JAK/STAT defects and immune dysregulation, and guiding therapeutic choices

IF 7.5 2区 医学 Q1 IMMUNOLOGY Immunological Reviews Pub Date : 2024-02-02 DOI:10.1111/imr.13312
Natalia S. Chaimowitz, Madison R. Smith, Lisa R. Forbes Satter
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Abstract

Inborn errors of immunity (IEIs) encompass a diverse spectrum of genetic disorders that disrupt the intricate mechanisms of the immune system, leading to a variety of clinical manifestations. Traditionally associated with an increased susceptibility to recurrent infections, IEIs have unveiled a broader clinical landscape, encompassing immune dysregulation disorders characterized by autoimmunity, severe allergy, lymphoproliferation, and even malignancy. This review delves into the intricate interplay between IEIs and the JAK–STAT signaling pathway, a critical regulator of immune homeostasis. Mutations within this pathway can lead to a wide array of clinical presentations, even within the same gene. This heterogeneity poses a significant challenge, necessitating individually tailored therapeutic approaches to effectively manage the diverse manifestations of these disorders. Additionally, JAK–STAT pathway defects can lead to simultaneous susceptibility to both infection and immune dysregulation. JAK inhibitors, with their ability to suppress JAK–STAT signaling, have emerged as powerful tools in controlling immune dysregulation. However, questions remain regarding the optimal selection and dosing regimens for each specific condition. Hematopoietic stem cell transplantation (HSCT) holds promise as a curative therapy for many JAK–STAT pathway disorders, but this procedure carries significant risks. The use of JAK inhibitors as a bridge to HSCT has been proposed as a potential strategy to mitigate these risks.

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JAK/STAT 缺陷和免疫失调,并指导治疗选择。
先天性免疫错误(IEIs)包括多种多样的遗传疾病,这些疾病会破坏免疫系统的复杂机制,导致各种临床表现。传统上,先天性免疫畸形与反复感染的易感性增加有关,但现在,先天性免疫畸形已展现出更广阔的临床前景,包括以自身免疫、严重过敏、淋巴细胞增殖甚至恶性肿瘤为特征的免疫调节失调疾病。本综述将深入探讨 IEIs 与 JAK-STAT 信号通路之间错综复杂的相互作用。该通路中的突变可导致多种临床表现,即使是同一基因也不例外。这种异质性带来了巨大的挑战,因此必须采取个性化的治疗方法,才能有效控制这些疾病的各种表现。此外,JAK-STAT通路缺陷可同时导致易感性和免疫失调。JAK 抑制剂能够抑制 JAK-STAT 信号传导,已成为控制免疫失调的有力工具。然而,有关针对每种特定病症的最佳选择和用药方案的问题依然存在。造血干细胞移植(HSCT)有望成为许多JAK-STAT通路疾病的治愈疗法,但这一过程存在巨大风险。有人提出使用JAK抑制剂作为造血干细胞移植的桥梁,作为减轻这些风险的潜在策略。
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来源期刊
Immunological Reviews
Immunological Reviews 医学-免疫学
CiteScore
16.20
自引率
1.10%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Immunological Reviews is a specialized journal that focuses on various aspects of immunological research. It encompasses a wide range of topics, such as clinical immunology, experimental immunology, and investigations related to allergy and the immune system. The journal follows a unique approach where each volume is dedicated solely to a specific area of immunological research. However, collectively, these volumes aim to offer an extensive and up-to-date overview of the latest advancements in basic immunology and their practical implications in clinical settings.
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