Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Sci Immunol. 2020 Jul 10;5(49). doi: 10.1126/sciimmunol.abc3979.
The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1 mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.
WAVE 调节复合物（WRC）对于组装构成真核细胞迁移主要驱动因素之一的外周分支肌动蛋白网络至关重要。在这里，我们揭示了造血特异性 WRC 成分 HEM1 对于免疫细胞发育的重要作用。胚系编码的 HEM1 缺陷是一种具有系统性自身免疫的先天性免疫缺陷，在细胞水平上表现为 WRC 不稳定、丝状肌动蛋白减少以及无法组装片状伪足。Hem1 小鼠表现出系统性自身免疫，与人类疾病相类似。在没有 Hem1 的情况下，B 细胞会失去维持 B 细胞受体信号强度所必需的细胞外刺激，而这种信号强度对于非自身反应性 B 细胞的存活是必需的。这会使 B 细胞命运选择的平衡向自身反应性 B 细胞倾斜，从而导致自身免疫。
