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Imbalance of circulating Tfr/Tfh ratio in patients with rheumatoid arthritis

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Abstract

Follicular helper T(Tfh) cells and follicular regulatory T(Tfr) cells are critical for the development and maintenance of germinal center and humoral immune responses. Accumulating evidence has demonstrated that the dysregulation of either Tfh or Tfr cells contributes to the pathogenesis of autoimmune diseases. The aim of this study was to examine the numbers of Tfh and Tfr cells in patients with rheumatoid arthritis (RA). Twenty-four patients with RA patients and 20 health controls (HCs) were enrolled in this study. We analyzed the numbers of Tfh (CD4+ CXCR5+ PD-1hi) cells and Tfr (CD4+ CXCR5+CD127lo) cells in 24 RA patients via flow cytometry. The level of the soluble PD-1 and its ligands (sPD-L1 and sPDL-2) were examined by ELISA. Flow cytometry revealed that both circulating Tfh and Tfr cells were increased in RA patients compared with HCs. More importantly, the ratio of Tfr/Tfh was decreased, indicating a disruption of the balance between Tfh and Tfr. The Tfr/Tfh ratio was inversely correlated with level of serum CRP, ESR, RF, anti-CCP, IgG and DAS28 index. We also found that the serum level of sPD-1 was significantly elevated in the RA patients, which was positively correlated with CRP, ESR and the number of Tfh cells. These results indicate that an imbalance of circulating Tfr and Tfh cells may be involved in the immunopathogenesis of RA and may provide novel insight for the development of RA therapies.

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Abbreviations

RA:

Rheumatoid arthritis

cTfh:

Circulating follicular helper T

cTfr:

Circulating follicular regulatory T

GC:

Germinal center

ELISA:

Enzyme‐linked immunosorbent assay

CRP:

C-reaction protein

ESR:

Erythrocyte sedimentation rate

IgG:

Immunoglobulin G

RF:

Rheumatoid factor

CXCR5:

CXC chemokine receptor 5

CCP:

Cyclic citrullinated peptide

sPD-1:

Soluble PD-1

sPD-L1:

Soluble PD-L1

sPD-L2:

Soluble PD-L2

DAS28:

Disease activity score in 28 joints

DMARDs:

Disease-modifying antirheumatic drug

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Acknowledgements

This work was supported by the following grants: foundation from clinical medical research center of Shenyang City (18_009-4-03 to PT.Y.), foundation from the Major State Research Development Program of Liaoning, China (No. 2017225024 to PT.Y.), foundation from the Project for Construction of Major Discipline Platform in Universities of Liaoning province, China (2017001 to PT.Y.), the Program of the Distinguished Professor of Liaoning Province, Rheumatology (2017 to PT.Y.).

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, First Affiliated Hospital, China Medical University, Shenyang, 110001, People’s Republic of China

    Xiuzhen Wang, Feng Xu, Lin Qi, Jianing Wang & Pingting Yang

  2. Department of Rheumatology and Immunology, First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121000, People’s Republic of China

    Xiuzhen Wang

  3. Department of First Cancer Institute, First Affiliated Hospital, China Medical University, Shenyang, 110001, People’s Republic of China

    Chunshu Yang

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Correspondence to Pingting Yang.

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The studies have been approved by the ethics committee of the first affiliated hospital of China Medical University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Wang, X., Yang, C., Xu, F. et al. Imbalance of circulating Tfr/Tfh ratio in patients with rheumatoid arthritis. Clin Exp Med 19, 55–64 (2019). https://doi.org/10.1007/s10238-018-0530-5

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