Abstract
OBJECTIVE: Accumulating evidence indicates that regulatory T cells (Tregs) may be involved in the pathogenesis of ankylosing spondylitis (AS). As different markers have been used to identify Tregs, some studies on the proportions of Tregs in AS patients have generated considerable controversy. To clarify the status of Tregs in such patients, we determine the proportion changes of peripheral Tregs during development of the disease, with different cellular markers. METHODS: We systematically searched Embase, PubMed, Cochrane, Web of Knowledge, FDA.gov, and Clinical Trials.gov for the studies reporting the proportion of Tregs in AS patients. Using the PRISMA guidelines, we performed a random-effects meta-analysis of the frequencies of peripheral Tregs defined in different ways. Inconsistency was evaluated using the I-squared index (I (2)), and publication bias was assessed by examining funnel plot asymmetry using the Begger and Egger tests. RESULTS: A total 29 studies involving 1732 participants were included in the meta-analysis. Their conclusions of using the diversity of Tregs surface markers were inconsistent with each other. No significant difference in the proportions of Tregs was evident regardless of the definitions used [-0.709, (-1.455, 0.037, p = 0.063), I (2) = 97.3%]. Six studies used "single CD25-positive" cells as Tregs, which revealed a significant increase in AS patients compared with healthy blood donors [0.736, (0.138, 1.334), p = 0.016, I (2) = 80.7%]. Notably, the proportions of "CD4(+)CD25(+)FOXP3(+)," "CD4(+)CD25(high)CD127(low/-)," or "CD4(+)CD25(+)CD127(low)" T cells were lower in AS patients [-2.856, (-4.645, -1.066), p = 0.002; -1.812, (-2.648, -0.977), p < 0.001; -1.12, (-1.605, -0.635), p < 0.001]. Tregs defined as "CD25(high)," "CD25(bright)," "CD25(bright/high)CD127(low/-)," "CD4(+)FOXP3(+)," "CD4(+)CD25(high)FOXP3(+)," and "CD4(+)CD25(+)CD127(-)" did not differ in proportion between AS patients and healthy blood donors. CONCLUSIONS: The levels of Tregs varied based on the cellular identification markers used. The proportions of CD4(+)CD25(+)FOXP3(+)Tregs, CD4(+)CD25(high)CD127(low/-), or CD4(+)CD25(+)CD127(low) in blood of AS patients were significantly decreased as compared with those in healthy blood donors, and our findings lend support to the idea that the Treg status of AS patients is important. And we recommend the above as the best definition of Tregs when evaluating the status of such patients.