Yang Linlin, Zerbato Barbara, Pessina Alex, Brambilla Luca, Andreani Virginia, Frey-Jakobs Stefanie, Fliegauf Manfred, Barbouche Mohamed-Ridha, Zhang Qiaoxia, Chiaradonna Ferdinando, Proietti Michele, Du Xin, Grimbacher Bodo
Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
Department of Hematology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Front Immunol. 2024 Dec 24;15:1500381. doi: 10.3389/fimmu.2024.1500381. eCollection 2024.
Hypomorphic mutations in the () gene cause a glycosylation disorder that leads to immunodeficiency. It is often associated with recurrent infections and atopy. The exact etiology of this condition remains unclear.
This study aimed to characterize the phenotypes and immunological features associated with PGM3 insufficiency and investigate potential disease mechanisms.
A systematic review of 44 published cases of PGM3 variants was performed, followed by T-cell phenotyping of two patients with PGM3 variants. A genotype-phenotypic severity study was conducted by comparing the residual PGM3 expression of the 12 reconstituted variants in human B cells. A PGM3 inhibitor was used to assess its effect on CD4+ T cell proliferation and differentiation.
Patients with PGM3 variants frequently presented with recurrent infections and atopy, accompanied by reduced naïve CD4+ T cell counts. A genotype-phenotype study showed that low levels of residual PGM3 expression are correlated with disease severity. Notably, inhibition of PGM3 activity impaired TCR-mediated CD4+ T cell proliferation and the synthesis of UDP-GlcNAc, complex N-glycans, O-GlcNAc, glycolytic stress, and mitochondrial respiration during proliferation in a dose-dependent manner. Partial loss of PGM3 activity was observed to preferentially enhance Th1 and Th2 differentiation, while attenuating Th17 and Treg differentiation, consistent with clinical observations.
PGM3 is a critical regulator of CD4+ T-cell proliferation and differentiation. These findings provide new insights into the diverse clinical manifestations and therapeutic development of PGM3 deficiency.
（）基因的亚效突变会导致一种糖基化紊乱，进而引发免疫缺陷。它常与反复感染和特应性疾病相关。这种疾病的确切病因仍不清楚。
本研究旨在描述与PGM3功能不足相关的表型和免疫学特征，并探究潜在的疾病机制。
对44例已发表的PGM3变异病例进行系统综述，随后对两名携带PGM3变异的患者进行T细胞表型分析。通过比较人类B细胞中12种重组变异体的残余PGM3表达，开展基因型-表型严重程度研究。使用PGM3抑制剂评估其对CD4+T细胞增殖和分化的影响。
携带PGM3变异的患者经常出现反复感染和特应性疾病，同时伴有初始CD4+T细胞计数减少。一项基因型-表型研究表明，残余PGM3表达水平低与疾病严重程度相关。值得注意的是，抑制PGM3活性会以剂量依赖的方式损害TCR介导的CD4+T细胞增殖以及增殖过程中UDP-GlcNAc、复合N-聚糖、O-GlcNAc的合成、糖酵解应激和线粒体呼吸。观察到PGM3活性部分丧失会优先增强Th1和Th2分化，同时减弱Th17和Treg分化，这与临床观察结果一致。
PGM3是CD4+T细胞增殖和分化的关键调节因子。这些发现为PGM3缺乏症的多样临床表现和治疗发展提供了新的见解。
