Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Pediatr Res. 2022 Jan;91(1):35-43. doi: 10.1038/s41390-021-01445-2. Epub 2021 Mar 17.
Primary immunodeficiency diseases (PIDs) caused by a single-gene defect generally are referred to as monogenic autoimmune disorders. For example, mutations in the transcription factor autoimmune regulator (AIRE) result in a condition called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; while mutations in forkhead box P3 lead to regulatory T cell (Treg)-deficiency-induced multiorgan inflammation, which in humans is called "immune dysregulation, polyendocrinopathy, enteropathy with X-linked inheritance" (or IPEX syndrome). Previous studies concluded that monogenic diseases are insensitive to commensal microbial regulation because they develop even in germ-free (GF) animals, a conclusion that has limited the number of studies determining the role of microbiota in monogenic PIDs. However, emerging evidence shows that although the onset of the disease is independent of the microbiota, several monogenic PIDs vary in severity in association with the microbiome. In this review, we focus on monogenic PIDs associated with Treg deficiency/dysfunction, summarizing the gut microbial dysbiosis that has been shown to be linked to these diseases. From limited studies, we have gleaned several mechanistic insights that may prove to be of therapeutic importance in the early stages of life. IMPACT: This review paper serves to refute the concept that monogenic PIDs are not linked to the microbiome. The onset of monogenic PIDs is independent of microbiota; single-gene mutations such as AIRE or Foxp3 that affect central or peripheral immune tolerance produce monogenic diseases even in a GF environment. However, the severity and outcome of PIDs are markedly impacted by the microbial composition. We suggest that future research for these conditions may focus on targeting the microbiome.
原发性免疫缺陷病（PID）由单一基因突变引起，通常被称为单基因自身免疫性疾病。例如，转录因子自身免疫调节因子（AIRE）的突变导致一种称为自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良的疾病；叉头框 P3 基因突变导致调节性 T 细胞（Treg）缺陷引起的多器官炎症，在人类中称为“免疫失调、多内分泌腺病、肠病伴 X 连锁遗传”（或 IPEX 综合征）。先前的研究得出结论，单基因疾病对共生微生物的调节不敏感，因为即使在无菌（GF）动物中也会发生这种疾病，这一结论限制了研究微生物群在单基因 PID 中的作用的数量。然而，新出现的证据表明，尽管疾病的发作与微生物群无关，但几种单基因 PID 的严重程度与微生物组有关。在这篇综述中，我们重点介绍与 Treg 缺陷/功能障碍相关的单基因 PID，总结了与这些疾病相关的肠道微生物失调。从有限的研究中，我们获得了一些可能在生命早期具有治疗重要性的机制见解。
本综述论文旨在反驳单基因 PID 与微生物组无关的概念。单基因 PID 的发作与微生物群无关；影响中枢或外周免疫耐受的 AIRE 或 Foxp3 等单基因突变即使在 GF 环境中也会产生单基因疾病。然而，PID 的严重程度和结果受到微生物组成的显著影响。我们建议，未来针对这些疾病的研究可能集中在靶向微生物组上。
