Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Nat Commun. 2023 Jun 22;14(1):3708. doi: 10.1038/s41467-023-39272-0.
We describe the first cases of germline biallelic null mutations in ARPC5, part of the Arp2/3 actin nucleator complex, in two unrelated patients presenting with recurrent and severe infections, early-onset autoimmunity, inflammation, and dysmorphisms. This defect compromises multiple cell lineages and functions, and when protein expression is reestablished in-vitro, the Arp2/3 complex conformation and functions are rescued. As part of the pathophysiological evaluation, we also show that interleukin (IL)-6 signaling is distinctively impacted in this syndrome. Disruption of IL-6 classical but not trans-signaling highlights their differential roles in the disease and offers perspectives for therapeutic molecular targets.
我们描述了两个无关联的患者中 ARPC5（Arp2/3 肌动蛋白成核复合物的一部分）种系双等位基因无效突变的首例病例，这两个患者表现为反复和严重的感染、早发自身免疫、炎症和畸形。这种缺陷影响多种细胞谱系和功能，当体外重新建立蛋白质表达时，Arp2/3 复合物构象和功能得以恢复。作为病理生理学评估的一部分，我们还表明，白细胞介素 (IL)-6 信号在该综合征中受到明显影响。阻断 IL-6 经典而非转信号通路突出了它们在疾病中的不同作用，并为治疗性分子靶点提供了新的思路。
