PLCG2基因的错义突变可能导致自身炎症、磷脂酰肌醇酶Cγ2相关抗体缺乏和免疫失调（APLAID）。我们在这里创造了一种携带APLAID突变（p.Ser707Tyr）的小鼠模型，并发现通过删除半胱氨酸1的功能不能完全消除皮肤和肺部的炎症浸润。此外，删除白细胞介素-6或肿瘤坏死因子也不能完全防止APLAID突变小鼠自身炎症的发生。总的来说，这些发现与APLAID患者对阻断白细胞介素-1、JAK1/2或肿瘤坏死因子治疗的反应不佳相一致。细胞因子分析显示，增加的粒细胞集落刺激因子（G-CSF）水平是小鼠和APLAID患者的最突出特征。值得注意的是，G-CSF抗体治疗完全逆转了APLAID小鼠的已建立疾病。此外，过度的骨髓造血得到了纠正，淋巴细胞数量反弹。通过从健康供体处进行骨髓移植，APLAID小鼠也完全得以挽救，这与非造血细胞主要产生的G-CSF的减少有关。总之，我们确定了APLAID是一种G-CSF驱动的自身炎症性疾病，可以进行靶向治疗。©2023作者。

Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and individuals with APLAID. Remarkably, treatment with a G-CSF antibody completely reversed established disease in APLAID mice. Furthermore, excessive myelopoiesis was normalized and lymphocyte numbers rebounded. APLAID mice were also fully rescued by bone marrow transplantation from healthy donors, associated with reduced G-CSF production, predominantly from non-hematopoietic cells. In summary, we identify APLAID as a G-CSF-driven autoinflammatory disease, for which targeted therapy is feasible.© 2023. The Author(s).