2023年3月30日出版的《自然—免疫学》杂志发表了澳大利亚沃尔特和伊丽莎霍尔医学研究所Seth L. Masters团队的最新成果，他们的研究发现G-CSF诱导抗体缺陷和免疫失调（APLAID）型自身炎症。

研究人员建立一个携带APLAY突变（p.Ser707Tyr）的小鼠模型，发现仅通过敲除caspase-1去除炎症小体的功能便可部分改善皮肤和肺部的炎症浸润。并且敲除白细胞介素-6或肿瘤坏死因子并不能完全阻止APLAY突变小鼠的自身炎症。总体而言，这些发现与APLAY个体对阻断白细胞介素-1、JAK1/2或肿瘤坏死因子的治疗反应不佳一致。细胞因子分析表明，粒细胞集落刺激因子（G-CSF）水平升高是APLAID小鼠和个体最明显的特征。

值得注意的是，用G-CSF抗体治疗完全逆转了APLAY小鼠的既定疾病；使得过度骨髓生成正常化和淋巴细胞数量反弹。通过移植健康供体的骨髓也可完全挽救APLAYD小鼠，这与G-CSF产生减少有关，其主要来自非造血细胞。总之，该研究表明APLAY是一种G-CSF驱动的自身炎症性疾病，并证明靶向治疗的可行性。

据介绍，PLCG2中的错义突变可引起自身炎症并伴有磷脂酶Cγ2相关APLAID。

附：英文原文

Title: G-CSF drives autoinflammation in APLAID

Author: Mulazzani, Elisabeth, Kong, Klara, Arstegui, Juan I., Ng, Ashley P., Ranathunga, Nishika, Abeysekera, Waruni, Garnham, Alexandra L., Ng, Sze-Ling, Baker, Paul J., Jackson, Jacob T., Lich, John D., Hibbs, Margaret L., Wicks, Ian P., Louis, Cynthia, Masters, Seth L.

Issue&Volume: 2023-03-30

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.

DOI: 10.1038/s41590-023-01473-6

Source: https://www.nature.com/articles/s41590-023-01473-6