TNF-α inhibitor therapy can improve the immune imbalance of CD4+ T cells and negative regulatory cells but not CD8+ T cells in ankylosing spondylitis

Abstract Background: Studies into ankylosing spondylitis (AS) and its relationship with immune function are controversial, and the correlation between the efficacy of TNF-α inhibitor and changes in immune function is unclear.Methods: A total of 40 immune cells were tested with flow cytometry, and the results of 105 HC (healthy control) subjects, 177 active-stage AS patients, and 23 AS cases before and after 12 weeks of TNF-α inhibitor therapy (Anbainuo) were analyzed.Results: Compared with the HC group, the proportion of immune cells, such as naïve and central memory CD4+T cells, in AS increased (p<0.0001), but effector memory and terminally differentiated CD4+T cells were decreased (p<0.01 and 0.0001, respectively). Naïve, central memory, and effector memory CD8+T cells were increased (p<0.0001, 0.001, and 0.01, respectively), but terminally differentiated CD8+T cells were decreased (p<0.0001). Th1 cells (helper T cells-1), Tfh1 cells (follicular helper T cells-1), Tc1 cells (cytotoxic T cells-1), and Tregs (regulatory T cells) were lower (p<0.01, 0.05, 0.0001, and 0.001, respectively), but Th17 cells, Tfh17 cells, and Tc cells were higher (p<0.001, 0.0001 and 0.001, respectively). The proportions of total B cells and class-switched B cells were increased (p<0.05), but non-switched B cells, plasma cells, memory B cells, and immature Bregs (regulatory B cells) were lower (p<0.01, 0.0001, 0.0001, and 0.0001, respectively). After Anbainuo therapy, the percentage of naïve CD4+ T cells had decreased (p<0.05) but Tregs and B10 cells (IL-10-producing regulatory B cells) had increased (p<0.01and 0.05, respectively), and the increase in Tregs was positively correlated with the decrease in CRP (C-reactive protein) (r= 0.489, p=0.018). Conclusions: We found that active-stage AS patients have an immunity imbalance involving multiple types of immune cells, including CD4+T cells, CD8+T cells, Th cells, Tfh cells, Tc cells, Tregs, Bregs, and B cells. TNF-α inhibitor Anbainuo can not only help to inhibit disease activity but can also improve the immune imbalance of CD4+ T cells and negative regulatory cells. But CD8 + T cells have not been rescued.

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Complementary Dendritic Cell–activating Function of CD8+ and CD4+ T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20011662 ◽

2002 ◽

Vol 195 (4) ◽

pp. 473-483 ◽

Cited By ~ 108

Author(s):

Robbie B. Mailliard ◽

Shinichi Egawa ◽

Quan Cai ◽

Anna Kalinska ◽

Svetlana N. Bykovskaya ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Class I ◽

Chronic Infections ◽

Cd40 Ligation ◽

Activation Level ◽

Tnf Α ◽

Ifn Γ

Dendritic cells (DCs) activated by CD40L-expressing CD4+ T cells act as mediators of “T helper (Th)” signals for CD8+ T lymphocytes, inducing their cytotoxic function and supporting their long-term activity. Here, we show that the optimal activation of DCs, their ability to produce high levels of bioactive interleukin (IL)-12p70 and to induce Th1-type CD4+ T cells, is supported by the complementary DC-activating signals from both CD4+ and CD8+ T cells. Cord blood– or peripheral blood–isolated naive CD8+ T cells do not express CD40L, but, in contrast to naive CD4+ T cells, they are efficient producers of IFN-γ at the earliest stages of the interaction with DCs. Naive CD8+ T cells cooperate with CD40L-expressing naive CD4+ T cells in the induction of IL-12p70 in DCs, promoting the development of primary Th1-type CD4+ T cell responses. Moreover, the recognition of major histocompatibility complex class I–presented epitopes by antigen-specific CD8+ T cells results in the TNF-α– and IFN-γ–dependent increase in the activation level of DCs and in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. The ability of class I–restricted CD8+ T cells to coactivate and polarize DCs may support the induction of Th1-type responses against class I–presented epitopes of intracellular pathogens and contact allergens, and may have therapeutical implications in cancer and chronic infections.

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The Role of β-Catenin in Th1 Immune Response against Tuberculosis and Profiles of Expression in Patients with Pulmonary Tuberculosis

Journal of Immunology Research ◽

10.1155/2021/6625855 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Kunlong Xiong ◽

Jinxia Niu ◽

Ruijuan Zheng ◽

Zhonghua Liu ◽

Yanzheng Song ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Mononuclear Cells ◽

Cd4 T Cell ◽

Cell Frequency ◽

Tnf Α ◽

Ifn Γ

β-Catenin is a key molecule of canonical Wnt/β-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of β-catenin in CD4+ T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4+ T cell-specific β-catenin conditional knockout mice (β-CAT-cKO mice) were aerosol infected with Mycobacteria tuberculosis (Mtb) H37RV with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-γ, TNF-α, and TCF-7 in the lungs of mice was measured. CD4, CD8, β-catenin, IFN-γ, and TNF-α in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of β-catenin, IFN-γ, TNF-α, and PD-1 in CD4+ and CD8+ T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-γ/TNF-α mRNA expression and secretion by CD4+ T cells in the lungs of infected β-CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. β-catenin expressions in CD4+ and CD8+ T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of β-catenin, resulted in the increase in CD4+ T cell frequency, as well as their secretion of IFN-γ and TNF-α. β-Catenin demonstrated a moderately positive correlation with PD-1 in CD4+ T cells. β-Catenin along with PD-1 and IFN-γ in CD4+ T cells had a high correlation with those in CD8+ T cells. In conclusion, β-catenin may be involved in the regulation of Th1 response and CD4+ T cell frequency in TB.

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Circulating cytokines and lymphocyte subsets in patients who have recovered from COVID-19

10.1101/2020.07.22.20160259 ◽

2020 ◽

Author(s):

Hasi Chaolu ◽

Xinri Zhang ◽

Xin Li ◽

Dongyan Li

Keyword(s):

T Cells ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Lymphocyte Subsets ◽

Healthy Controls ◽

Tnf Α ◽

Ifn Γ ◽

Circulating Cytokines

To investigate the immune status of people who previously had COVID-19 infections, we recruited patients 2 weeks post-recovery and analyzed circulating cytokines and lymphocyte subsets. We measured levels of total lymphocytes, CD4+ T cells, CD8+ T cells, CD19+ B cells, CD56+ NK cells, and the serum concentrations of interleukin (IL)-1, IL-4, IL-6, IL-8, IL-10, transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) by flow cytometry. We found that in most post-recovery patients, levels of total lymphocytes (66.67%), CD3+ T cells (54.55%), CD4+ T cells (54.55%), CD8 + T cells (81.82%), CD19+ B cells (69.70%), and CD56+ NK cells(51.52%) remained lower than normal, whereas most patients showed normal levels of IL-2 (100%), IL-4 (80.88%), IL-6 (79.41%), IL-10 (98.53%), TNF-α (89.71%), IFN-γ (100%) and IL-17 (97.06%). Compared to healthy controls, 2-week post-recovery patients had significantly lower absolute numbers of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells, along with significantly higher levels of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL-17. Among post-recovery patients, T cells, particularly CD4+ T cells, were positively correlated with CD19+ B cell counts. Additionally, CD8+ T cells positively correlated with CD4+ T cells and IL-2 levels, and IL-6 positively correlated with TNF-α and IFN-γ. These correlations were not observed in healthy controls. By ROC curve analysis, post-recovery decreases in lymphocyte subsets and increases in cytokines were identified as independent predictors of rehabilitation efficacy. These findings indicate that the immune system has gradually recovered following COVID-19 infection; however, the sustained hyper-inflammatory response for more than 14 days suggests a need to continue medical observation following discharge from the hospital. Longitudinal studies of a larger cohort of recovered patients are needed to fully understand the consequences of the infection.

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Circulating Cytokines and Lymphocyte Subsets in Patients Who Have Recovered from COVID-19

BioMed Research International ◽

10.1155/2020/7570981 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Hasichaolu ◽

Xinri Zhang ◽

Xin Li ◽

Dongyan Li

Keyword(s):

T Cells ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Lymphocyte Subsets ◽

Healthy Controls ◽

Cell Counts ◽

Tnf Α ◽

Ifn Γ

To investigate the immune status of people who previously had COVID-19 infections, we recruited two-week postrecovery patients and analyzed circulating cytokine and lymphocyte subsets. We measured levels of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells and the serum concentrations of interleukin- (IL-) 1, IL-4, IL-6, IL-8, IL-10, transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) by flow cytometry. We found that in most postrecovery patients, levels of total lymphocytes (66.67%), CD3+ T cells (54.55%), CD4+ T cells (54.55%), CD8+ T cells (81.82%), CD19+ B cells (69.70%), and CD56+ NK cells (51.52%) remained lower than normal, whereas most patients showed normal levels of IL-2 (100%), IL-4 (80.88%), IL-6 (79.41%), IL-10 (98.53%), TNF-α (89.71%), IFN-γ (100%), and IL-17 (97.06%). Compared to healthy controls, two-week postrecovery patients had significantly lower absolute numbers of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells, along with significantly higher levels of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17. Among postrecovery patients, T cells, particularly CD4+ T cells, were positively correlated with CD19+ B cell counts. Additionally, CD8+ T cells were positively correlated with CD4+ T cells and IL-2 levels, and IL-6 positively correlated with TNF-α and IFN-γ. These correlations were not observed in healthy controls. By ROC curve analysis, postrecovery decreases in lymphocyte subsets and increases in cytokines were identified as independent predictors of rehabilitation efficacy. These findings indicate that the immune system gradually recovers following COVID-19 infection; however, the sustained hyperinflammatory response for more than 14 days suggests a need to continue medical observation following discharge from the hospital. Longitudinal studies of a larger cohort of recovered patients are needed to fully understand the consequences of the infection.

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Immune dysfunction in ankylosing spondylitis (AS) and the potential of tumor necrosis factor-α (TNF-α) inhibitor Anbainuo as an effective treatment

10.21203/rs.2.21954/v1 ◽

2020 ◽

Author(s):

Mingcan Yang ◽

Qing Lv ◽

Qiujing Wei ◽

Yutong Jiang ◽

Jun Qi ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Immune Function ◽

Cd8 T Cells ◽

Immune Cells ◽

Cd4 T Cells ◽

Helper T Cells ◽

Effector Memory ◽

Regulatory B Cells ◽

Tnf Α

Abstract Background Studies into ankylosing spondylitis (AS) and its relationship with immune function are controversial, and the correlation between the efficacy of TNF-α inhibitor and changes in immune function is unclear. Methods A total of 40 immune cells were tested with flow cytometry, and the results of 105 HC (healthy control) subjects, 177 active-stage AS patients, and 23 AS cases before and after 12 weeks of Anbainuo therapy were analyzed. Results Compared with the HC group, the proportion of immune cells, such as naïve and central memory CD4+T cells, in AS increased (p<0.0001), but effector memory and terminally differentiated CD4+T cells were decreased (p<0.01 and 0.0001, respectively). Naïve, central memory, and effector memory CD8+T cells were increased (p<0.0001, 0.001, and 0.01, respectively), but terminally differentiated CD8+T cells were decreased (p<0.0001). Th1 cells (helper T cells-1), Tfh1 cells (follicular helper T cells-1), Tc1 cells (cytotoxic T cells-1), and Tregs (regulatory T cells) were lower (p<0.01, 0.05, 0.0001, and 0.001, respectively), but Th17 cells, Tfh17 cells, and Tc cells were higher (p<0.001, 0.0001 and 0.001, respectively). The proportions of total B cells and class-switched B cells were increased (p<0.05), but non-switched B cells, plasma cells, memory B cells, and immature Bregs (regulatory B cells) were lower (p<0.01, 0.0001, 0.0001, and 0.0001, respectively). After Anbainuo therapy, the percentage of Tregs and B10 cells (IL-10-producing regulatory B cells) had increased (p<0.01and 0.05, respectively), and the increase in Tregs was positively correlated with the decrease in CRP (C-reactive protein) (r= 0.489, p=0.018). Conclusions We found that, in terms of both innate and acquired immunity, active-stage AS patients have an immunity imbalance involving multiple types of immune cells, including CD4+T cells, CD8+T cells, Th cells, Tfh cells, Tc cells, Tregs, Bregs, and B cells. Anbainuo can not only help to inhibit disease activity and partial immune function imbalance in AS but can also increase the number of negative regulatory cells in inflammation.

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Effect of All-transretinoic Acid on Th17 and T Regulatory Cell Subsets in Patients with Ankylosing Spondylitis

The Journal of Rheumatology ◽

10.3899/jrheum.121100 ◽

2013 ◽

Vol 40 (4) ◽

pp. 476-483 ◽

Cited By ~ 16

Author(s):

Katayoon Bidad ◽

Eisa Salehi ◽

Ahmadreza Jamshidi ◽

Ali Akbar Saboor-Yaraghi ◽

Mona Oraei ◽

...

Keyword(s):

T Cells ◽

Ankylosing Spondylitis ◽

Cd4 T Cells ◽

T Regulatory Cells ◽

Interleukin 10 ◽

Orphan Receptor ◽

Healthy Controls ◽

T Regulatory Cell ◽

Tnf Α ◽

Ifn Γ

Objective.We compared Th17 and T regulatory cells in patients with ankylosing spondylitis (AS) and in healthy controls. The effect of all-transretinoic acid (ATRA) was studied on cultured CD4+ T cells of patients with AS compared to controls.Methods.Eighteen patients with AS and 18 age- and sex-matched healthy controls were included. CD4+ T cells were separated and cultured in conditions of anti-CD3 and anti-CD28 stimulation with and without ATRA. Intracellular and secreted cytokines, transcription factors, and gene expression were evaluated after 72 h.Results.The frequency of CD4+IL-17+ T cells was significantly higher in patients with AS compared to controls, and ATRA could significantly decrease it. The frequency of forkhead box protein 3 (FOXP3)+ retinoic acid-related orphan receptor γt (RORγt) negative T-bet negative CD4+ cells was significantly lower in cases compared to controls. Intracellular and secreted interferon-γ (IFN-γ) was not significantly different between cases and controls. ATRA significantly increased intracellular IFN-γ in cases but not in controls. Tumor necrosis factor-α (TNF-α) secretion was significantly higher and interleukin 10 secretion was significantly lower in culture supernatant of cases compared to controls. ATRA could significantly decrease TNF-α secretion in cases.Conclusion.Our findings favor a pathogenic role for Th17 cells in AS. Th1 cells did not seem to contribute in the pathogenesis of this disease. The effect of ATRA as an immunomodulator on deviated immune cells was associated with decreased inflammatory markers. This association could be a reason for a clinical trial of ATRA in patients with AS.

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AB0049 IMMUNE DYSFUNCTION IN ANKYLOSING SPONDYLITIS (AS) AND THE POTENTIAL OF TUMOR NECROSIS FACTOR-Α (TNF-α) INHIBITOR ANBAINUO AS AN EFFECTIVE TREATMENT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5119 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1327.2-1327

Author(s):

M. Yang ◽

Q. Lv ◽

Q. Wei ◽

J. Gu

Keyword(s):

T Cells ◽

Ankylosing Spondylitis ◽

B Cells ◽

Immune Function ◽

Cd8 T Cells ◽

Immune Cells ◽

Cd4 T Cells ◽

Helper T Cells ◽

Effector Memory ◽

Follicular Helper

Background:Studies into ankylosing spondylitis (AS) and its relationship with immune function are controversial, and the correlation between the efficacy of TNF-α inhibitor and changes in immune function is unclear.Objectives:We conducted a prospective study of T-cell and B-cell subset distribution and analyzed lymphocyte function in AS patients to further clarify changes to the immune system caused by AS and to explore resistance that could contribute to relapse after treatment.Methods:A total of 40 immune cells were tested with flow cytometry, and the results of 105 HC (healthy control) subjects, 177 active-stage AS patients, and 23 AS cases before and after 12 weeks of Anbainuo therapy were analyzed.Results:Compared with the HC group, the proportion of immune cells, such as naïve and central memory CD4+T cells, in AS increased (p<0.0001), but effector memory and terminally differentiated CD4+T cells were decreased (p<0.01 and 0.0001, respectively). Naïve, central memory, and effector memory CD8+T cells were increased (p<0.0001, 0.001, and 0.01, respectively), but terminally differentiated CD8+T cells were decreased (p<0.0001). Th1 cells (helper T cells-1), Tfh1 cells (follicular helper T cells-1), Tc1 cells (cytotoxic T cells-1), and Tregs (regulatory T cells) were lower (p<0.01, 0.05, 0.0001, and 0.001, respectively), but Th17 cells, Tfh17 cells, and Tc cells were higher (p<0.001, 0.0001 and 0.001, respectively). The proportions of total B cells and class-switched B cells were increased (p<0.05), but non-switched B cells, plasma cells, memory B cells, and immature Bregs (regulatory B cells) were lower (p<0.01, 0.0001, 0.0001, and 0.0001, respectively). After Anbainuo therapy, the percentage of Tregs and B10 cells (IL-10-producing regulatory B cells) had increased (p<0.01and 0.05, respectively), and the increase in Tregs was positively correlated with the decrease in CRP (C-reactive protein) (r= 0.489, p=0.018).Conclusion:We found that, in terms of both innate and acquired immunity, active-stage AS patients have an immunity imbalance involving multiple types of immune cells, including CD4+T cells, CD8+T cells, Th cells, Tfh cells, Tc cells, Tregs, Bregs, and B cells. Anbainuo can not only help to inhibit disease activity and partial immune function imbalance in AS but can also increase the number of negative regulatory cells in inflammation.References:[1]Long, S., et al., High frequency of circulating follicular helper T cells is correlated with B cell subtypes in patients with ankylosing spondylitis. Exp Ther Med, 2018. 15(5): p. 4578-4586.[2]An, H., et al., The absolute counts of peripheral T lymphocyte subsets in patient with ankylosing spondylitis and the effect of low-dose interleukin-2. Medicine (Baltimore), 2019. 98(15): p. e15094.Acknowledgments:Thanks to Professor Zhinan Yin for his support and assistance with this studyDisclosure of Interests:None declared

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