Background

Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging.

Objective

We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis.

Methods

Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines.

Results

Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease.

Conclusions

We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.

中文翻译：

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由组成型活性 SRC 家族激酶 HCK 驱动的早发性肺和皮肤血管炎

背景

先天性免疫缺陷是一种以不同程度的免疫失调为特征的遗传疾病，可表现为免疫缺陷、自身免疫或自身炎症。下一代测序在临床上的常规使用有助于识别越来越多的先天性免疫错误，揭示免疫学重要基因在人类病理中的作用。然而，尽管取得了这些进展，但治疗仍然极具挑战性。

客观的

我们试图报告由造血细胞激酶 (HCK) 中的从头激活突变 p.Tyr515* 引起的一种新的单基因自身炎症性疾病。该疾病的特征是皮肤血管炎和发展为纤维化的慢性肺部炎症。

方法

进行全外显子组测序、Sanger 测序、质谱和蛋白质印迹以鉴定和表征致病性HCK突变。在原代细胞中和体外在转导细胞系中证实了突变 HCK 的失调。

结果

缺乏 C 末端抑制性酪氨酸 Tyr522 的突变 HCK 表现出增加的激酶活性和增强的骨髓细胞启动、迁移和效应功能，例如炎性细胞因子 IL-1β、IL-6、IL-8 和 TNF-α 的产生，以及产生活性氧。这些异常功能通过肺和皮肤的炎性白细胞浸润来反映。此外，对疾病临床过程的概述，包括治疗，为 Janus 激酶 1/2 抑制剂鲁索替尼在炎症性肺病中的治疗效果提供了证据。

结论

我们提出 HCK 驱动的肺和皮肤血管炎是一种新型的先天性免疫缺陷自身炎症性疾病。