Skip to main content
Top
Published in: Arthritis Research & Therapy 1/2020

01-12-2020 | Ankylosing Spondylitis | Research article

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

Authors: Mingcan Yang, Qing Lv, Qiujing Wei, Yutong Jiang, Jun Qi, Min Xiao, Linkai Fang, Ya Xie, Shuangyan Cao, Zhiming Lin, Yanli Zhang, Liudan Tu, Minjing Zhao, Yunfeng Pan, Ou Jin, Jieruo Gu

Published in: Arthritis Research & Therapy | Issue 1/2020

Login to get access

Abstract

Background

Studies into ankylosing spondylitis (AS) and its relationship with immune imbalance are controversial, and the correlation between the efficacy of TNF-α inhibitor and changes in immune imbalance is unclear.

Methods

A total of 40 immune cells were tested with flow cytometry, and the results of 105 healthy control (HC) 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 < 0.01 and 0.05, respectively), and the increase in Tregs was positively correlated with the decrease in C-reactive protein (CRP) (r = 0.489, P = 0.018).

Conclusions

We found that active-stage AS patients have an immunity imbalance of frequency 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 in frequency. But CD8+ T cells have not been rescued.
Appendix
Available only for authorised users
Literature
1.
go back to reference Simone D, Al MM, Bowness P. Progress in our understanding of the pathogenesis of ankylosing spondylitis. Rheumatology (Oxford). 2018;57(suppl_6):vi4–9.CrossRef Simone D, Al MM, Bowness P. Progress in our understanding of the pathogenesis of ankylosing spondylitis. Rheumatology (Oxford). 2018;57(suppl_6):vi4–9.CrossRef
2.
go back to reference Colbert RA, et al. From HLA-B27 to spondyloarthritis: a journey through the ER. Immunol Rev. 2010;233(1):181–202.CrossRef Colbert RA, et al. From HLA-B27 to spondyloarthritis: a journey through the ER. Immunol Rev. 2010;233(1):181–202.CrossRef
3.
go back to reference Wang C, et al. T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis. Exp Ther Med. 2015;9(1):250–6.CrossRef Wang C, et al. T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis. Exp Ther Med. 2015;9(1):250–6.CrossRef
4.
go back to reference Smith JA. Update on ankylosing spondylitis: current concepts in pathogenesis. Curr Allergy Asthma Rep. 2015;15(1):489.CrossRef Smith JA. Update on ankylosing spondylitis: current concepts in pathogenesis. Curr Allergy Asthma Rep. 2015;15(1):489.CrossRef
5.
go back to reference Ye L, et al. TCR usage, gene expression and function of two distinct FOXP3(+) Treg subsets within CD4(+) CD25(hi) T cells identified by expression of CD39 and CD45RO. Immunol Cell Biol. 2016;94(3):293–305.CrossRef Ye L, et al. TCR usage, gene expression and function of two distinct FOXP3(+) Treg subsets within CD4(+) CD25(hi) T cells identified by expression of CD39 and CD45RO. Immunol Cell Biol. 2016;94(3):293–305.CrossRef
6.
go back to reference Miao J, Zhu P. Functional defects of Treg cells: new targets in rheumatic diseases, including ankylosing spondylitis. Curr Rheumatol Rep. 2018;20(5):30.CrossRef Miao J, Zhu P. Functional defects of Treg cells: new targets in rheumatic diseases, including ankylosing spondylitis. Curr Rheumatol Rep. 2018;20(5):30.CrossRef
7.
go back to reference Bautista-Caro MB, et al. Increased frequency of circulating CD19+CD24hiCD38hi B cells with regulatory capacity in patients with ankylosing spondylitis (AS) naive for biological agents. PLoS One. 2017;12(7):e0180726.CrossRef Bautista-Caro MB, et al. Increased frequency of circulating CD19+CD24hiCD38hi B cells with regulatory capacity in patients with ankylosing spondylitis (AS) naive for biological agents. PLoS One. 2017;12(7):e0180726.CrossRef
8.
go back to reference 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):4578–86.PubMedPubMedCentral 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):4578–86.PubMedPubMedCentral
9.
go back to reference Mavropoulos A, et al. Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis. Arthritis Rheumatol. 2016;68(2):494–504.CrossRef Mavropoulos A, et al. Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis. Arthritis Rheumatol. 2016;68(2):494–504.CrossRef
10.
go back to reference Matsushita T, et al. Decreased levels of regulatory B cells in patients with systemic sclerosis: association with autoantibody production and disease activity. Rheumatology (Oxford). 2016;55(2):263–7.CrossRef Matsushita T, et al. Decreased levels of regulatory B cells in patients with systemic sclerosis: association with autoantibody production and disease activity. Rheumatology (Oxford). 2016;55(2):263–7.CrossRef
11.
go back to reference Chen M, et al. Defective function of CD24(+) CD38(+) regulatory B cells in ankylosing spondylitis. DNA Cell Biol. 2016;35(2):88–95.CrossRef Chen M, et al. Defective function of CD24(+) CD38(+) regulatory B cells in ankylosing spondylitis. DNA Cell Biol. 2016;35(2):88–95.CrossRef
12.
go back to reference Schulte-Wrede U, et al. An explorative study on deep profiling of peripheral leukocytes to identify predictors for responsiveness to anti-tumour necrosis factor alpha therapies in ankylosing spondylitis: natural killer cells in focus. Arthritis Res Ther. 2018;20(1):191.CrossRef Schulte-Wrede U, et al. An explorative study on deep profiling of peripheral leukocytes to identify predictors for responsiveness to anti-tumour necrosis factor alpha therapies in ankylosing spondylitis: natural killer cells in focus. Arthritis Res Ther. 2018;20(1):191.CrossRef
13.
go back to reference van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361–8.CrossRef van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361–8.CrossRef
14.
go back to reference Chen XX, et al. A randomized, controlled trial of efficacy and safety of Anbainuo, a bio-similar etanercept, for moderate to severe rheumatoid arthritis inadequately responding to methotrexate. Clin Rheumatol. 2016;35(9):2175–83.CrossRef Chen XX, et al. A randomized, controlled trial of efficacy and safety of Anbainuo, a bio-similar etanercept, for moderate to severe rheumatoid arthritis inadequately responding to methotrexate. Clin Rheumatol. 2016;35(9):2175–83.CrossRef
15.
go back to reference Zochling J. Measures of symptoms and disease status in ankylosing spondylitis: Ankylosing Spondylitis Disease Activity Score (ASDAS), Ankylosing Spondylitis Quality of Life Scale (ASQoL), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Global Score (BAS-G), Bath Ankylosing Spondylitis Metrology Index (BASMI), Dougados Functional Index (DFI), and Health Assessment Questionnaire for the Spondylarthropathies (HAQ-S). Arthritis Care Res (Hoboken). 2011;63(Suppl 11):S47–58.CrossRef Zochling J. Measures of symptoms and disease status in ankylosing spondylitis: Ankylosing Spondylitis Disease Activity Score (ASDAS), Ankylosing Spondylitis Quality of Life Scale (ASQoL), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Global Score (BAS-G), Bath Ankylosing Spondylitis Metrology Index (BASMI), Dougados Functional Index (DFI), and Health Assessment Questionnaire for the Spondylarthropathies (HAQ-S). Arthritis Care Res (Hoboken). 2011;63(Suppl 11):S47–58.CrossRef
16.
go back to reference Li Z, et al. Epigenetic and gene expression analysis of ankylosing spondylitis-associated loci implicate immune cells and the gut in the disease pathogenesis. Genes Immun. 2017;18(3):135–43.CrossRef Li Z, et al. Epigenetic and gene expression analysis of ankylosing spondylitis-associated loci implicate immune cells and the gut in the disease pathogenesis. Genes Immun. 2017;18(3):135–43.CrossRef
17.
go back to reference Allen RL, et al. Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J Immunol. 1999;162(9):5045–8.PubMed Allen RL, et al. Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J Immunol. 1999;162(9):5045–8.PubMed
18.
go back to reference Bowness P, et al. Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol. 2011;186(4):2672–80.CrossRef Bowness P, et al. Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol. 2011;186(4):2672–80.CrossRef
19.
go back to reference Bridgewood C, et al. Interleukin-23 pathway at the enthesis: the emerging story of enthesitis in spondyloarthropathy. Immunol Rev. 2020;294(1):27–47.CrossRef Bridgewood C, et al. Interleukin-23 pathway at the enthesis: the emerging story of enthesitis in spondyloarthropathy. Immunol Rev. 2020;294(1):27–47.CrossRef
20.
go back to reference Sherlock JP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069–76.CrossRef Sherlock JP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069–76.CrossRef
21.
go back to reference Duan Z, et al. The immune dysfunction in ankylosing spondylitis patients. Biosci Trends. 2017;11(1):69–76.CrossRef Duan Z, et al. The immune dysfunction in ankylosing spondylitis patients. Biosci Trends. 2017;11(1):69–76.CrossRef
22.
go back to reference 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):e15094.CrossRef 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):e15094.CrossRef
23.
go back to reference Niu XY, et al. Peripheral B-cell activation and exhaustion markers in patients with ankylosing spondylitis. Life Sci. 2013;93(18–19):687–92.CrossRef Niu XY, et al. Peripheral B-cell activation and exhaustion markers in patients with ankylosing spondylitis. Life Sci. 2013;93(18–19):687–92.CrossRef
24.
go back to reference Sulicka J, et al. Endothelial dysfunction is independent of inflammation and altered CCR7 T cell expression in patients with ankylosing spondylitis. Clin Exp Rheumatol. 2017;35(5):844–9.PubMed Sulicka J, et al. Endothelial dysfunction is independent of inflammation and altered CCR7 T cell expression in patients with ankylosing spondylitis. Clin Exp Rheumatol. 2017;35(5):844–9.PubMed
25.
go back to reference Croft M. The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol. 2014;26(3):183–90.CrossRef Croft M. The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol. 2014;26(3):183–90.CrossRef
26.
go back to reference Dulic S, et al. The impact of anti-TNF therapy on CD4+ and CD8+ cell subsets in ankylosing spondylitis. Pathobiology. 2018;85(3):201–10.CrossRef Dulic S, et al. The impact of anti-TNF therapy on CD4+ and CD8+ cell subsets in ankylosing spondylitis. Pathobiology. 2018;85(3):201–10.CrossRef
27.
go back to reference Sakaguchi S, et al. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.CrossRef Sakaguchi S, et al. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.CrossRef
28.
go back to reference Valizadeh A, et al. Potential role of regulatory B cells in immunological diseases. Immunol Lett. 2019;215:48–59.CrossRef Valizadeh A, et al. Potential role of regulatory B cells in immunological diseases. Immunol Lett. 2019;215:48–59.CrossRef
29.
go back to reference Mauri C, Menon M. The expanding family of regulatory B cells. Int Immunol. 2015;27(10):479–86.CrossRef Mauri C, Menon M. The expanding family of regulatory B cells. Int Immunol. 2015;27(10):479–86.CrossRef
30.
go back to reference Matsumoto M, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity. 2014;41(6):1040–51.CrossRef Matsumoto M, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity. 2014;41(6):1040–51.CrossRef
31.
go back to reference Shen P, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507(7492):366–70.CrossRef Shen P, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507(7492):366–70.CrossRef
32.
go back to reference Kamada N, et al. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13(5):321–35.CrossRef Kamada N, et al. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13(5):321–35.CrossRef
33.
go back to reference Orchard TR, et al. Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology. 2000;118(2):274–8.CrossRef Orchard TR, et al. Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology. 2000;118(2):274–8.CrossRef
34.
go back to reference Feldtkeller E, et al. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int. 2003;23(2):61–6.CrossRef Feldtkeller E, et al. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int. 2003;23(2):61–6.CrossRef
35.
go back to reference Finak G, et al. Standardizing flow cytometry immunophenotyping analysis from the human ImmunoPhenotyping consortium. Sci Rep. 2016;6:20686.CrossRef Finak G, et al. Standardizing flow cytometry immunophenotyping analysis from the human ImmunoPhenotyping consortium. Sci Rep. 2016;6:20686.CrossRef
Metadata
Title
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
Authors
Mingcan Yang
Qing Lv
Qiujing Wei
Yutong Jiang
Jun Qi
Min Xiao
Linkai Fang
Ya Xie
Shuangyan Cao
Zhiming Lin
Yanli Zhang
Liudan Tu
Minjing Zhao
Yunfeng Pan
Ou Jin
Jieruo Gu
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2020
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-020-02226-8

Other articles of this Issue 1/2020

Arthritis Research & Therapy 1/2020 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.