Sección de Infectología, Reumatología e Inmunología Pediátrica, UGC de Pediatría, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla/Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Red de Investigación Translacional en Infectología Pediátrica.
Departamento de Farmacología, Pediatría, y Radiología, Facultad de Medicina, Universidad de Sevilla, Seville, Spain.
Curr Opin Allergy Clin Immunol. 2024 Dec 1;24(6):440-447. doi: 10.1097/ACI.0000000000001039. Epub 2024 Oct 17.
The identification of STAT1 gain-of-function (GOF) in 2011 and STAT3 GOF in 2014 has advanced our understanding of the host immunity along the JAK/STAT pathway and allowed targeted treatment approaches. We review the clinical features and pathogenesis of STAT1 and STAT3 GOF and how this has shaped new approaches to therapy.
STAT1 GOF, initially described in patients with chronic mucocutaneous candidiasis (CMC) and autoimmune thyroid disease, is now recognized to cause early-onset multisystem autoimmunity and a range of infections. STAT3 GOF comprises mostly lymphoproliferation and autoimmunity but also with varying severity, including some with life threatening organ dysfunction. Treatment has evolved along with the understanding of the pathogenesis, with patients now receiving JAK inhibition to block upstream of the STAT defect with good response in autoimmunity and CMC in STAT1 GOF. Blockade of IL-6 signaling has also been used in STAT3 GOF. Hematopoietic cell transplantation had initial poor outcomes, but outcomes are now improving with focus on the control of inflammation pretransplant.
Understanding the pathogenesis of STAT1 and STAT3 GOF has allowed great recent advancements in therapy, but many questions remain as to the best approach to therapy for each patient's clinical presentation as well as the durability of these therapies.
2011 年发现 STAT1 获得性功能（GOF），2014 年发现 STAT3 GOF，这使我们深入了解了 JAK/STAT 通路中的宿主免疫，并为靶向治疗方法提供了依据。我们回顾了 STAT1 和 STAT3 GOF 的临床特征和发病机制，以及这如何为新的治疗方法提供了依据。
最初在患有慢性黏膜皮肤念珠菌病（CMC）和自身免疫性甲状腺疾病的患者中描述的 STAT1 GOF，现在被认为会导致早发性多系统自身免疫和一系列感染。STAT3 GOF 主要表现为淋巴组织增生和自身免疫，但严重程度不同，包括一些危及生命的器官功能障碍。随着对发病机制的认识不断深入，治疗方法也在不断发展，目前患者接受 JAK 抑制治疗以阻断 STAT 缺陷的上游，在 STAT1 GOF 中对自身免疫和 CMC 有良好的反应。IL-6 信号的阻断也已用于 STAT3 GOF。造血细胞移植的初始结果不佳，但现在通过在移植前控制炎症，结果正在改善。
对 STAT1 和 STAT3 GOF 的发病机制的了解，使治疗方法在最近取得了重大进展，但对于每位患者的临床表现以及这些治疗方法的耐久性，仍有许多问题需要解答。
