The Regulatory B Cell in Active Systemic Lupus Erythematosus Patients: A Systemic Review and Meta-analysis

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By:Xiaohuan Chen, Lei Liu, Lei Liao, Yahui Wang, Jiacheng Shi, Hanyou Mo

DOI: https://doi.org/10.30564/jhp.v2i1.1594

Abstract:

Background: The study of regulatory B cells (Bregs) in systemic lupus erythematosus (SLE) has been in full swing in recent years, but the number and function of Bregs in SLE patients have also present quite contradictory results. Therefore, we conducted a meta-analysis to verify the changes in Bregs in active SLE. Methods: We identified studies reporting the proportions of Bregs in SLE patients by searching Pubmed, Embase, Web of Science, Cochrane and CNKI. Due to the degree of heterogeneity is very high, we used a random effects model to assess the mean differences in percentages of Bregs between active SLE and controls. Then, sensitivity analysis and subgroup analysis were performed to verify potential sources of heterogeneity. Results: Seven eligible articles involving 301 active SLE patients and 218 controls were included in the meta-analysis. The pooled percentages of Bregs were found no significant difference between active SLE patients and healthy controls [0.259, (−1.150, 1.668), p = 0.719], with great heterogeneity ( I2 = 97.5%) . The result of sensitivity analysis showed that exclusion of any single study or single article did not materially resolve the heterogeneity, but after excluding the article conducted by Cai X and his colleagues, the percentages of Bregs were significantly higher in active SLE than those in controls [1.394, (0.114,2.675), p = 0.033]. The results of subgroup analysis revealed that when the disease activity was judged by SLEDAI score ≥ 5, the percentages of Bregs were significantly lower in the SLE groups than in the control groups[-1.99,(-3.241,-0.739), p = 0.002], but when the threshold of SLEDAI score ≥ 6 chosen for active SLE, the percentages of Bregs were significantly increased in the SLE groups[2.546,(1.333,3.759), p < 0.001]. Meanwhile, other subgroup analysis based on the different phenotypes of Bregs, diagnostic criteria, enrolled research countries, treatment status, and organ involvement did not differ in proportion of Bregs between SLE patients and controls. Conclusions: The study implies that Bregs may play a role in the pathogenesis of active SLE, and the thresholds of SLEDAI score to distinguish between active and inactive SLE patients are important factors affecting the percentages of Bregs.

References:

[1] Mizoguchi A, Bhan AK. A case for regulatory B cells[J]. J Immunol, 2006, 176: 705-710. DOI:https://doi.org/10.4049/jimmunol.176.2.705 [2] Morris A, Moller G. Regulation of cellular antibody synthesis effect of adoptively transferred antibody-producing spleen cells on cellular antibody synthesis[J]. J Immunol, 1968, 101: 439-445. DOI:https://doi.org/10.1084/jem.127.2.291 [3] Wolf SD, Dittel BN, Hardardottir F, et al. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice[J]. J Exp Med,1996, 184: 2271-2278. DOI:https://doi.org/10.1084/jem.184.6.2271 [4] Berthelot JM, Jamin C, Amrouche K, et al. Regulatory B cells play a key role in immune system balance[J]. Joint Bone Spine, 2013, 80: 18-22. DOI:https://doi.org/10.1016/j.jbspin.2012.04.010 [5] Blair PA，Norena LY，Flores-Borja F, et al. CD19 (+) CD24 (hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients[J].Immunity, 2010, 32(1) : 129-140. DOI:https://doi.org/10.1016/j.immuni.2009.11.009 [6] Iwata Y, Matsushita T, Horikawa M, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells[J]. Blood, 2011, 117(2): 530-541. DOI:https://doi.org/10.1182/blood-2010-07-294249 [7] Kessel A, Haj T, Peri R, et al. Human CD19 (+) CD25 (high) B regulatory cells suppress proliferation of CD4 (+) T cells and enhance Foxp3 and CTLA4 expression in T-regulatory cells[J]. Autoimmunity Rev, 2012, 11(9):670-677. DOI:https://doi.org/10.1016/j.autrev.2011.11.018 [8] X Cai, X Li, X Lin, et al. Expression of regulatory B cells in peripheral blood of patients with systemic lupus erythematosus[J]. Zhonghua Yi Xue Za Zhi.2015, 95(17): 1310-3. DOI:https://doi.org/10.3760/cma.j.issn.0376-2491. 2015. 17. 007 [9] Heinemann K, Wilde B, Hoerning A, et al. Decreased IL-10(+) regulatory B cells (Bregs) in lupus nephritis patients[J]. Scand J Rheumatol. 2016, 45(4): 312-6. DOI:https://doi.org/10.3109/03009742.2015.1126346 [10] H Wang, C Liu, W Chen, G Ding. The skewed frequency of B-cell subpopulation CD19+CD24hiCD38hi cells in peripheral blood mononuclear cells is correlated with the elevated serum sCD40L in patients with active systemic lupus erythematosus[J]. J Cell Biochem. 2019: 1-8.DOI:https://doi.org/10.1002/jcb.28427 [11] Vadasz Z, Peri R, Eiza N, Slobodin G, Balbir-Gurman A, Toubi E. The Expansion of CD25 high IL-10 high FoxP3 high B Regulatory Cells Is in Association with SLE Disease Activity[J]. J Immunol Res. 2015,2015: 254245.DOI:https://doi.org/10.1155/2015/254245 [12] T Wang, Z Li, X Li, et al. Expression of CD19+CD24highCD38high B cells, IL-10 and IL-10R in peripheral blood from patients with systemic lupus erythematosus[J]. Mol Med Rep. 2017, 16(5): 6326-6333.DOI:https://doi.org/10.3892/mmr.2017.7381 [13] X Yang, J Yang, Y Chu, et al. T follicular helper cells and regulatory B cells dynamics in systemic lupus erythematosus[J]. PLoS One. 2014, 9(2): e88441.DOI:https://doi.org/10.1371/journal.pone.0088441 [14] Z Wang, F Wang, Y Wang. Study on CD19+CD24hiCD38hiBreg cells in the patients with systemic lupus erythematosus[J]. Chinese modern doctor.2018, 56(32): 15-18.DOI:https://doi.org/CNKI:SUN:ZDYS.0.2018-32-006 [15] Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample[J]. BMC Med Res Methodol. 2005,5: 13.DOI:https://doi.org/10.1186/1471-2288-5-13 [16] Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W.The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies[J]. Rheumatology (Oxford). 2017,56(11): 1945-1961. DOI:https://doi.org/10.1093/rheumatology/kex260 [17] XM Deng, SX Yan, W Wei. The role of regulatory B cells in SLE and the effect of glucocorticoids[C].Collection of papers of Anhui pharmacology society annual meeting, 2012, 2012: 29-30. http://kns.cnki.net/kcms/detail/detail.aspxdbcode=CPFD&filename=AHSK201209002033&dbname=CPFD0914 [18] Matsumoto M, Baba A, Yokota T, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation[J]. Immunity.2014, 41(6): 1040-51. DOI:https://doi.org/10.1016/j.immuni.2014.10.016 [19] Iwata Y, Matsushita T, Horikawa M, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells[J]. Blood. 2011, 117(2): 530-41. DOI:https://doi.org/10.1182/blood-2010-07-294249 [20] Rincón-Arévalo H, Sanchez-Parra CC, Castaño D, Yassin L, Vásquez G. Regulatory B Cells and Mechanisms[J]. Int Rev Immunol. 2016, 35(2): 156-76. DOI:https://doi.org/10.3109/08830185.2015.1015719 [21] Gibson TP, Dibona GF. Use of the American Rheumatism Association’s preliminary criteria for the classification of systemic lupus erythematosus. AnnIntern Med. 1972, 77(5): 754-6. DOI:https://doi.org/10.7326/0003-4819-77-5-754 [22] Khan A, Shah MH, Nauman M, et al. Clinical manifestations of patients with Systemic Lupus Erythematosus (SLE) in Khyber Pakhtunkhwa[J]. J Pak Med Assoc. 2017, 67(8): 1180-1185. https://jpma.org.pk/article-details/8308?article_id=8308 [23] Yen EY, Shaheen M, Woo J, et al. 46-Year Trends in Systemic Lupus Erythematosus Mortality in the United States, 1968 to 2013: A Nationwide Population-Based Study[J]. Ann Intern Med. 2017, 167(11): 777-785. DOI:https://doi.org/10.7326/M17-0102 [24] Yee CS, Farewell VT, Isenberg DA, et al. The use of Systemic Lupus Erythematosus Disease Activity Index-2000 to define active disease and minimal clinically meaningful change based on data from a large cohort of systemic lupus erythematosus patients[J]. Rheumatology (Oxford). 2011, 50(5): 982-8. DOI:https://doi.org/10.1093/rheumatology/keq376 [25] J Fan, J Luo, C Yan, et al. Methotrexate, combined with cyclophosphamide attenuates murine collagen induced arthritis by modulating the expression level of Breg and DCs[J]. Mol Immunol. 2017, 90: 106-117. DOI:https://doi.org/10.1016/j.molimm.2017.07.001 [26] Szabó K, Papp G, Szántó A, Tarr T, Zeher M. A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjögren’s syndrome and systemic lupus erythematosus[J]. Clin Exp Immunol. 2016, 183(1): 76-89. DOI:https://doi.org/10.1111/cei.12703 [27] Makiyama A, Chiba A, Noto D, et al. Expanded circulating peripheral helper T cells in systemic lupus erythematosus: association with disease activity and B cell differentiation[J]. Rheumatology (Oxford). 2019, 58(10): 1861-1869. DOI:https://doi.org/10.1093/rheumatology/kez077 [28] Iwata Y, Matsushita T, Horikawa M, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells[J]. Blood. 2011, 117(2): 530-41. DOI:https://doi.org/10.1182/blood-2010-07-294249 [29] Tedder TF. B10 cells: a functionally defined regulatory B cell subset[J]. J Immunol. 2015, 194(4): 1395-401. DOI:https://doi.org/10.4049/jimmunol.1401329 [30] Ray A, Basu S, Williams CB, Salzman NH, Dittel BN. A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand[J]. J Immunol. 2012, 188(7): 3188-98. DOI:https://doi.org/10.4049/jimmunol.1103354 [31] N Gao, Dresel J, Eckstein V, et al. Impaired suppressive capacity of activation-induced regulatory B cells in systemic lupus erythematosus[J]. Arthritis Rheumatol. 2014, 66(10): 2849-61. DOI:https://doi.org/10.1002/art.38742 [32] SX Zhang, XW Ma, YF Li, et al. The Proportion of Regulatory T Cells in Patients with Systemic Lupus Erythematosus: A Meta-Analysis[J]. J Immunol Res.2018, 2018: 7103219. DOI:https://doi.org/10.1155/2018/7103219