目的:杂合子STAT1功能增益(GOF)突变是先天性免疫错误中慢性粘膜皮肤念珠菌病(CMC)的最常见原因。临床上,这些突变表现为广泛的免疫失调,包括自身免疫性疾病,血管疾病,和恶性肿瘤。免疫失调的致病机制及其对免疫细胞的影响尚未完全理解。在治疗中,JAK抑制剂已经在一些患者中显示出治疗有效性。
方法:我们分析了临床表现,细胞表型,5名台湾STAT1GOF患者的功能影响。
结果:我们在2个台湾家庭的5名患者中发现了两个新的GOF突变,出现CMC症状,迟发性酒渣鼻,和自身免疫。患者细胞显示出增强的磷酸化和延迟的去磷酸化。先天和适应性免疫细胞都有改变,包括CD38+HLADR+CD8+T细胞的扩增,向Th1倾斜激活的Tfh细胞,减少记忆,边缘区和无能B细胞,所有主要的功能性树突状细胞谱系,和经典单核细胞的减少。Baricitinib显示出治疗效果,无副作用。
结论:我们的研究提供了台湾STAT1GOF患者的第一个全面的临床和分子特征,并强调了可能与STAT1GOF患者自身免疫有关的T和B细胞亚群失调。它还证明了baricitinib在儿科患者中的治疗安全性和有效性。需要进一步的研究来描绘异常STAT1信号传导如何导致细胞群体的变化以及更好地与疾病的临床表现联系。
OBJECTIVE: Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients.
METHODS: We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF.
RESULTS: We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients\' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38+HLADR +CD8+ T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects.
CONCLUSIONS: Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease.