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The Proportion of Regulatory T Cells in Patients with Systemic Lupus Erythematosus: A Meta-Analysis.

1. Introduction

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by highly variable clinical manifestations associated with widespread inflammation and overproduction of autoantibodies [1]. Growing evidence suggests that regulatory T cells (Tregs) maintain peripheral tolerance by controlling and limiting harmful immune responses [2]. Failure to maintain appropriate numbers of functional Tregs plays an important role in SLE pathogenesis [3].

However, initial studies of Treg status in the peripheral blood (PB) of patients with SLE have generated controversial results. One reason for the inconsistencies is that multiple phenotypes of Tregs are identified using different markers [3]. Tregs were first described as a peripheral [CD4.sup.+] subpopulation expressing interleukin- (IL-) 2 receptor alpha chains (CD25) [4]. Further studies revealed that CD25 was expressed not only on Tregs but also on activated cells lacking regulatory functions, although the [CD4.sup.+] T cell subset expressed the highest levels of CD25 ([CD4.sup.+][CD25.sup.high]) and exhibited in vitro immunosuppressive features [5]. Forkhead box protein P3 (FOXP3), a transcription factor expressed at high levels in authentic Tregs, plays a key role in Treg development and is thought to be one of the most specific Treg cell markers [6]. However, the marker cannot be used to sort live cells as the protein is intracellular. In addition, CD127, the alpha chain of the IL-7 receptor, was reported to be upregulated on human T cells after activation and downregulated on Tregs [7], being inversely correlated with the FOXP3 expression level. Thus, costaining for CD127 and CD25 has been proposed to efficiently discriminate between Tregs and activated T cells [8]. The available data on the proportions and phenotypes of Tregs of SLE patients are contradictory; more studies are required to better understand the role played by Tregs during the disease course.

Here, we meta-analyze reports documenting the proportion of Treg cells among [CD4.sup.+] T cells in the PB of patients with active and inactive SLE, as well as healthy controls, to better understand Treg malfunctions in patients with SLE.

2. Methods

2.1. Data Sources and Searches. This meta-analysis was performed as suggested by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement and was registered at the International Prospective Register of Systematic Reviews (no. CRD42017060258) [9]. We searched for relevant studies published between January 1, 1950, and March 1,2018, using PubMed, Embase, the Cochrane database, the Web of Knowledge, Clinical Trials.gov, and FDA.gov, with no restrictions in terms of the primary outcome or publication language. We used the MeSH terms "lupus erythematosus, systemic" and "T-lymphocytes, regulatory" and their combination. All potentially eligible studies were considered except for reviews and murine experiments. Key articles listed in the references were retrieved manually.

2.2. Study Selection and Data Extraction. The inclusion criteria were (1) evaluation of the proportion of Tregs among [CD4.sup.+] T cells of SLE patients using the 1997 revised American College of Rheumatology criteria, (2) available as a full text article, and (3) information on the number of patients and controls. Two investigators independently selected and identified relevant publications, and a third investigator resolved any disagreements. The evidence levels of the studies were assessed based on the 2011 guidelines of the Oxford Center for Evidence-Based Medicine [10]. Quality assessment was done with the Newcastle-Ottawa Quality Assessment Scale, which can be used to assess the quality of nonrandomized studies [11].

We recorded patient baseline characteristics and their country of origin, the year of publication, the number of patients and controls, the definition of Tregs used (including [CD25.sup.+], [CD25.sup.bright], [CD25.sup.high], [CD25.sup.low/-] [FOXP3.sup.+], [FOXP3.sup.+], [CD25.sup.+][FOXP3.sup.+], [CD25.sup.high][FOXP3.sup.+], [CD25.sup.+][CD127.sup.-], [CD25.sup.bright/high][CD127.sup.low/-], and [CD25.sup.high][CD127.sup.low/-] [FOXP3.sup.+]), and the mean (or median) and standard deviation (SD) of the proportion of Tregs among [CD4.sup.+] T cells. Data on the proportion of Tregs in patients with active and inactive SLE were also extracted.

2.3. Statistical Analysis. For continuous outcomes (the proportions of Tregs among [CD4.sup.+] T cells of patients with active and inactive SLE and healthy controls), we calculated standardized mean differences (SMDs) and compared these values using a random effects model (REM) (the DerSimonian and Laird method) [12]. When Treg percentages were reported as medians with interquartile ranges (IQRs), we calculated means and SD (SD = IQR/1.35) [13]. The Cochrane chi-squared test was used to explore between-study heterogeneity. As heterogeneity was high ([I.sup.2] > 75%), we drew forest plots and performed subgroup analyses to explore the possible effects of study characteristics on outcomes. Publication bias was assessed by examining funnel plot asymmetry using the Begger and Egger tests (p [greater than or equal to] 0.05). Preplanned sensitivity analysis was performed by omitting each study individually and calculating the remaining pooled effect. All statistical analyses were conducted using Stata software (ver. 12.0).

3. Results

3.1. Study Characteristics. We identified 2264 studies, of which 44 (with data on 1772 patients and 1007 controls) were included in analysis (Figure 1). The details are shown in Table 1. The average age of the SLE patients ranged from 8.7-45.4 years; the proportion of females ranged from 56.7-100%, the disease duration from 1.5-28.6 years, the average erythrocyte sedimentation rate from 18.6-78.8 mm/hour, and the SLE Disease Activity Index (SLEDAI) from 2.0-17.4. Patients were treated with corticosteroids (CS) and immunosuppressants including cyclophosphamide (CTX), azathioprine (AZA), cyclosporin A (CsA), mycophenolate mofetil (MMF), and chloroquine (HCQ). All controls were healthy without any autoimmune disease. All studies were poor-quality case-control studies or case series; thus, they were all of evidence level 4. We regarded all studies as case-control studies and scored them using the Newcastle-Ottawa Quality Assessment Scale (NOQAS); all studies had a score of 3-5.

3.2. Proportion of Tregs in the PB of SLE Patients. We initially compared the proportion of Tregs in SLE patients and healthy controls regardless of the Treg definition used. Surprisingly, no significant difference was apparent in any study [-0.113, (-0.552, 0.362), p = 0.613]. Also, heterogeneity, as assessed by the [I.sup.2] statistic, was 95.7% (p < 0.001) and thus very high. The Egger test revealed no publication bias (t = 0.70, p = 0.491) (Figure 2).

We hypothesized that the primary reason for the unexpected results might be that the definitions of Tregs were inconsistent. Thus, we performed subgroup analysis based on the Treg definitions to explore the potential sources of heterogeneity. First, we analyzed studies that identified Tregs only as "[CD25.sup.-]positive" (Supplementary Figure 1). Pooled analysis of all 18 trials revealed a significant decrease in the proportion of Tregs in SLE patients compared to controls [-1.428, (-1.982, -0.873), p <0.001] with statistically significant between-study heterogeneity ([I.sup.2] = 93.4%, p < 0.001) and publication bias detected by the Egger test (t = -4.29, p = 0.001). In detail, we found significant differences in the proportion of Tregs between SLE patients and healthy controls when Tregs were defined as "[CD25.sup.+]" cells [-1.512, (-2.488, -0.535), p = 0.002] and as "[CD25.sup.high]" cells [-1.074, (-1.830, -0.318), p = 0.005]. However, in two studies, the proportion of Tregs defined as "[CD25.sup.bright]" cells did not differ significantly between patients and healthy controls [-3.495, (-9.197, 2.207), p = 0.230] (Table 2).

Second, we analyzed studies in which Tregs were defined as "[FOXP3.sup.+]" cells (Supplementary Figure 2). Pooled analysis of all 36 trials revealed no significant difference in the proportion of such Tregs between SLE patients and controls [0.042, (-0.548, 0.632), p = 0.889]. Statistically significant heterogeneity was evident among the studies ([I.sup.2] = 96.6%, p < 0.001). The Egger test detected no publication bias (t = 0.81, p = 0.424). Among the studies, five used "[CD25.sup.low/-][FOXP3.sup.+]" to define Tregs, and three simply "[FOXP3.sup.+]"; the proportion of Tregs in SLE patients appeared to be higher than in controls [5.409, (2.112, 8.705), p = 0.001; 1.101, (0.435, 1.768), p = 0.001, resp.]. However, pooling of these data with those of other studies identifying Tregs as "[CD25.sup.high/+][FOXP3.sup.+]" cells revealed a lower proportion of Tregs in patients than controls; Tregs were identified as "[CD25.sup.+][FOXP3.sup.+]" cells [-1.279, (-2.079, -0.479), p = 0.00] and "[CD25.sup.high][FOXP3.sup.+]" cells [-0.663, (-1.289, -0.036), p = 0.038] (Table 2).

Finally, the other eight groups that used "[CD127.sup.-]negative" to define Tregs showed that such cell numbers decreased in SLE patients [-1.093, (-2.002, -0.183), p = 0.018] with statistical heterogeneity ([I.sup.2] = 92.6%, p <0.001) and publication bias (t = -3.05, p = 0.022). More specifically, pooling the data of four studies in which Tregs was identified as "[CD25.sup.+][CD127.sup.-]" cells revealed a significant difference between SLE patients and controls [-1.093, (-2.002, -0.183), p = 0.018], but no significant difference was apparent when Tregs were defined as "[CD25.sup.bright/high][CD127.sup.low/-]" cells [-12.392, (-37.922, 12.138), p = 0.341] or "[CD25.sup.high][CD127.sup.low/-] [FOXP3.sup.+]" cells [-0.667, (-2.664, 1.331), p = 0.513] (Supplementary Figure 3 and Table 2).

As heterogeneity was apparent, we used a random effects model to prepare forest plots. We hypothesize that the significant heterogeneity might have been caused by differences in the experimental methods and clinical type and severity of disease among the different studies.

3.3. Disease Activity and the Proportion of Tregs in PB. To further assess the effect of disease activity, we analyzed 22 studies that reported the proportion of Tregs in active and inactive SLE patients, regardless of the Tregs definitions used. We found a significant reduction in the proportion of Tregs in patients with active compared to inactive disease [-0.520, (-0.976, -0.086), p = 0.019]. The heterogeneity, as assessed by the [I.sup.2] statistic, was 88.9% (p < 0.001) (Figure 3). No publication bias was evident in the Egger test (t = 0.52, p = 0.608).

4. Discussion

It is now widely accepted that the immune system includes Tregs that specialize in the maintenance of immune tolerance and homeostasis and secrete various immunosuppressive and anti-inflammatory cytokines, such as transforming growth factor-[beta] (TGF-[beta]), IL-10, IL-27, and IL-35 [14]. Treg deficiencies have been suggested to contribute to the immunological aberrations seen in SLE and other autoimmune diseases [3]. As Tregs exhibit multiple phenotypic features and express various markers, especially inconsistent markers were used to identify Treg cells in flow cytometry in previous studies, the proportion of Tregs in the PB of SLE patients has been controversial. To elucidate Treg status in such patients, we meta-analyzed their proportions relative to [CD4.sup.+] T cells in SLE patients. As expected, the proportion of Tregs in patients with active SLE patients was significantly less than that in those with inactive SLE, suggesting that Treg cell depletion accelerated disease progression. However, the overall meta-analysis found no significant difference in Treg proportions between patients and healthy controls, although significant between-study heterogeneity was evident. We considered that the primary reasons for such unexpected results were due to inconsistent definitions of Tregs based on diverse markers used; thus, we subanalyzed the Treg data by the markers used for Treg identification, including CD25, FOXP3, and CD127.

Expression of CD25, the alpha chain of the IL-2 receptor [15], correlates positively with Treg functionality. The Treg-suppressive capacity is restricted to the [CD4.sup.+] T cells that express the highest levels of CD25 [16]. We found out that SLE patients had a lower proportion of Tregs termed "single [CD25.sup.-]positive" compared to healthy controls. However, no such significance was evident when Tregs were defined as "[CD25.sup.bright]," indicating that use of the surface marker CD25 alone is inadequate. In 2008, Han et al. [17] found out that [CD25.sup.high] cells included a large proportion of FOXP3- cells that could not be classified as Tregs. Other activated [CD4.sup.+] T cells also express CD25 [16, 18], suggesting that more precise markers are needed to identify Tregs.

FOXP3 is a crucial regulator of Treg gene expression, being required for both Treg generation and survival [19]. Scurfy (Sf) mice with Treg abnormalities harbor a missense mutation in FOXP3 [6] and develop anti-dsDNA, anti-Smith, and antinuclear antibodies similar to those of SLE patients. Such FOXP3 mutant mice also exhibit multiorgan inflammation of systems usually involved in SLE [20]. However, when Tregs were defined as "FOXP3-positive" cells, the proportions of such cells did not differ between SLE patients and controls because the definitions of Tregs were complicated by the addition of CD25 status, giving "[CD25.sup.-]negative and FOXP3-positive" and "CD25 and FOXP3 double positive." This phenomenon may be explained by the findings of other studies indicating that the [CD4.sup.+][CD25.sup.-][FOXP3.sup.+] T cells of SLE were dysfunctional Tregs [21, 22] and may even be previously activated conventional T cells [23].

To distinguish Tregs from conventional [CD4.sup.+] T cells, the inclusion of additional markers, such as CD127, has been proposed, because Tregs express low levels of this protein (whereas activated T cells express high levels). We found a lower proportion of [CD127.sup.-]negative Tregs in SLE patients compared with healthy controls, suggesting that CD127 combined with other markers could be used to identify Tregs.

Further, the controversial status of Tregs in PB of SLE patients might also be related to the different subsets of Tregs. Tregs can be classified into nTregs [24], iTregs [25], Tr1 cells [26], Th1-like, Th2-like, or Th17-like Tregs [27], and so forth. One of the largest Treg subsets is nTregs, which are developed from the thymus and express CD4, CD25, and FOXP3 [24]. In contrast to nTregs, iTregs are generated in the periphery and induced to express FOXP3 in response to foreign antigens that are much intrinsically unstable in inflammatory compared to nTregs [25]. Interestingly, inflammatory conditions of stimulation can skew nTreg differentiation to Tr1 cells in active lupus [28]. Tr1 cells are another subset of [CD4.sup.+] T cells in the absence of FOXP3 expression characterized by the ability to secrete IL-10 and inhibit T cell responses by disrupting the metabolic state of T effector cells [26]. Although there are important differences of these cells, there is no definitive protein markers that effectively distinguishes among all these Treg cell populations in vitro or in vivo. To date, it is still challenging to value the real status of above Treg subsets in patients with SLE.

The limitations of our work include the fact that we did not consider disease duration or treatment, as both the drugs used and disease staging were inconsistent; however, these factors might affect the proportion of Tregs in PB. Additionally, disease activity was scored differently among studies; some regarded active SLE to be present when the SLEDAI was [greater than or equal to]6, but others used different cutoffs; these differences may have influenced the results. Moreover, Tregs are usually evaluated in PB, in which tissue Treg cell status may fluctuate [3]. Also, information on Treg aberrations in lymphoid tissues or at sites of active disease, for example, the skin of patients with cutaneous lupus [29] or the kidneys of patients with active glomerulonephritis [30], was lacking.

5. Conclusion

In conclusion, we suggest that the reported variations of Treg status among SLE patients are attributable to inconsistent Treg identification; different markers are employed. Here, we analyzed the effects of the use of such markers on the reported proportion of Tregs. Our findings lend support to the idea that the Treg status of SLE patients is important, but we could not determine the best definition of Tregs. Further studies are needed on the definition and function of Tregs.

https://doi.org/10.1155/2018/7103219

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

Sheng-Xiao Zhang and Xiao-Wen Ma contributed to the work equally and should be regarded as co-first authors.

Supplementary Materials

Supplementary Table 1: background of SLE patients in each study. Supplementary Table 2: characteristics of the included studies measuring disease activity in patients with SLE. Supplementary Figure 1: forest plot of subgroup analyses of the proportion of Tregs, defined in terms of [CD25.sup.-]positivity (alone), among [CD4.sup.+] T cells in PB. (a) Standardized mean differences (SMDs) (the proportion of Tregs ["[CD25.sup.+]" cells] among [CD4.sup.+] T cells in the PB of SLE patients minus that of control subjects) as estimated by meta-analysis. (b) SMDs when Tregs were defined as "[CD25.sup.bright]" cells. (c) SMDs when Tregs were defined as "[CD25.sup.high]" cells. Supplementary Figure 2: forest plots of subgroup analyses of the proportion of Tregs defined as FOXP3-positive among [CD4.sup.+] T cells in PB. (a) SMDs (the proportion of Tregs ["[CD25.sup.low/-][FOXP3.sup.+]" cells] among CD4 T cells in the PB of SLE patients minus that of control subjects) as estimated by meta-analysis. (b) SMDs when Tregs were defined as "[FOXP3.sup.+]" cells. (c) SMDs when Tregs were defined as "[CD25.sup.+][FOXP3.sup.+]" cells. (d) SMDs when Tregs were defined as "CD25hlgh[FOXP3.sup.+]" cells. Supplementary Figure 3: forest plots of the subgroup analyses of the proportion of Tregs that were [CD127.sup.-]negative among PB [CD4.sup.+] T cells. (a) SMDs (the proportion of Tregs ["[CD25.sup.+][CD127.sup.-]" cells] among [CD4.sup.+] T cells in the PB of SLE patients minus that of control subjects) as estimated by meta-analysis. (b) SMDs when Tregs were defined as "[CD25.sup.high][CD127.sup.low/-]" cells. (c) SMDs when Tregs were defined as "[CD25.sup.high][CD127.sup.-]" cells. (d) SMDs when Tregs were defined as "[CD25.sup.high][CD127.sup.low/-][FOXP3.sup.+]" cells. Supplementary Figure 4: funnel plot for publication bias in an association analysis of Treg proportions in PB, regardless of the Treg definitions used, between systemic lupus erythematosus (SLE) patients and healthy controls. Supplementary Figure 5: funnel plot for publication bias in an association analysis of the proportion of Tregs, defined in terms of CD25positivity (alone), among [CD4.sup.+] T cells in PB. Supplementary Figure 6: funnel plot for publication bias in an association analysis of the proportion of Tregs defined as FOXP3positive among [CD4.sup.+] T cells in PB. Supplementary Figure 7: funnel plot for publication bias in an association analysis of the proportion of Tregs that were [CD127.sup.-]negative among PB [CD4.sup.+] T cells. (Supplementary Materials)

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[46] C. Prado, B. de Paz, P. Lopez, J. Gomez, J. Rodriguez-Carrio, and A. Suarez, "Relationship between FOXP3 positive populations and cytokine production in systemic lupus erythematosus," Cytokine, vol. 61, no. 1, pp. 90-96, 2013.

[47] J. R. Kim, J. N. Chae, S. H. Kim, and J. S. Ha, "Subpopulations of regulatory T cells in rheumatoid arthritis, systemic lupus erythematosus, and Behcet's disease," Journal of Korean Medical Science, vol. 27, no. 9, pp. 1009-1013, 2012.

[48] Q. Xing, H. Su, J. Cui, and B. Wang, "Role of Treg cells and TGF-[beta]1 in patients with systemic lupus erythematosus: a possible relation with lupus nephritis," Immunological Investigations, vol. 41, no. 1, pp. 15-27, 2011.

[49] X. Pan, X. Yuan, Y. Zheng et al., "Increased [CD45RA.sup.+]FOXP3(low) regulatory T cells with impaired suppressive function in patients with systemic lupus erythematosus," PLoS One, vol. 7, no. 4, article e34662, 2012.

[50] N. Yu, X. Li, W. Song et al., "[CD4.sup.+][CD25.sup.+][CD127.sup.low/-] T cells: a more specific Treg population in human peripheral blood," Inflammation, vol. 35, no. 6, pp. 1773-1780, 2012.

[51] Q. Xing, B. Wang, H. Su, J. Cui, and J. Li, "Elevated Th17 cells are accompanied by [FOXP3.sup.+] Treg cells decrease in patients with lupus nephritis," Rheumatology International, vol. 32, no. 4, pp. 949-958, 2012.

[52] W. Kleczynska, B. Jakiela, H. Plutecka, M. Milewski, M. Sanak, and J. Musial, "Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus," Folia Histochemica et Cytobiologica, vol. 49, no. 4, pp. 646-653, 2011.

[53] D. Mesquita Jr, W. de Melo Cruvinel, J. A. P. Araujo et al., "Systemic lupus erythematosus exhibits a dynamic and continuum spectrum of effector/regulatory T cells," Scandinavian Journal of Rheumatology, vol. 40, no. 1, pp. 41-50, 2011.

[54] A. Henriques, L. Ines, M. Couto et al., "Frequency and functional activity of Th17, Tc17 and other T-cell subsets in systemic lupus erythematosus," Cellular Immunology, vol. 264, no. 1, pp. 97-103, 2010.

[55] J. L. Suen, H. T. Li, Y. J. Jong, B. L. Chiang, and J. H. Yen, "Altered homeostasis of [CD4.sup.+][FOXP3.sup.+] regulatory T-cell subpopulations in systemic lupus erythematosus," Immunology, vol. 127, no. 2, pp. 196-205, 2009.

[56] M. Atfy, G. E. Amr, A. M. Elnaggar, H. A. Labib, A. Esh, and A. M. Elokely, "Impact of [CD4.sup.+][CD25.sup.high] regulatory T-cells and FOXP3 expression in the peripheral blood of patients with systemic lupus erythematosus," The Egyptian Journal of Immunology, vol. 16, no. 1, pp. 117-126, 2009.

[57] D. M. Li, X. P. Li, X. M. Li et al., "Expression of FOXP3 in [CD4.sup.+][CD39.sup.+] T cells of patients with systemic lupus erythematosus and dynamic observation of treatment with glucocorticoid," Zhonghua Yi Xue Za Zhi, vol. 89, no. 23, pp. 1636-1638, 2009.

[58] H. Y. Lee, Y. K. Hong, H. J. Yun, Y. M. Kim, J. R. Kim, and W. H. Yoo, "Altered frequency and migration capacity of [CD4.sup.+][CD25.sup.+] regulatory T cells in systemic lupus erythematosus," Rheumatology, vol. 47, no. 6, pp. 789-794, 2008.

[59] R. K. C. Venigalla, T. Tretter, S. Krienke et al., "Reduced [CD4.sup.+],[CD25.sup.-] T cell sensitivity to the suppressive function of [CD4.sup.+],[CD25.sup.high],[CD127.sup.-/low] regulatory T cells in patients with active systemic lupus erythematosus," Arthritis & Rheumatism, vol. 58, no. 7, pp. 2120-2130, 2008.

[60] M. Bonelli, A. Savitskaya, K. von Dalwigk et al., "Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE)," International Immunology, vol. 20, no. 7, pp. 861-868, 2008.

[61] M. Bonelli, K. von Dalwigk, A. Savitskaya, J. S. Smolen, and C. Scheinecker, "FOXP3 expression in [CD4.sup.+] T cells of patients with systemic lupus erythematosus: a comparative phenotypic analysis," Annals of the Rheumatic Diseases, vol. 67, no. 5, pp. 664-671, 2008.

[62] N. A. Azab, I. H. Bassyouni, Y. Emad, G. A. Abd El-Wahab, G. Hamdy, and M. A. Mashahit, "[CD4.sup.+][CD25.sup.+] regulatory T cells (Treg) in systemic lupus erythematosus (SLE) patients: the possible influence of treatment with corticosteroids," Clinical Immunology, vol. 127, no. 2, pp. 151-157, 2008.

[63] S. Hu, W. Xiao, F. Kong, D. Ke, R. Qin, and M. Su, "Regulatory T cells and their molecular markers in peripheral blood of the patients with systemic lupus erythematosus," Journal of Huazhong University of Science and Technology [Medical Sciences], vol. 28, no. 5, pp. 549-552, 2008.

[64] B. Yan, S. Ye, G. Chen, M. Kuang, N. Shen, and S. Chen, "Dysfunctional [CD4.sup.+],[CD25.sup.+] regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-a-producing antigen-presenting cells," Arthritis & Rheumatism, vol. 58, no. 3, pp. 801-812, 2008.

[65] S. S. Zhao, X. M. Li, X. P. Li et al., "Expression of [CD4.sup.+][CD25.sup.+][CD127.sup.low/-] T cells in patients with systemic lupus erythematosus," Zhonghua Yi Xue Za Zhi, vol. 88, no. 7, pp. 453-456, 2008.

[66] B. H. Hahn, M. Anderson, E. le, and A. L. Cava, "Anti-DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients," Arthritis and Rheumatism, vol. 58, no. 8, pp. 2488-2497, 2008.

[67] B. Zhang, X. Zhang, F. L. Tang, L. P. Zhu, Y. Liu, and P. E. Lipsky, "Clinical significance of increased [CD4.sup.+][CD25.sup.-][Foxp3.sup.+] T cells in patients with new-onset systemic lupus erythematosus," Annals of the Rheumatic Diseases, vol. 67,no. 7, pp. 1037-1040, 2008.

[68] S. Barath, M. Aleksza, T. Tarr, S. Sipka, G. Szegedi, and E. Kiss, "Measurement of natural ([CD4.sup.+][CD25.sup.high]) and inducible ([CD4.sup.+]IL-10+) regulatory T cells in patients with systemic lupus erythematosus," Lupus, vol. 16, no. 7, pp. 489-496, 2007.

[69] E. Y. Lyssuk, A. V. Torgashina, S. K. Soloviev, E. L. Nassonov, and S. N. Bykovskaia, "Reduced number and function of [CD4.sup.+][CD25.sup.high][FOXP3.sup.+] regulatory T cells in patients with systemic lupus erythematosus," Advances in Experimental Medicine and Biology, vol. 601, pp. 113-119, 2007.

[70] J. H. Lee, L. C. Wang, Y. T. Lin, Y. H. Yang, D. T. Lin, and B. L. Chiang, "Inverse correlation between [CD4.sup.+] regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus," Immunology, vol. 117, no. 2, pp. 280-286, 2006.

[71] A. Suarez, P. Lopez, J. Gomez, and C. Gutierrez, "Enrichment of [CD4.sup.+][CD25.sup.high] T cell population in patients with systemic lupus erythematosus treated with glucocorticoids," Annals of the Rheumatic Diseases, vol. 65, no. 11, pp. 1512-1517, 2006.

[72] J. C. Crispin, A. Martinez, and J. Alcocer-Varela, "Quantification of regulatory T cells in patients with systemic lupus erythematosus," Journal of Autoimmunity, vol. 21, no. 3, pp. 273-276, 2003.

Sheng-Xiao Zhang, (1) Xiao-Wen Ma, (2) Yu-Feng Li, (3) Na-Ling Lai, (1) Ze-Hao Huang, (1) Kai Fan, (1) Cai-Hong Wang (ID), (1) and Xiao-Feng Li (1)

(1) Department of Rheumatology, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, Shanxi 030001, China

(2) Department of Hematology, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, Shanxi 030001, China

(3) Department of Neurology, Shanxi Dayi Hospital Affiliated to Shanxi Medical University, 99 Longcheng Street, Taiyuan, Shanxi 030024, China

Correspondence should be addressed to Cai-Hong Wang; snwch@sina.com

Received 26 March 2018; Revised 21 July 2018; Accepted 31 July 2018; Published 3 September 2018

Academic Editor: Keshav Raj Sigdel

Caption: Figure 1: The study selection process.
Table 1: Characteristics of the individual studies included
in the meta-analysis.

Author (ref.)            Publish      Country       EL (a)   Q (b)
                          year

Mesquita, D., Jr.,        2018         Brazil         4        4
  et al. [31]
Ferreira et al. [32]      2017           UK           4        5
Singla et al. [33]        2017          USA           4        4
Wang et al. [34]          2017         China          4        5
Zahran et al. [35]        2016         Egypt          4        4
Margiotta et al. [36]     2016         Italy          4        3
Zabinska et al. [37]      2016         Poland         4        4
Handono et al. [38]       2016       Indonesia        4        5
Legorreta-Haquet          2016         Mexico         4        3
 et al. [39]
Eltayeb et al. [40]       2014         Egypt          4        3
Dal Ben et al. [41]       2014         Brazil         4        4
Tselios et al. [42]       2014         Greece         4        4
Bonelli et al. [43]       2014        Austria         4        4
Szmyrka-Kaczmarek         2014         Poland         4        4
  et al. [44]
Longhi et al. [451        2013     United Kingdom     4        3
Prado et al. [46]         2013         Spain          4        3
Kim et al. [47]           2012         Korea          4        3
Xinget al. [48]           2012         China          4        4
Pan et al. [49]           2012         China          4        3
Yu et al. [50]            2012         China          4        4
Xing et al. [51]          2012         China          4        4
Kleczynska et al. [52]    2011         Poland         4        4
Mesquita et al. [53]      2011         Brazil         4        4
Henriques et al. [54]     2010        Portugal        4        4
Suen et al. [55]          2009         China          4        4
Bonelli et al. [21]       2009        Austria         4        4
Atfy et al. [56]          2009         Egypt          4        4
Li et al. [57]            2009     China/Chinese      4        4
Lee et al. [58]           2008         Korea          4        3
Vemgalla et al. [59]      2008        Germany         4        4
Bonelli et al. [60]       2008        Austria         4        3
Bonelli et al. [61]       2008        Austria         4        3
Azab et al. [62]          2008         Egypt          4        4
Hu et al. [63]            2008         China          4        4
Yan et al. [64]           2008         China          4        3
Zhao et al. [65]          2008     China/Chinese      4        3
Hahn et al. [66]          2008        America         4        4
Zhang et al. [67]         2008         China          4        4
Barath et al. [68]        2007        Hungary         4        4
Lyssuk et al. [69]        2007         Russia         4        3
Lee et al. [70]           2006         Taiwan         4        3
Suarez et al. [71]        2006         Spain          4        3
Miyara et al. [30]        2005         France         4        5
Crispin et al. [72]       2003         Mexico         4        3

                          Case
Author (ref.)            numbers
                           SLE     HC

Mesquita, D., Jr.,         37      10
  et al. [31]
Ferreira et al. [32]       34      24
Singla et al. [33]          2      1
Wang et al. [34]           47      25
Zahran et al. [35]         20      20
Margiotta et al. [36]      13      11
Zabinska et al. [37]       54      19
Handono et al. [38]        62      62
Legorreta-Haquet           47      17
  et al. [39]
Eltayeb et al. [40]        37      20
Dal Ben et al. [41]        25      25
Tselios et al. [42]        100     20
Bonelli et al. [43]        61      36
Szmyrka-Kaczmarek          21      13
  et al. [44]
Longhi et al. [451         12      10
Prado et al. [46]          75      29
Kim et al. [47]            13      22
Xinget al. [48]            20      22
Pan et al. [49]            41      15
Yu et al. [50]             16      30
Xing et al. [51]           60      28
Kleczynska et al. [52]     15      11
Mesquita et al. [53]       57      26
Henriques et al. [54]      34      13
Suen et al. [55]           87      36
Bonelli et al. [21]        22      15
Atfy et al. [56]           30      10
Li et al. [57]             47      22
Lee et al. [58]            20      21
Vemgalla et al. [59]       26      19
Bonelli et al. [60]        58      24
Bonelli et al. [61]        17      8
Azab et al. [62]           24      24
Hu et al. [63]             38      16
Yan et al. [64]            25      15
Zhao et al. [65]           29      24
Hahn et al. [66]           36      32
Zhang et al. [67]          21      11
Barath et al. [68]         72      41
Lyssuk et al. [69]         43      17
Lee et al. [70]            27      15
Suarez et al. [71]         110     56
Miyara et al. [30]         107     82

Crispin et al. [72]        30      10

Author (ref.)                     Tregs' definition

Mesquita, D., Jr.,            [CD4.sup.+][FOXP3.sup.+]
  et al. [31]
Ferreira et al. [32]       [CD25.sup.low] [CD127.sup.low]
                                    [FOXP3.sup.+]
                              [CD25.sup.+][FOXP3.sup.+]
Singla et al. [33]         [CD25.sup.high][FOXP3.sup.high]
Wang et al. [34]              [CD25.sup.+][FOXP3.sup.+]
Zahran et al. [35]         [CD25.sup.+/high][FOXP3.sup.+]
Margiotta et al. [36]       [CD25.sup.high][FOXP3.sup.+]
Zabinska et al. [37]          [CD25.sup.+][FOXP3.sup.+]
                              [CD25.sup.+][CD127.sup.-]
Handono et al. [38]           [CD25.sup.+][FOXP3.sup.+]
Legorreta-Haquet          [CD25.sup.high][CD127.sup.low/-]
 et al. [39]                        [FOXP3.sup.+]
Eltayeb et al. [40]        [CD25.sup.bright] [FOXP3.sup.+]
Dal Ben et al. [41]          [CD25.sup.+] [FOXP3.sup.+]
                                    [CD25.sup.+]
Tselios et al. [42]         [CD25.sup.high] [FOXP3.sup.+]
Bonelli et al. [43]          [CD25.sup.-] [FOXP3.sup.+]
Szmyrka-Kaczmarek           [CD25.sup.high][FOXP3.sup.+]
  et al. [44]                [CD25.sup.+] [CD25.sup.+]
                                    [CD127.sup.-]
                              [CD25.sup.+][FOXP3.sup.+]
Longhi et al. [451         [CD25.sup.high] [CD127.sup.-]
                            [CD25.sup.high][FOXP3.sup.+]
                            [CD25.sup.high][FOXP3.sup.+]

Prado et al. [46]            [FOXP3.sup.+] [CD25.sup.-]
                                    [FOXP3.sup.+]
Kim et al. [47]             [CD25.sup.high][FOXP3.sup.+]
Xinget al. [48]               [CD25.sup.+][FOXP3.sup.+]
                                   [CD25.sup.high]

Pan et al. [49]               [CD25.sup.+][FOXP3.sup.+]
Yu et al. [50]                [CD25.sup.+][FOXP3.sup.+]
                             [CD25.sup.+] [CD127.sup.-]
Xing et al. [51]              [CD25.sup.+][FOXP3.sup.+]
Kleczynska et al. [52]      [CD25.sup.high][FOXP3.sup.+]
Mesquita et al. [53]      [CD25.sup.high] [CD127.sup.low/-]
                                    [FOXP3.sup.+]
Henriques et al. [54]    [CD25.sup.bright] [CD127.sup.low/-]
Suen et al. [55]            [CD25.sup.high][FOXP3.sup.+]
Bonelli et al. [21]              [CD25.sup.-] [FOXP3.sup.+]
Atfy et al. [56]                   [CD25.sup.high]
                                    [CD25.sup.+]
Li et al. [57]                [CD25.sup.+][FOXP3.sup.+]
Lee et al. [58]                     [CD25.sup.+]
                             [CD25.sup.low][FOXP3.sup.+]
Vemgalla et al. [59]        [CD25.sup.high][FOXP3.sup.+]
Bonelli et al. [60]                [CD25.sup.high]
Bonelli et al. [61]                [CD25.sup.high]
                                    [FOXP3.sup.+]
Azab et al. [62]                    [CD25.sup.+]
Hu et al. [63]                      [CD25.sup.+]
Yan et al. [64]               [CD25.sup.+][FOXP3.sup.+]
                              [CD25.sup.+][FOXP3.sup.+]
Zhao et al. [65]                 [CD25.sup.+]CD127~
                                   [CD25.sup.high]
Hahn et al. [66]                   [CD25.sup.high]
Zhang et al. [67]             [CD25.sup.+][FOXP3.sup.+]
Barath et al. [68]          [CD25.sup.high][FOXP3.sup.+]
Lyssuk et al. [69]            [CD25.sup.+][FOXP3.sup.+]
                                    [CD25.sup.+]
Lee et al. [70]                     [CD25.sup.+]
Suarez et al. [71]                 [CD25.sup.high]
Miyara et al. [30]               [CD25.sup.bright]
                                    [CD25.sup.+]
Crispin et al. [72]              [CD25.sup.bright]

Author (ref.)            Data type

Mesquita, D., Jr.,       Calculated
  et al. [31]
Ferreira et al. [32]     Calculated
Singla et al. [33]       Calculated
Wang et al. [34]         Calculated
Zahran et al. [35]        Original
Margiotta et al. [36]     Original
Zabinska et al. [37]     Calculated
                         Calculated
Handono et al. [38]       Original
Legorreta-Haquet         Calculated
 et al. [39]
Eltayeb et al. [40]       Original
Dal Ben et al. [41]       Original
                          Original
Tselios et al. [42]      Calculated
Bonelli et al. [43]       Original
Szmyrka-Kaczmarek         Original
  et al. [44]            Original
                          Original
Longhi et al. [451       Original
                         Original
                         Original
                         Calculated
Prado et al. [46]        Calculated
Kim et al. [47]          Calculated
Xinget al. [48]           Original
                          Original
                          Original
Pan et al. [49]          Calculated
Yu et al. [50]            Original
Xing et al. [51]         Calculated
Kleczynska et al. [52]   Calculated
Mesquita et al. [53]     Calculated
Henriques et al. [54]    Calculated
Suen et al. [55]         Calculated
Bonelli et al. [21]       Original
Atfy et al. [56]         Calculated
                         Calculated
Li et al. [57]           Calculated
Lee et al. [58]           Original
                         Calculated
Vemgalla et al. [59]     Calculated
Bonelli et al. [60]      Calculated
Bonelli et al. [61]      Calculated
                         Calculated
Azab et al. [62]          Original
Hu et al. [63]           Calculated
Yan et al. [64]          Calculated
                          Original
Zhao et al. [65]          Original
                          Original
Hahn et al. [66]         Calculated
Zhang et al. [67]        Calculated
Barath et al. [68]        Original
Lyssuk et al. [69]        Original
                          Original
Lee et al. [70]          Calculated
Suarez et al. [71]        Original
Miyara et al. [30]       Calculated
                         Calculated
Crispin et al. [72]      Calculated

                         % of Tregs among [CD4.sup.+] T
Author (ref.)            cells [mean (or median) [+ or -] SD]

                                 SLE                     HC

Mesquita, D., Jr.,        6.49 [+ or -] 4.99     3.05 [+ or -] 1.76
  et al. [31]
Ferreira et al. [32]      18.8 [+ or -] 2.64     6.39 [+ or -] 0.74

                          4.48 [+ or -] 0.49            2.97
Singla et al. [33]        1.02 [+ or -] 0.97            0.58
Wang et al. [34]          2.32 [+ or -] 0.15     3.02 [+ or -] 0.34
Zahran et al. [35]        1.32 [+ or -] 0.25     2.24 [+ or -] 0.52
Margiotta et al. [36]     1.27 [+ or -] 0.9       2.8 [+ or -] 1.2
Zabinska et al. [37]      1.10 [+ or -] 1.27     3.36 [+ or -] 0.52
                          5.79 [+ or -] 2.13     8.11 [+ or -] 1.4
Handono et al. [38]        2.3 [+ or -] 2.1       0.9 [+ or -] 0.8
Legorreta-Haquet          1.54 [+ or -] 0.84     2.92 [+ or -] 0.73
 et al. [39]
Eltayeb et al. [40]       52.6 [+ or -] 4.2      45.6 [+ or -] 6.4
Dal Ben et al. [41]       0.74 [+ or -] 0.34     1.83 [+ or -] 0.77
                          1.28 [+ or -] 0.89     1.81 [+ or -] 0.8
Tselios et al. [42]       0.99 [+ or -] 0.36     1.49 [+ or -] 0.19
Bonelli et al. [43]        5.1 [+ or -] 0.5       1.1 [+ or -] 0.2
Szmyrka-Kaczmarek        18.57 [+ or -] 10.44   32.08 [+ or -] 11.54
  et al. [44]             6.75 [+ or -] 3.73     6.65 [+ or -] 1.59
                          88.9 [+ or -] 3.2      92.5 [+ or -] 0.7
Longhi et al. [451        9.27 [+ or -] 2.2      19.9 [+ or -] 2.5
                          89.5 [+ or -] 0.5      99.2 [+ or -] 0.1
                          1.07 [+ or -] 0.37     2.04 [+ or -] 0.17
                          1.65 [+ or -] 1.41     1.47 [+ or -] 0.68
Prado et al. [46]        10.22 [+ or -] 5.10     6.41 [+ or -] 3.13
Kim et al. [47]           6.71 [+ or -] 5.37     3.13 [+ or -] 1.61
Xinget al. [48]            4.6 [+ or -] 1.3       5.0 [+ or -] 1.3
                          5.12 [+ or -] 0.67     6.12 [+ or -] 0.74
                          2.08 [+ or -] 0.32     2.76 [+ or -] 0.49
Pan et al. [49]           3.44 [+ or -] 0.74     3.90 [+ or -] 0.40
Yu et al. [50]            1.53 [+ or -] 0.8      3.97 [+ or -] 1.21
                          2.46 [+ or -] 1.12     4.43 [+ or -] 1.05
Xing et al. [51]          4.57 [+ or -] 1.07     6.09 [+ or -] 0.86
Kleczynska et al. [52]    1.80 [+ or -] 1.56     2.10 [+ or -] 0.67
Mesquita et al. [53]      0.97 [+ or -] 1.04     0.66 [+ or -] 0.50
Henriques et al. [54]     8.16 [+ or -] 3.53     7.10 [+ or -] 2.70
Suen et al. [55]          0.64 [+ or -] 0.39     0.86 [+ or -] 0.39
Bonelli et al. [21]        7.5 [+ or -] 1.0       1.4 [+ or -] 0.4
Atfy et al. [56]          6.18 [+ or -] 1.90     8.07 [+ or -] 2.04
                         15.29 [+ or -] 5.97     21.3 [+ or -] 5.0
Li et al. [57]            3.37 [+ or -] 1.83      3.5 [+ or -] 1.4
Lee et al. [58]           15.2 [+ or -] 0.2      22.1 [+ or -] 0.9
                         10.68 [+ or -] 1.63      6.3 [+ or -] 0.4
Vemgalla et al. [59]      2.35 [+ or -] 0.51     1.75 [+ or -] 0.10
Bonelli et al. [60]       1.15 [+ or -] 1.00      2.0 [+ or -] 0.1
Bonelli et al. [61]       1.06 [+ or -] 0.40     1.8 [+ or -] 0.16
                         13.02 [+ or -] 3.60      6.5 [+ or -] 1.3
Azab et al. [62]         10.37 [+ or -] 4.44     7.78 [+ or -] 4.69
Hu et al. [63]            4.91 [+ or -] 2.97    16.25 [+ or -] 3.19
Yan et al. [64]           8.00 [+ or -] 1.64     4.78 [+ or -] 0.43
                           2.1 [+ or -] 1.2       4.0 [+ or -] 1.4
Zhao et al. [65]           4.7 [+ or -] 2.3       5.0 [+ or -] 1.2
                           0.8 [+ or -] 0.4       1.8 [+ or -] 0.8
Hahn et al. [66]          1.24 [+ or -] 0.50     1.85 [+ or -] 0.81
Zhang et al. [67]         4.51 [+ or -] 3.30     4.68 [+ or -] 5.77
Barath et al. [68]        3.06 [+ or -] 1.45     4.26 [+ or -] 1.01
Lyssuk et al. [69]         1.8 [+ or -] 0.8       4.9 [+ or -] 1.4
                           6.1 [+ or -] 3.8      10.3 [+ or -] 3.9
Lee et al. [70]           8.13 [+ or -] 2.80     9.78 [+ or -] 2.11
Suarez et al. [71]        8.34 [+ or -] 7.04     5.47 [+ or -] 2.43
Miyara et al. [30]        0.95 [+ or -] 0.62     1.29 [+ or -] 0.38
                          18.6 [+ or -] 8.18     20.6 [+ or -] 5.9
Crispin et al. [72]       1.6 [+ or -] 0.04      2.57 [+ or -] 0.3

SLE: systemic lupus erythematosus. (a) Evidence level (EL) of each
study was based on Oxford Center for Evidence-Based Medicine 2011.
(b) Quality (Q) of each study was based on the Newcastle-Ottawa
Quality Assessment Scale case.

Table 2: Subgroup analysis based on different
definitions of Tregs in PB of patients with SLE.

Definition of Tregs              Number of
                                  studies

                                             SMD (a)

Single CD25-positive                18       -1.428
[CD25.sup.+]                         9       -1.512
[CD25.sup.bright]                    2       -3.495
[CD25.sup.high]                      7       -1.074
Associated with FOXP3-positive      29       -0.043
[CD25.sup.low/-][FOXP3.sup.+]        4        5.275
[FOXP3.sup.+]                        2        1.377
[CD25.sup.+][FOXP3.sup.+]           13       -1.142
[CD25.sup.high][FOXP3.sup.+]        10       -0.701
Associated with CD127-negative       8       -1.093
[CD25.sup.+] [CD127.sup.-]           4       -1.128
[CD25.sup.bright/high]               2       -12.392
  [CD127.sup.low/-]
[CD25.sup.high]                      2       -0.667
  [CD127.sup.low/-]
  [FOXP3.sup.+]

Definition of Tregs              Test of association

                                      95% CI         p value

Single CD25-positive             (-1.982, -0.873)    <0.001
[CD25.sup.+]                     (-2.488, -0.535)     0.002
[CD25.sup.bright]                 (-9.197, 2.207)     0.230
[CD25.sup.high]                  (-1.830, -0.318)     0.005
Associated with FOXP3-positive    (-0.641, 0.554)     0.887
[CD25.sup.low/-][FOXP3.sup.+]     (1.415, 9.136)      0.007
[FOXP3.sup.+]                     (0.124, 2.631)      0.031
[CD25.sup.+][FOXP3.sup.+]        (-1.942, -0.341)     0.005
[CD25.sup.high][FOXP3.sup.+]     (-1.283, -0.118)     0.018
Associated with CD127-negative   (-2.002, -0.183)     0.018
[CD25.sup.+] [CD127.sup.-]       (-1.894, -0.361)     0.004
[CD25.sup.bright/high]           (-37.922, 12.138)    0.341
  [CD127.sup.low/-]
[CD25.sup.high]                   (-2.664, 1.331)     0.513
  [CD127.sup.low/-]
  [FOXP3.sup.+]

Definition of Tregs              Test of               Egger's test
                                 heterogeneity

                                 [I.sub.2]   p value    t        p

Single CD25-positive               93.4      <0.001    -4.29   0.001
[CD25.sup.+]                       93.9      <0.001    -4.20   0.004
[CD25.sup.bright]                  97.9      <0.001     --      --
[CD25.sup.high]                    92.0      <0.001    -4.28   0.008
Associated with FOXP3-positive     96.3      <0.001    0.55    0.585
[CD25.sup.low/-][FOXP3.sup.+]      98.3      <0.001    4.05    0.056
[FOXP3.sup.+]                      80.1       0.025     --      --
[CD25.sup.+][FOXP3.sup.+]          95.2      <0.001    -2.01   0.069
[CD25.sup.high][FOXP3.sup.+]       89.6      <0.001    -0.63   0.544
Associated with CD127-negative     92.6      <0.001    -3.05   0.022
[CD25.sup.+] [CD127.sup.-]         81.0       0.001    -1.12   0.379
[CD25.sup.bright/high]             97.5      <0.001     --      --
  [CD127.sup.low/-]
[CD25.sup.high]                    96.1      <0.001     --      --
  [CD127.sup.low/-]
  [FOXP3.sup.+]

PB: peripheral blood; SLE: systemic lupus erythematosus; SMD:
standard mean difference; CI: confidence interval; [I.sup.2]:I-squared
index. (a) Magnitude of Cohen's d effect size (SMD): 0.2-0.5, small
effect; 0.5-0.8, medium effect; >0.8, large effect.

Figure 2: Forest plot of the overall meta-analysis of regulatory T
cell (Treg) proportions in peripheral blood (PB), regardless of the
Treg definitions used, between systemic lupus erythematosus (SLE)
patients and healthy controls.

Study ID                             SMD (95% CI)        Weight (%)

Mesquita, D., Jr., et al. [31]     0.76 (0.04, 1.47)        2.35
Ferreira et al. [32]               5.96 (4.74, 7.18)        2.10
Wang et al. [34]                  -3.00 (-3.70, -2.31)      2.36
Zahran et al. [35]                -2.25 (-3.06, -1.45)      2.32
Margiotta et al. [36]             -1.46 (-2.37, -0.55)      2.27
Zabinska et al. [37]              -1.18 (-1.73, -0.62)      2.41
Handono et al. [38]                0.88 (0.51, 1.25)        2.47
Legorreta-Haquet et al. [39]      -1.70 (-2.33, -1.07)      2.39
Dal Ben et al. [41]               -0.63 (-1.19, -0.06)      2.41
Tselios et al. [42]               -1.48 (-1.99, -0.96)      2.43
Bonelli et al. [43]                9.63 (8.20, 11.06)       1.98
Margiotta, D. (2014)               0.03 (-0.66, 0.72)       2.36
Azza, A. (2014)                    1.38 (0.78, 1.98)        2.40
Maria, S. (2013)                  -1.49 (-2.45, -0.53)      2.24
Prado et al. [46]                  0.82 (0.38, 1.26)        2.45
Kim et al. [47]                   -0.31 (-1.00, 0.38)       2.37
Xing et al. [48]                  -1.41 (-2.09, -0.73)      2.37
Pan et al. [49]                   -0.69 (-1.29, -0.08)      2.40
Yu et al. [50]                    -2.24 (-3.01, -1.48)      2.33
Xing et al. [51]                  -1.51 (-2.01, -1.00)      2.43
Kleczynska et al. [52]            -0.24 (-1.02, 0.54)       2.33
Mesquita et al. [53]               0.34 (-0.13, 0.81)       2.44
Henriques et al. [54]              0.32 (-0.32, 0.96)       2.38
Suen et al. [55]                  -0.56 (-0.96, -0.17)      2.46
Bonelli et al. [21]                7.49 (5.61, 9.36)        1.72
Atfy et al. [56]                  -1.04 (-1.80, -0.29)      2.34
Li et al. [57]                    -0.08 (-0.58, 0.43)       2.43
Lee et al. [58]                   10.46 (-12.86, -8.06)     1.43
Venigalla et al. [59]              3.45 (2.51, 4.39)        2.25
Bonelli et al. [60]               -1.00 (-1.51, -0.50)      2.43
Bonelli et al. [61]                2.11 (1.07, 3.15)        2.20
Azab et al. [62]                   0.57 (-0.01, 1.14)       2.41
Hu et al. [63]                    -3.74 (-4.66, -2.81)      2.26
Yan et al. [64]                    2.42 (1.58, 3.26)        2.30
Zhao et al. [65]                  -0.16 (-0.70, 0.38)       2.42
Hahn et al. [66]                  -0.92 (-1.42, -0.42)      2.43
Zhang et al. [67]                 -0.04 (-0.77, 0.69)       2.35
Barath et al. [68]                -0.92 (-1.32, -0.52)      2.46
Lyssuk et al. [69]                -1.10 (-1.69, -0.50)      2.40
Lee et al. [70]                   -0.64 (-1.29, 0.01)       2.38
Suarez et al. [71]                 0.49 (0.16, 0.81)        2.48
Miyara et al. [30]                -0.64 (-0.94, -0.35)      2.48
Crispin et al. [72]               -0.26 (-0.98, 0.46)       2.35
Overall (I-squared = 95.7%,       -0.11 (-0.55, 0.33)     100.00
  p = 0.000)

NOTE: weights are from random effects analysis.

Figure 3: Forest plot of the overall meta-analysis of the
proportion of Tregs in PB, regardless of the Treg definition
used, in patients with active and inactive SLE.

Study ID                             SMD (95% CI)       Weight (%)

Mesquita, D., Jr., et al. [31]   -0.74 (-1.41, -0.07)      4.95
Zabinska et al. [37]             -1.57 (-2.25, -0.89)      4.93
Legorreta-Haquet et al. [39]     -0.20 (-0.77, 0.38)       5.10
Tselios et al. [42]              -1.81 (-2.32, -1.31)      5.20
Pan et al. [49]                  -0.97 (-1.72, -0.22)      4.82
Mesquita et al. [53]             -0.06 (-0.58, 0.46)       5.18
Henriques et al. [54]            -0.03 (-0.70, 0.65)       4.94
Suen et al. [55]                 -0.21 (-0.65, 0.24)       5.28
Bonelli et al. [21]               1.45 (0.45, 2.45)        4.34
Atfy et al. [56]                 -0.09 (-0.82, 0.64)       4.84
Li et al. [57]                   -1.29 (-1.93, -0.64)      4.99
Venigalla et al. [59]             1.63 (0.73, 2.52)        4.54
Bonelli et al. [60]              -2.62 (-3.66, -1.59)      4.28
Bonelli et al. [61]              -2.97 (-4.43, -1.52)      3.49
Hu et al. [63]                   -0.49 (-1.13, 0.16)       4.99
Yan et al. [64]                   3.16 (1.94, 4.37)        3.94
Zhang et al. [67]                -0.18 (-1.03, 0.68)       4.62
Barath et al. [68]                0.20 (-0.33, 0.72)       5.17
Lee et al. [70]                  -0.89 (-1.71, -0.07)      4.69
Miyara et al. [30]               -1.22 (-1.64, -0.80)      5.31
Crispin et al. [72]              -2.24 (-3.20, -1.28)      4.43
Overall (I-squared = 88.9%,      -0.53 (-0.98, -0.09)     100.00
  p = 0.000)

NOTE: weights are from random effects analysis.
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Author:Zhang, Sheng-Xiao; Ma, Xiao-Wen; Li, Yu-Feng; Lai, Na-Ling; Huang, Ze-Hao; Fan, Kai; Wang, Cai-Hong;
Publication:Journal of Immunology Research
Article Type:Clinical report
Date:Jan 1, 2018
Words:9418
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