人类 STAT3 功能增益变体会导致小鼠局部 Th17 失调和皮肤炎症。

IF 12.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-11 DOI:10.1084/jem.20232091
Kelsey A Toth, Erica G Schmitt, Ana Kolicheski, Zev J Greenberg, Elizabeth Levendosky, Nermina Saucier, Kelsey Trammel, Vasileios Oikonomou, Michail S Lionakis, Eynav Klechevsky, Brian S Kim, Laura G Schuettpelz, Naresha Saligrama, Megan A Cooper
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引用次数: 0

摘要

STAT3的基因功能增益(GOF)变异会导致与早发多自体免疫和免疫失调有关的先天性免疫错误。为了研究组织特异性免疫失调,我们使用了一种携带导致人类疾病的错义变体(p.G421R)的小鼠模型。我们在 STAT3 GOF 小鼠中观察到了自发的和咪喹莫特(IMQ)诱导的皮肤炎症,这些炎症与细胞内在的局部 Th17 反应有关。CD4+ T细胞足以驱动皮肤炎症,并在扩增的克隆中显示出Il22表达的增加。疾病的某些方面,包括表皮厚度增加,也需要上皮细胞中存在 STAT3 GOF。用JAK抑制剂治疗可改善皮肤疾病,但不会影响Th17的局部招募和细胞因子的产生。这些发现共同支持了Th17反应参与STAT3 GOF器官特异性免疫失调的发展,并表明STAT3 GOF在组织中的存在对疾病很重要,可以用JAK抑制剂来靶向治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A human STAT3 gain-of-function variant drives local Th17 dysregulation and skin inflammation in mice.

Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without affecting local Th17 recruitment and cytokine production. These findings collectively support the involvement of Th17 responses in the development of organ-specific immune dysregulation in STAT3 GOF and suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.

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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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