VEXAS（液泡，E1酶，X连锁，自身炎症性，嵌合）综合症是由泛素样修饰酶激活酶1（UBA1）基因体细胞突变导致的一种多效性严重的自身炎症性疾病。为了阐明VEXAS的病理生理学，我们对VEXAS患者的单个骨髓单个核细胞和造血干细胞和祖细胞（HSPCs）进行了转录组测序。在VEXAS中，HSPCs在中性粒细胞分化中偏向增多，而在淋巴细胞分化中偏向减少。在VEXAS中，多个炎症途径（干扰素和肿瘤坏死因子α）在原始造血细胞中早期起到激活作用，并且特别在髓系中发生炎症，UBA1突变细胞中炎症明显。蛋白质降解的失调可能导致VEXAS HSPCs中更高的应激反应，这与炎症呈正相关。 TCR使用受限，T细胞中的细胞毒性和IFN-γ信号发送增加。在VEXAS综合症中，异常炎症和髓样优势似乎是与UBA1突变的造血干细胞内在相关的。

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a pleiotropic, severe autoinflammatory disease caused by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. To elucidate VEXAS pathophysiology, we performed transcriptome sequencing of single bone marrow mononuclear cells and hematopoietic stem and progenitor cells (HSPCs) from VEXAS patients. HSPCs are biased toward myeloid (granulocytic) differentiation, and against lymphoid differentiation in VEXAS. Activation of multiple inflammatory pathways (interferons and tumor necrosis factor alpha) occurs ontogenically early in primitive hematopoietic cells and particularly in the myeloid lineage in VEXAS, and inflammation is prominent in UBA1-mutated cells. Dysregulation in protein degradation likely leads to higher stress response in VEXAS HSPCs, which positively correlates with inflammation. TCR usage is restricted and there are increased cytotoxicity and IFN-γ signaling in T cells. In VEXAS syndrome, both aberrant inflammation and myeloid predominance appear intrinsic to hematopoietic stem cells mutated in UBA1.Published by Elsevier Inc.