Meta-Analysis of Changes in the Number and Proportion of Regulatory T Cells in Patients with Ankylosing Spondylitis

Abstract

Studies on the number and proportion of regulatory T cells (Tregs) in ankylosing spondylitis (AS) patients have been controversial, which has led to a disagreement regarding the role of Tregs in the pathogenesis of AS. To clarify this debate, we conducted a meta-analysis to verify the reported changes in Tregs during AS. We systematically searched the PubMed, Foreign Medical Retrieval System (FMRS), and China National Knowledge Infrastructure (CNKI) web of knowledge databases for eligible articles. A meta-analysis of studies that examined the proportion and number of Tregs among peripheral blood mononuclear cells (PBMCs) and CD4⁺ T cells was performed using Stata software. Further, subgroup analysis was performed based on Treg definition markers and disease activity to identify potential sources of heterogeneity. Forty-seven studies involving a total of 4373 participants were included in the meta-analysis. The Treg/PBMC and Treg/CD4⁺ T cell ratios were significantly lower in AS patients than those in healthy controls (HCs). A subgroup analysis indicated that patients defined by CD4⁺CD25^+/high, CD4⁺CD25⁺CD127^low/-, and CD4⁺CD25⁺FOXP3⁺ had much lower Treg/PBMC and Treg/CD4⁺ T cell ratios than HCs. Active AS patients also had a substantially lower proportion of Tregs/PBMCs and Treg/CD4⁺ T cells than HCs. The proportion of Tregs among both PBMCs and CD4⁺ T cells was significantly decreased in AS patients. Treg definition markers and disease activity may influence the proportion of Tregs measured among the PBMC and CD4⁺ T cell populations. Further study of the correlation between AS disease activity and the proportion of Tregs in peripheral blood is needed to determine the physiological role of this association. This study implies that loss of Tregs may play a role in the pathogenesis of AS and helps clarify the contradictory Treg results in AS patients. This trial is registered with PROSPERO (CRD42019147064).

Figure 1

Flow chart of studies included in the meta-analysis.

Figure 2

Forest plot of the percentage changes of Tregs in AS patients compared with HCs. SMD: standardized mean difference; CI: confidence interval; AS: ankylosing spondylitis; HC: healthy control; PBMC: peripheral blood mononuclear cell.

Figure 3

Forest plots generated by meta-analysis for the findings of Tregs/CD4⁺ T cells in AS patients and HCs. SMD: standardized mean difference; CI: confidence interval; AS: ankylosing spondylitis; HC: healthy control; PBMC: peripheral blood mononuclear cell.

Figure 4

Funnel plot. For interpretation of any publication bias among studies, visual inspection of the generated funnel plot was employed to evaluate symmetry. The funnel plot appears symmetrical.

Figure 5

Sensitivity analysis. (a) Sensitivity analysis of Tregs/PBMCs in AS patients and HCs. (b) Sensitivity analysis of Tregs/CD4⁺ T cells in AS patients and HCs.