B cells orchestrate pro‐survival and pro‐apoptotic inputs during unfolded protein response (UPR) to translate, fold, sort, secrete and recycle immunoglobulins. In common variable immunodeficiency (CVID) patients, activated B cells are predisposed to an overload of abnormally processed, misfolded immunoglobulins. Using highly accurate transcript measurements, we show that expression of UPR genes and immunoglobulin chains differs qualitatively and quantitatively during the first 4 h of chemically induced UPR in B cells from CVID patients and a healthy subject. We tested thapsigargin or tunicamycin as stressors and 4‐phenylbutyrate, dimethyl sulfoxide and tauroursodeoxycholic acid as chemical chaperones. We found an early and robust decrease of the UPR upon endoplasmic reticulum (ER) stress in CVID patient cells compared to the healthy control consistent with the disease phenotype. The chemical chaperones increased the UPR in the CVID patient cells in response to the stressors, suggesting that misfolded immunoglobulins were stabilized. We suggest that the AMP‐dependent transcription factor alpha branch of the UPR is disturbed in CVID patients, underlying the observed expression behavior.

中文翻译：

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化学伴侣可以逆转来自常见可变免疫缺陷患者的B细胞中未折叠的蛋白质反应过程中调节电路的早期抑制。

B细胞在未折叠的蛋白反应（UPR）期间协调促存活和促凋亡输入，以翻译，折叠，分类，分泌和回收免疫球蛋白。在常见的可变免疫缺陷症（CVID）患者中，活化的B细胞易导致异常处理，折叠错误的免疫球蛋白超负荷。使用高精度的转录本测量，我们显示了在CVID患者和健康受试者的B细胞中，化学诱导的UPR的前4小时内，UPR基因和免疫球蛋白链的表达在质量和数量上都存在差异。我们测试了thapsigargin或衣霉素作为应激源，并测试了4-苯基丁酸酯，二甲基亚砜和tauroursodeoxycholic酸作为化学伴侣。我们发现，与符合疾病表型的健康对照相比，CVID患者细胞中内质网（ER）应激时UPR的早期且强劲的下降。化学伴侣分子响应应激源而增加了CVID患者细胞的UPR，表明错误折叠的免疫球蛋白得以稳定。我们建议，在CVID患者中，UPR的AMP依赖转录因子α分支受到干扰，这是观察到的表达行为的基础。