Hypoxia is a potent molecular signal for cellular metabolism, mitochondrial function, and migration. Conditions of low oxygen tension trigger regulatory cascades mediated via the highly conserved HIF-1 α post-translational modification system. In the adaptive immune response, B cells (Bc) are activated and differentiate under hypoxic conditions within lymph node germinal centers, and subsequently migrate to other compartments. During migration, they traverse through changing oxygen levels, ranging from 1-5% in the lymph node to 5-13% in the peripheral blood. Interestingly, the calcineurin inhibitor cyclosporine A is known to stimulate prolyl hydroxylase activity, resulting in HIF-1 α destabilization and may alter Bc responses directly. Over 60% of patients taking calcineurin immunosuppressant medications have hypo-gammaglobulinemia and poor vaccine responses, putting them at high risk of infection with significantly increased morbidity and mortality. We demonstrate that O 2 tension is a previously unrecognized Bc regulatory switch, altering CXCR4 and CXCR5 chemokine receptor signaling in activated Bc through HIF-1 α expression, and controlling critical aspects of Bc migration. Our data demonstrate that calcineurin inhibition hinders this O 2 regulatory switch in primary human Bc. This previously unrecognized effect of calcineurin inhibition directly on human Bc has significant and direct clinical implications.

中文翻译：

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环孢菌素a通过破坏hIF- 1α依赖性，o ₂感应的分子开关来直接影响体外人和小鼠b细胞的迁移

缺氧是细胞代谢，线粒体功能和迁移的有效分子信号。低氧张力条件触发了通过高度保守的HIF-1α翻译后修饰系统介导的调节级联反应。在适应性免疫应答中，B细胞（Bc）在低氧条件下在淋巴结生发中心内被激活并分化，随后迁移到其他区室。在迁移过程中，它们穿越变化的氧气水平，范围从淋巴结中的1-5％到外周血中的5-13％。有趣的是，已知钙调神经磷酸酶抑制剂环孢菌素A会刺激脯氨酰羟化酶活性，从而导致HIF-1α不稳定，并可能直接改变Bc反应。服用钙调神经磷酸酶免疫抑制剂的患者中有60％以上患有低球蛋白球蛋白血症和较差的疫苗反应，使他们处于感染的高风险中，发病率和死亡率显着增加。我们证明O 2张力是以前无法识别的Bc调节开关，通过HIF-1α表达改变激活的Bc中的CXCR4和CXCR5趋化因子受体信号传导，并控制Bc迁移的关键方面。我们的数据表明钙调神经磷酸酶抑制阻碍了原代人Bc中的O 2调节开关。钙调神经磷酸酶抑制直接对人Bc的这种先前无法识别的作用具有重要而直接的临床意义。我们证明O 2张力是以前无法识别的Bc调节开关，通过HIF-1α表达改变激活的Bc中的CXCR4和CXCR5趋化因子受体信号传导，并控制Bc迁移的关键方面。我们的数据表明钙调神经磷酸酶抑制阻碍了原代人Bc中的O 2调节开关。钙调神经磷酸酶直接抑制人Bc的这种先前无法识别的作用具有重大而直接的临床意义。我们证明O 2张力是以前无法识别的Bc调节开关，通过HIF-1α表达改变激活的Bc中的CXCR4和CXCR5趋化因子受体信号传导，并控制Bc迁移的关键方面。我们的数据表明钙调神经磷酸酶抑制阻碍了原代人Bc中的O 2调节开关。钙调神经磷酸酶直接抑制人Bc的这种先前无法识别的作用具有重大而直接的临床意义。