School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Pediatr Res. 2022 Oct;92(4):1099-1107. doi: 10.1038/s41390-021-01882-z. Epub 2021 Dec 24.
The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy.
We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients.
We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells.
Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN.
In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17. These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 + Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment. Enhancing the expression of functional CD4 + CD46 + Tr1 cells may be a useful therapeutic approach for LN.
人 CD4+T 细胞中补体调节蛋白 CD46 和 CD3 的结合诱导了 1 型调节性 T 细胞（Tr1）和白细胞介素-10（IL-10）的分泌。本研究旨在通过狼疮肾炎（LN）患者 CD46 细胞质 Cyt1 尾巴阐明 Tr1 细胞的分子变化，以响应静脉注射甲基强的松龙（ivMP）治疗。
我们招募了 40 名 LN 儿科患者和 30 名健康对照者。在给予 ivMP 治疗前和治疗后 3 天收集临床特征和外周血单核细胞。从 5 例 LN 和 5 例微小病变肾病综合征患者中采集肾脏标本。
我们发现活跃的 LN 患者存在缺陷的 CD46 介导的 T 辅助 1 型收缩（IL-10 转换）。ivMP 治疗增强了 LN 的缓解，恢复了 IL-10 的产生，增加了 CD46-Cyt1/Cyt2 比值、AKT 和 cAMP 反应元件结合蛋白磷酸化，并诱导了表达趋化因子受体分子 CCR4、CCR6 和 CCR7 的 CD3/CD46 激活的 Tr1 细胞的迁移。
改变 CD46-Cyt1/Cyt2 表达模式和 CD3/CD46 激活的 Tr1 细胞分泌 IL-10 的药物干预可用于治疗活跃的 LN 患者。
在 LN 患者中，ivMP 与 Tr1 细胞产生的 IL-10 增加以及 CD46-Cyt1/Cyt2 比值和 AKT 磷酸化增加有关，并对 CCL17 产生更强的迁移潜力。这些结果表明，在活跃的 LN 患者中，CD4+CD46+Tr1 细胞中 CD46 同工型 Cyt1 和 Cyt2 的表达水平不同，但可通过皮质类固醇治疗纠正。增强功能性 CD4+CD46+Tr1 细胞的表达可能是治疗 LN 的一种有用方法。
