Department of Pediatrics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
Department of Pediatrics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
Clin Microbiol Infect. 2022 Nov;28(11):1429-1434. doi: 10.1016/j.cmi.2022.03.004. Epub 2022 Mar 11.
Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to infections caused by intracellular pathogens, such as mycobacteria, due to impaired IFN-γ immunity. To date, 18 different genes associated with MSMD have been reported.
This review describes recent discoveries, a 2020-2021 update, in MSMD through the introduction of three novel genetic disorders, namely, AR IFN-γ, T-bet, and ZNFX1 complete deficiency, as well as molecular mechanisms underlying multifocal osteomyelitis in patients with this condition.
PubMed databases were searched for reports of MSMD since January 2020. Relevant articles and their references were screened.
The review covers a general overview, known genes, classifications, symptoms, and treatments for MSMD. MSMD is classified into two groups: isolated MSMD and syndromic MSMD. Among the 18 genes responsible, 13 cause isolated MSMD, which is characterized by selective predisposition to one or more mycobacterial and related infections, and 8 cause syndromic MSMD, which involves the combination of the mycobacterial disease infectious phenotype with additional clinical phenotypes. Among the three genetic etiologies described herein, AR IFN-γ deficiency is classified as isolated MSMD, whereas AR T-bet and ZNFX1 deficiency are classified as syndromic MSMD. Multifocal osteomyelitis is a representative symptom of MSMD, and a high frequency of multifocal osteomyelitis is reported in MSMD patients due to impaired IFN-γ responses, such as with AD IFN-γR1, AD IFN-γR2, or AD STAT1 deficiency. Impaired inhibition of osteoclast differentiation and bone resorption owing to a poor response to IFN-γ has been shown to be in association with multifocal osteomyelitis in MSMD.
Over the past decade, genetic dissection by next-generation sequencing techniques has contributed to the understanding of the molecular bases of human immunity to mycobacteria. However, genetic etiologies are lacking for half of MSMD cases. Further studies will be needed to elucidate the pathogenesis of MSMD.
孟德尔易感性分枝杆菌病（MSMD）的特征是由于 IFN-γ 免疫受损，对分枝杆菌等细胞内病原体引起的感染具有选择性易感性。迄今为止，已经报道了 18 个与 MSMD 相关的不同基因。
通过介绍三种新的遗传疾病，即 AR IFN-γ、T-bet 和 ZNFX1 完全缺乏，以及这种情况下多灶性骨髓炎的分子机制，描述 2020-2021 年 MSMD 的最新发现。
PubMed 数据库检索了 2020 年 1 月以来关于 MSMD 的报告。筛选了相关文章及其参考文献。
综述涵盖了 MSMD 的一般概述、已知基因、分类、症状和治疗。MSMD 分为两组：孤立型 MSMD 和综合征型 MSMD。在负责的 18 个基因中，13 个导致孤立型 MSMD，其特征是对一种或多种分枝杆菌和相关感染具有选择性易感性，8 个导致综合征型 MSMD，涉及分枝杆菌疾病感染表型与其他临床表型的结合。本文描述的三种遗传病因中，AR IFN-γ 缺乏被归类为孤立型 MSMD，而 AR T-bet 和 ZNFX1 缺乏则归类为综合征型 MSMD。多灶性骨髓炎是 MSMD 的一个代表性症状，由于 IFN-γ 反应受损，如 AD IFN-γR1、AD IFN-γR2 或 AD STAT1 缺乏，MSMD 患者多灶性骨髓炎的频率较高。IFN-γ 反应不良导致破骨细胞分化和骨吸收抑制受损，与 MSMD 中的多灶性骨髓炎有关。
在过去的十年中，下一代测序技术的遗传剖析有助于理解人类对分枝杆菌的免疫分子基础。然而，MSMD 病例中有一半的遗传病因尚不清楚。需要进一步的研究来阐明 MSMD 的发病机制。
