochemistry and triple-fluorescence immunostaining methods. Our results showed that specific staining of CD4, CXCR5 and ICOS could be found on infiltrating immune cells in rheumatoid synovium tissues. The use of triple-fluorescence immunostaining and confocal laser scanning showed immunolocalization of CD4+CXCR5+ICOS+T cells (Tfh cells) in the rheumatoid synovium tissues, whereas these signals were absent in osteoarthritis (OA) synovium and in normal synovium tissues. Thus the data from our present preliminary study support the notion that CD4+CXCR5+ICOS+Tfh cells could be found in rheumatoid synovium tissues from RA patients, indicating the possibility that this T cell subset in synovium tissues may have important roles in the pathogenesis and progression of RA.

Inhibition of Increased Circulating Tfh Cell by Anti-CD20 Monoclonal Antibody in Patients with Type 1 Diabetes

ObjectivesFollicular helper T (Tfh) cells exert an important role in autoimmune diseases. Whether it might be involved in type 1 diabetes (T1D) is unknown. Our aim was to investigate the role of Tfh cells in patients with T1D and the effect of anti-CD20 monoclonal antibody (rituximab) on Tfh cells from T1D patients.Patients and MethodsFifty-four patients with T1D and 37 healthy controls were enrolled in the current study. 20 of those patients were treated with rituximab. The frequencies of circulating CD4+CXCR5+ICOS+T cells were analyzed by flow cytometry. The serum autoantibodies were detected by radioligand assay. The levels of IL-21, IL-6 and BCL-6 were assessed using ELISA and/or real-time PCR.ResultsIncreased frequencies of circulating Tfh cells together with enhanced expression of IL-21 were detected in patients. The correlation between the frequencies of circulating Tfh cells and the serum autoantibodies or C-peptide level was comfirmed. After rituximab therapy, follow-up analysis demonstrated that the frequencies of circulating Tfh cell and serum IA2A were decreased. The levels of IL-21, IL-6 and Bcl-6 mRNA were decreased after treatment. Furthermore, beta cell function in 10 of 20 patients was improved.ConclusionsThese data indicate Tfh cells may participate in the T1D-relatede immune responses and B cells might play a role in the development of Tfh responses in the disease progression.

Circulating TFH Subset Distribution Is Strongly Affected in Lupus Patients with an Active Disease

Follicular helper T cells (TFH) represent a distinct subset of CD4+ T cells specialized in providing help to B lymphocytes, which may play a central role in autoimmune diseases having a major B cell component such as systemic lupus erythematosus. Recently, TFH subsets that share common phenotypic and functional characteristics with TFH cells from germinal centers, have been described in the peripheral blood from healthy individuals. The aim of this study was to analyze the distribution of such populations in lupus patients. Circulating TFH cell subsets were defined by multicolor flow cytometry as TFH17 (CXCR3-CCR6+), TFH1 (CXCR3 + CCR6-) or TFH2 (CXCR3-CCR6-) cells among CXCR5 + CD45RA-CD4+ T cells in the peripheral blood of 23 SLE patients and 23 sex and age-matched healthy controls. IL-21 receptor expression by B cells was analyzed by flow cytometry and the serum levels of IL-21 and Igs were determined by ELISA tests. We found that the TFH2 cell subset frequency is strongly and significantly increased in lupus patients with an active disease (SLEDAI score>8), while the TFH1 cell subset percentage is greatly decreased. The TFH2 and TFH1 cell subset frequency alteration is associated with the presence of high Ig levels and autoantibodies in patient’s sera. Moreover, the TFH2 cell subset enhancement correlates with an increased frequency of double negative memory B cells (CD27-IgD-CD19+ cells) expressing the IL-21R. Finally, we found that IgE levels in lupus patients’ sera correlate with disease activity and seem to be associated with high TFH2 cell subset frequency. In conclusion, our study describes for the first time the distribution of circulating TFH cell subsets in lupus patients. Interestingly, we found an increased frequency of TFH2 cells, which correlates with disease activity. Our results suggest that this subset might play a key role in lupus pathogenesis.

Enhancement of CD154/IL4 proliferation by the T follicular helper (Tfh) cytokine, IL21 and increased numbers of circulating cells resembling Tfh cells in chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) cells encounter T-cells and proliferate in response to T-cell signals in the lymph node microenvironment. In this report we determined interleukin 21 (IL21) function in CLL and showed that IL21 and interleukin 4 (IL4) act co-operatively to promote leukaemic cell proliferation without apoptosis or differentiation We further show that IL21 increased side population (SP) cells, which are associated with resistance to chemotherapy and increased self-renewal capacity in CLL. IL21 and IL4 are the major cytokines produced by the recently described CD4(+) T follicular helper (Tfh) cell subset. Determination of Tfh cells in peripheral blood showed that patients had significantly increased numbers as compared to normal subjects although no association was found between Tfh numbers and IGHV gene mutational status or clinical stage. Our data suggests that the Tfh cytokines, IL4 and IL21, contribute to driving leukaemic cell proliferation in the lymph node microenvironment, and may contribute to the specific production of cells resistant to conventional chemotherapy. We suggest that increased circulating Tfh cells is a component of T-cell dysregulation in CLL. Our findings have implications for the therapeutic use of IL21.

Expansion of circulating counterparts of follicular helper T cells in patients with myasthenia gravis

Growing evidence has demonstrated that dysfunction of follicular helper T (TFH) cells results in an abnormal positive selection of autoreactive B cells, which contributes to the development of autoimmune diseases. This study reveals that the frequency of circulating counterparts of TFH cells in myasthenia gravis (MG) patients is significantly higher compared to healthy controls. Interestingly, the frequencies of circulating TFH cells were positively correlated with the levels of serum anti-AChR Ab in MG patients. Our data suggest the presence of overactivation and expansion of circulating counterparts of TFH cells in MG patients, which may contribute to the immunopathogenesis of MG.

Inhibition of Aberrant Circulating Tfh Cell Proportions by Corticosteroids in Patients with Systemic Lupus Erythematosus

ObjectiveTo observe the proportion of peripheral T follicular helper (Tfh) cells in patients with systemic lupus erythematosus (SLE) and to assess the role of steroids on Tfh cells from SLE patients.MethodsPeripheral blood mononuclear cells (PBMCs) from 42 SLE patients and 22 matched healthy subjects were collected to assess proportions of circulating CXCR5+PD1+/CD4+ T cells (Tfh), CD4+CCR6+ T cells (Th17-like) and CD19+CD138+ plasma cells by flow cytometry. 8 of the patients had their blood redrawn within one week after receiving methylprednisolone pulse treatment. Disease activity was evaluated by SLE disease activity index. To test the effect of IL-21 and corticosteroids on Tfh cells in vitro, PBMCs harvested from another 15 SLE patients were cultured with medium, IL-21, or IL-21+ dexamethasone for 24 hours and 72 hours. PBMCs from an independent 23 SLE patients were cultured with different concentrations of dexamethasone for 24 hours.ResultsCompared to normal controls, percentages of circulating Tfh cells, but not Th17 cells, were elevated in SLE patients and correlated with disease activity. Proportions of Tfh cells in SLE patients were positively correlated with those of plasma cells and serum levels of antinuclear antibodies. After methylprednisolone pulse treatment, both percentages and absolute numbers of circulating Tfh cells were significantly decreased. In vitro cultures showed an increase of Tfh cell proportion after IL-21 stimulation that was totally abolished by the addition of dexamethasone. Both 0.5 and 1 µM dexamethasone decreased Tfh cells dose dependently (overall p = 0.013).ConclusionsWe demonstrated that elevated circulating Tfh cell proportions in SLE patients correlated with their disease activities, and circulating levels of plasma cells and ANA. Corticosteroids treatment down-regulated aberrant circulating Tfh cell proportions both in vivo and in vitro, making Tfh cells a new treatment target for SLE patients.

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

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 of CD4+CXCR5+ICOShigh Tfh 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.

Increased Frequency of Follicular Helper T Cells in Patients with Autoimmune Thyroid Disease

Follicular helper T (Tfh) cells exert an important role in the autoimmune diseases. Our study aimed to explore the role of Tfh cells in patients with autoimmune thyroid disease (AITD). Tfh cell is a new subset regulating the antibody production of B cell. Previous studies implicated CD4+CXCR5+ICOShigh or CD4+CXCR5+PD-1high as the markers of circulating Tfh cells. Sixty-five patients with AITD and 30 healthy controls were enrolled in the current study. The percentages of circulating Tfh cells were assessed by flow cytometry. The correlation between the percentages of CD4+CXCR5+ICOShigh T cells and the levels of autoantibodies or hormones was also analyzed. Additionally, polyphasic methods were applied to investigate the status of Tfh cells in thyroid glands of Hashimoto's thyroiditis patients. Increased percentages of circulating Tfh cells in AITD patients were detected, and a positive correlation between the percentages of circulating Tfh cells and the serum concentrations of anti-TSH receptor-Ab/thyroperoxidase-Ab/thyroglobulin-Ab was confirmed. A positive or modest relationship between the percentages of circulating Tfh cells and serum free T3 or free T4 was revealed in Graves' disease patients. Additionally, follow-up analysis indicated that in some Graves' disease patients the percentage of circulating Tfh cells decreased after treatment. Furthermore, a certain number of CD4+CXCR5+ICOShigh T cells together with enhanced expression of IL-21 and Bcl-6 mRNA were detected in thyroid tissues from Hashimoto's thyroiditis patients. The current study discovered an increased frequency of Tfh cells in AITD patients, which implies that this cell subset might play an important role in the pathogenesis of AITD.

Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus

In the sanroque mouse model of lupus, pathologic germinal centers (GCs) arise due to increased numbers of follicular helper T (Tfh) cells, resulting in high-affinity anti-double-stranded DNA antibodies that cause end-organ inflammation, such as glomerulonephritis. The purpose of this study was to examine the hypothesis that this pathway could account for a subset of patients with systemic lupus erythematosus (SLE). An expansion of Tfh cells is a causal, and therefore consistent, component of the sanroque mouse phenotype. We validated the enumeration of circulating T cells resembling Tfh cells as a biomarker of this expansion in sanroque mice, and we performed a comprehensive comparison of the surface phenotype of circulating and tonsillar Tfh cells in humans. This circulating biomarker was enumerated in SLE patients (n = 46), Sjögren's syndrome patients (n = 17), and healthy controls (n = 48) and was correlated with disease activity and end-organ involvement. In sanroque mice, circulating Tfh cells increased in proportion to their GC counterparts, making circulating Tfh cells a feasible human biomarker of this novel mechanism of breakdown in GC tolerance. In a subset of SLE patients (14 of 46), but in none of the controls, the levels of circulating Tfh cells (defined as circulating CXCR5+CD4+ cells with high expression of Tfh-associated molecules, such as inducible T cell costimulator or programmed death 1) were increased. This cellular phenotype did not vary with time, disease activity, or treatment, but it did correlate with the diversity and titers of autoantibodies and with the severity of end-organ involvement. These findings in SLE patients are consistent with the autoimmune mechanism in sanroque mice and identify Tfh effector molecules as possible therapeutic targets in a recognizable subset of patients with SLE.