Interleukin-35 promotes Breg expansion and interleukin-10 production in CD19(+) B cells in patients with ankylosing spondylitis.
Interleukin-35 promotes Breg expansion and interleukin-10 production in CD19(+) B cells in patients with ankylosing spondylitis.
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DOI：
10.1007/s10067-022-06137-8
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发表时间：
2022-08
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
IL-35是一种强大的免疫抑制和抗炎细胞因子，由p35亚基和EB病毒诱导基因3(EBI3)亚基组成，抑制CD4+效应T细胞的增殖，促进调节性T细胞(Treg)的增殖。然而，IL-35对强直性脊柱炎(AS)中调节性B细胞(Bregs)的影响尚未被探讨。本研究的目的是(1)检测AS患者血清IL-35水平和外周血中Bregs的百分比；(2)探讨二者在AS发病机制中的关系。77例AS患者(AS组)，其中47例为非活动期AS患者，30例为活动期AS患者，59例健康对照(HCS)。采用ELISA法检测血清IL-35、IL-10水平，RT-qPCR法检测p35、EBI3mRNA水平。流式细胞仪检测CD19+B细胞中CD19+CD24hiCD38hi、CD19+CD24hiCD27+Bregs和IL-35受体(IL-12Rβ2、IL-27Rα和gp130)、IL-10、p-STAT1、p-STAT3和p-STAT4的百分率。采用皮尔逊相关系数分析IL-35水平与Bregs百分率的相关性。采用重组(R)IL-35与外周血单个核细胞(PBMC)混合培养的方法检测IL-35对Bregs的作用。AS患者血清IL-35和IL-10水平、p35和EBI3mRNA水平以及CD19+CD24hiCD38hi和CD19+CD24hiCD27+Bregs的百分率均显著低于HCS组。活动期AS患者CD19+CD24hiCD38hi和CD19+CD24hiCD27+Bregs的百分率明显低于非活动期AS患者。AS患者血清IL-35水平与CD19+CD24hiCD38hi、CD19+CD24hiCD27+Bregs百分比呈正相关。强直性脊柱炎患者外周血中表达IL-12Rβ-2和IL-27Rα，但不表达gp130亚基。RIL-35可有效促进CD19+CD24hiCD38hi Breg的扩增和IL-10的产生。同时，rIL-35还可促进CD19+B细胞IL-12Rβ2和IL-27Rα的表达及信号转导通路1和3的磷酸化。这些结果表明，IL-35的产生减少可能与AS患者的Bregs缺陷有关。IL-35可诱导CD19+CD24hiCD38hi Bregs的增殖和IL-10的产生，提示IL-35可作为进一步研究AS新的治疗方法的参考。
IL-35 is a potent immunosuppressive and anti-inflammatory cytokine, consisting of a p35 subunit and an Epstein–Barr virus–induced gene 3 (EBI3) subunit, which suppresses CD4+ effector T cell proliferation and promotes regulatory T cell (Treg) expansion. However, the effects of IL-35 on regulatory B cells (Bregs) in ankylosing spondylitis (AS) have not been explored. The present study aimed (i) to measure serum IL-35 levels and the percentages of Bregs in the peripheral blood of patients with AS and (ii) to explore their relationships in the pathogenesis of AS. A total of 77 patients with AS (AS group), including 47 inactive AS and 30 active AS cases, and 59 healthy controls (HCs) were enrolled into this study. The serum levels of IL-35 and IL-10 were detected by ELISA, and the mRNA levels of p35 and EBI3 were measured by RT–qPCR. The percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs and IL-35 receptor (IL-12Rβ2, IL-27Rα and gp130), IL-10, p-STAT1, p-STAT3, and p-STAT4 in CD19+ B cells were detected by flow cytometry. The correlations between IL-35 levels and percentages of Bregs were analyzed by determining Pearson’s correlation coefficient. The effect of IL-35 on Bregs was determined by mix-culture of recombinant (r) IL-35 with peripheral blood mononuclear cells (PBMCs). The serum IL-35 and IL-10 levels, p35 and EBI3 mRNA levels, and the percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs were significantly lower in AS patients than those in HCs. In addition, the percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs in active AS patients were significantly lower than those in inactive AS patients. The serum IL-35 levels were positively correlated with the percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs in AS patients. IL-12Rβ2 and IL-27Rα, but not gp130 subunit, were expressed in CD19+ B cells in AS patients. RIL-35 could effectively promote CD19+CD24hiCD38hi Breg expansion and IL-10 production. Meanwhile, rIL-35 also promoted the expression of IL-12Rβ2 and IL-27Rα and the phosphorylation of STAT1 and STAT3 in CD19+ B cells. These results demonstrated that reduced IL-35 production may be associated with Bregs defects in AS patients. RIL-35 induced the proliferation of CD19+CD24hiCD38hi Bregs and IL-10 production, suggesting that IL-35 may serve as a reference for further investigation to develop novel treatments for AS.
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影响因子：
16.6
作者：
Dambuza IM;He C;Choi JK;Yu CR;Wang R;Mattapallil MJ;Wingfield PT;Caspi RR;Egwuagu CE
通讯作者：
Egwuagu CE
影响因子：
2.7
作者：
Long, Siqi;Ma, Li;Shang, Xianwen
通讯作者：
Shang, Xianwen
影响因子：
5.4
作者：
Niedbala, Wanda;Wei, Xiao-qing;Liew, Foo Y.
通讯作者：
Liew, Foo Y.
影响因子：
2.7
作者：
Wang C;Liao Q;Hu Y;Zhong D
通讯作者：
Zhong D
影响因子：
3.1
作者：
Chen, Meng;Zhang, Lei;Li, Shufeng
通讯作者：
Li, Shufeng