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<p>The Janus Kinase 3 (JAK3) germline gain-of-function (GOF) mutation is a rare inborn error of immunity, first reported in 2020, characterized by lymphopenia and chronic NK-cell proliferation. However, its role in autoimmunity remains unclear, and no direct association with hyper-IgE syndrome (HIES) has been established. In this study, we describe a patient presenting with HIES, myositis, lymphopenia, and autoimmune hypothyroidism. Whole-exome sequencing identified a novel compound heterozygous JAK3 mutation (c.2524_2525delinsTT and c.2805G &gt; C), predicted to be deleterious. Flow cytometry and RNA sequencing of peripheral blood mononuclear cells revealed a significant reduction in T cells and NK cells, particularly naïve CD4<sup>+</sup> T cells, accompanied by a marked imbalance in T cell subsets. This led to constitutive activation of JAK1 and JAK3, along with increased STAT3 and STAT5 phosphorylation. Tofacitinib treatment significantly improved the patient’s symptoms. Our findings expand the clinical spectrum of JAK3-associated immune dysregulation, linking it for the first time to HIES and multiple autoimmune manifestations. Furthermore, this study suggests that tofacitinib may be a potential therapeutic option for JAK3 signaling–associated immune dysregulation.</p>

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Tofacitinib as a Successful Treatment for Hyper-IgE Syndrome and Autoimmunity Associated with Constitutive Activation of JAK3

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Yuxin Pei,
  • Bei Jin,
  • Reyila Abasi,
  • Cheng Cheng,
  • Hongjie Zhuang,
  • Shuhan Zeng,
  • Mengjie Jiang,
  • Heying Pei,
  • Xiaoyun Jiang

摘要

The Janus Kinase 3 (JAK3) germline gain-of-function (GOF) mutation is a rare inborn error of immunity, first reported in 2020, characterized by lymphopenia and chronic NK-cell proliferation. However, its role in autoimmunity remains unclear, and no direct association with hyper-IgE syndrome (HIES) has been established. In this study, we describe a patient presenting with HIES, myositis, lymphopenia, and autoimmune hypothyroidism. Whole-exome sequencing identified a novel compound heterozygous JAK3 mutation (c.2524_2525delinsTT and c.2805G > C), predicted to be deleterious. Flow cytometry and RNA sequencing of peripheral blood mononuclear cells revealed a significant reduction in T cells and NK cells, particularly naïve CD4+ T cells, accompanied by a marked imbalance in T cell subsets. This led to constitutive activation of JAK1 and JAK3, along with increased STAT3 and STAT5 phosphorylation. Tofacitinib treatment significantly improved the patient’s symptoms. Our findings expand the clinical spectrum of JAK3-associated immune dysregulation, linking it for the first time to HIES and multiple autoimmune manifestations. Furthermore, this study suggests that tofacitinib may be a potential therapeutic option for JAK3 signaling–associated immune dysregulation.