Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Center for Digestive Diseases Research and Clinical Translation of Shanghai Jiao Tong University School, China.
Department of Immunology, Basic Medical College of Weifang Medical University, Weifang, China.
Mol Immunol. 2024 Sep;173:71-79. doi: 10.1016/j.molimm.2024.07.009. Epub 2024 Jul 26.
The treatment of food allergy (FA) needs improvement. The treatment of immune disorders can be improved by regulating epigenetic marks, which is a promising method. The objective of this research is to alleviate experimental FA by employing an inhibitor of DNA methyltransferase-1 (DNMT1).
Ovalbumin was used as the specific antigen to establish a mouse model of FA. Intestinal IL-35 regulatory B cells (Breg cells) were isolated from FA mice, and characterized using immunological approaches.
FA mice had a lower frequency of IL-35 Breg cells, which was inversely correlated with their FA response. The quantity of IL-35 was lower in intestinal Breg cells from FA mice. Hypermethylation status was detected in the Il35 promoter, which was accompanied with high levels of H3K9me3. Enforced expression of DNMT1 hindered the promoter activity of the IL35 gene. Administration of an inhibitor of DNMT1 (RG108) restored the immune regulatory capacity of FA intestinal Bregs, and effectively suppressed the expression of DNMT1, and attenuated experimental FA.
The elevated quantity of DNMT1 in intestinal Breg cells compromises the expression of IL-35 and affects the immune regulatory functions, which facilitates the development of FA. The immune regulatory functions of intestinal Breg cells are restored and experimental FA is attenuated by inhibiting DNMT1.
食物过敏（FA）的治疗需要改进。通过调节表观遗传标记可以改善免疫紊乱的治疗，这是一种很有前途的方法。本研究的目的是通过使用 DNA 甲基转移酶-1（DNMT1）抑制剂来减轻实验性 FA。
使用卵清蛋白作为特异性抗原建立 FA 小鼠模型。从小鼠肠道分离出白细胞介素-35（IL-35）调节性 B 细胞（Breg 细胞），并采用免疫学方法进行鉴定。
FA 小鼠中 IL-35 Breg 细胞的频率较低，与 FA 反应呈负相关。FA 小鼠肠道 Breg 细胞中的 IL-35 含量较低。在 Il35 启动子中检测到高甲基化状态，伴随着 H3K9me3 水平升高。DNMT1 的过表达抑制了 IL35 基因的启动子活性。给予 DNMT1 抑制剂（RG108）可恢复 FA 肠道 Breg 的免疫调节能力，有效抑制 DNMT1 的表达，并减轻实验性 FA。
肠道 Breg 细胞中 DNMT1 数量的增加会损害 IL-35 的表达，并影响其免疫调节功能，从而促进 FA 的发生。通过抑制 DNMT1，恢复肠道 Breg 细胞的免疫调节功能并减轻实验性 FA。
