Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep Med. 2023 Aug 15;4(8):101160. doi: 10.1016/j.xcrm.2023.101160.
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.
VEXAS（空泡、E1 酶、X 连锁、自身炎症、体细胞）综合征是一种多系统、严重的自身炎症性疾病，由泛素样修饰酶激活酶 1（UBA1）基因的体细胞突变引起。为了阐明 VEXAS 的发病机制，我们对 VEXAS 患者的单个骨髓单核细胞和造血干细胞和祖细胞（HSPC）进行了转录组测序。HSPC 在 VEXAS 中偏向于髓系（粒细胞）分化，而不是淋巴系分化。在 VEXAS 中，多个炎症途径（干扰素和肿瘤坏死因子-α）在原始造血细胞中很早就发生了先天激活，特别是在髓系中，炎症在 UBA1 突变细胞中很明显。蛋白质降解的失调可能导致 VEXAS HSPC 中的应激反应增加，这与炎症呈正相关。TCR 的使用受到限制，T 细胞中的细胞毒性和 IFN-γ 信号增加。在 VEXAS 综合征中，UBA1 突变的造血干细胞中似乎存在异常炎症和髓系优势。
