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G-CSF 驱动 APLAID 的自身炎症。

G-CSF drives autoinflammation in APLAID.

机构信息

Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.

出版信息

Nat Immunol. 2023 May;24(5):814-826. doi: 10.1038/s41590-023-01473-6. Epub 2023 Mar 30.

DOI:10.1038/s41590-023-01473-6
PMID:36997670
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10154231/
Abstract

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.

摘要

PLCG2 上的错义突变可导致伴有 PLCγ2 相关抗体缺陷和免疫失调的自身炎症（APLAID）。在这里，我们构建了一个携带 APLAID 突变（p.Ser707Tyr）的小鼠模型，发现通过缺失半胱天冬酶-1 消除炎症小体功能，仅能部分改善皮肤和肺部的炎症浸润。此外，缺失白细胞介素-6 或肿瘤坏死因子并不能完全防止 APLAID 突变小鼠发生自身炎症。总的来说，这些发现与 APLAID 患者对阻断白细胞介素-1、JAK1/2 或肿瘤坏死因子的治疗反应不佳的情况一致。细胞因子分析显示，APLAID 患者和小鼠中最显著的特征是粒细胞集落刺激因子（G-CSF）水平升高。值得注意的是，用 G-CSF 抗体治疗可完全逆转 APLAID 小鼠的已建立疾病。此外，过度的髓样细胞生成得到了纠正，淋巴细胞数量得到了恢复。来自健康供体的骨髓移植也完全挽救了 APLAID 小鼠，伴随着 G-CSF 产生的减少，主要来自非造血细胞。总之，我们将 APLAID 确定为一种由 G-CSF 驱动的自身炎症性疾病，针对该疾病的靶向治疗是可行的。

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