Mackie Joseph, Suan Daniel, McNaughton Peter, Haerynck Filomeen, O'Sullivan Michael, Guerin Antoine, Ma Cindy S, Tangye Stuart G
Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW, Australia.
Clin Exp Immunol. 2025 Jan 21;219(1). doi: 10.1093/cei/uxaf005.
Signal transducer and activator of transcription 3 (STAT3) orchestrates crucial immune responses through its pleiotropic functions as a transcription factor. Patients with germline monoallelic dominant negative or hypermorphic STAT3 variants, who present with immunodeficiency and/or immune dysregulation, have revealed the importance of balanced STAT3 signaling in lymphocyte differentiation and function, and immune homeostasis. Here, we report a novel missense variant of unknown significance in the DNA-binding domain of STAT3 in a patient who experienced hypogammaglobulinemia, lymphadenopathy, hepatosplenomegaly, immune thrombocytopenia, eczema, and enteropathy over a 35-year period.
In vitro demonstration of prolonged STAT3 activation due to delayed dephosphorylation, and enhanced transcriptional activity, confirmed this to be a novel pathogenic STAT3 gain-of-function variant. Peripheral blood lymphocytes from this patient, and patients with confirmed STAT3 Gain-of-function Syndrome, were collected to investigate mechanisms of disease pathogenesis.
B cell dysregulation was evidenced by a loss of class-switched memory B cells and a significantly expanded CD19hiCD21lo B cell population, likely influenced by a skewed CXCR3+ TFH population. Interestingly, unlike STAT3 dominant negative variants, cytokine secretion by activated peripheral blood STAT3 GOF CD4+ T cells and frequencies of Treg cells were intact, suggesting CD4+ T cell dysregulation likely occurs at sites of disease rather than the periphery.
This study provides an in-depth case study in confirming a STAT3 gain-of-function variant and identifies lymphocyte dysregulation in the peripheral blood of patients with STAT3 gain-of-function syndrome. Identifying cellular biomarkers of disease provides a flow cytometric-based screen to guide validation of additional novel STAT3 gain-of-function variants as well as provide insights into putative mechanisms of disease pathogenesis.
信号转导与转录激活因子3（STAT3）作为一种转录因子，通过其多效性功能协调关键的免疫反应。患有种系单等位基因显性负性或超形态STAT3变异的患者表现出免疫缺陷和/或免疫失调，这揭示了平衡的STAT3信号在淋巴细胞分化和功能以及免疫稳态中的重要性。在此，我们报告了一名患者的STAT3 DNA结合域中一个意义不明的新型错义变异，该患者在35年的时间里出现了低丙种球蛋白血症、淋巴结病、肝脾肿大、免疫性血小板减少、湿疹和肠病。
体外实验证明，由于去磷酸化延迟导致STAT3激活延长以及转录活性增强，证实这是一种新型的致病性STAT3功能获得性变异。收集该患者以及确诊为STAT3功能获得性综合征患者的外周血淋巴细胞，以研究疾病发病机制。
类别转换记忆B细胞的缺失和显著扩大的CD19hiCD21lo B细胞群体证明了B细胞失调，这可能受CXCR3+滤泡辅助性T细胞群体失衡的影响。有趣的是，与STAT3显性负性变异不同，活化的外周血STAT3功能获得性CD4+ T细胞分泌的细胞因子以及调节性T细胞的频率是完整的，这表明CD4+ T细胞失调可能发生在疾病部位而非外周。
本研究提供了一个深入的病例研究，以确认STAT3功能获得性变异，并确定STAT3功能获得性综合征患者外周血中的淋巴细胞失调。识别疾病的细胞生物标志物提供了一种基于流式细胞术的筛查方法，以指导对其他新型STAT3功能获得性变异的验证，并深入了解疾病发病机制的推定机制。
