Mitochondrial reactive oxygen species suppress humoral immune response through reduction of CD19 expression in B cells in mice
Mitochondrial reactive oxygen species suppress humoral immune response through reduction of CD19 expression in B cells in mice
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DOI：
10.1002/eji.201646342
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发表时间：
2017-02-01
影响因子：
5.4
通讯作者：
Homma, Yoshimi
中科院分区：
文献类型：
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作者：
Ogura, Masato;Inoue, Takeshi;Homma, Yoshimi
活性氧（ROS）参与包括免疫应答在内的多种过程的调节。为了评估线粒体产生的代谢ROS对B细胞功能和发育的影响，我们创建了在B细胞中表达琥珀酸脱氢酶A的磷酸化缺陷突变体（bSDHA（Y215 F））的转基因（Tg）小鼠。雄性bSDHAY 215 F小鼠的脾B细胞产生的ROS是对照小鼠的3倍，IgM、IgG（1）和IgG（3）的产生减少，IgG（1）对T细胞依赖性抗原的亲和力成熟减少。免疫后，雄性bSDHAY 215 F小鼠进一步显示出抑制的生发中心（GC）形成和GC B细胞增殖。信号分析揭示了内在BCR反应的缺陷，如林恩、Btk和PLC γ 2的激活，从而导致细胞内Ca 2+动员减少。值得注意的是，在来自雄性bSDHAY 215 F小鼠的B细胞中，BCR连接后B细胞共受体CD 19的表达水平及其与林恩的相互作用显著降低。这些结果表明，线粒体ROS通过减少B细胞中的CD 19表达和由此产生的BCR信号传导来抑制体液免疫应答。因此，雄性小鼠的B细胞免疫可能比雌性小鼠更容易受到氧化应激的影响。
Reactive oxygen species (ROS) are implicated in the modulation of diverse processes including immune responses. To evaluate the effects of metabolic ROS produced by mitochondria on B-cell function and development, we created transgenic (Tg) mice expressing a phosphorylation- defective mutant of succinate dehydrogenase A in B cells (bSDHA(Y215F)). Splenic B cells in male, but not female, bSDHAY215F mice produced three times more ROS than those in the control mice, and had decreased production of IgM, IgG(1), and IgG(3), and affinity maturation of IgG(1) against T-cell-dependent antigens. Following immunization, the male bSDHAY215F mice further displayed suppressed germinal center (GC) formation, and proliferation of GC B cells. Signaling analysis revealed defects in the intrinsic BCR responses, such as activation of Lyn, Btk, and PLC gamma 2, thus resulting in reduced intracellular Ca2+ mobilization. Notably, the expression levels of B-cell co-receptor CD19 and its interaction with Lyn after BCR ligation were significantly reduced in B cells from male bSDHAY215F mice. These results suggest that mitochondrial ROS suppress humoral immune responses through reduction of CD19 expression and resultant BCR signaling in B cells. Therefore, B-cell immunity may be more labile to oxidative stress in male mice than in female mice.