Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Mol Immunol. 2024 Oct;174:41-46. doi: 10.1016/j.molimm.2024.08.002. Epub 2024 Aug 24.
Colony stimulating factor 1 receptor (CSF1R) is an essential receptor for both colony stimulating factor 1 (CSF1) and interleukin (IL) 34 signaling expressed on monocyte precursors and myeloid cells, including monocytes, dendritic cells (DC), and microglia. In humans, dominant heterozygous pathogenic variants in CSF1R cause a neurological condition known as CSF1R-related disorder (CSF1R-RD), typically with late onset, previously referred to as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). CSF1R-RD is characterized by microglia reduction and altered monocyte function; however, the impact of pathogenic CSF1R variants on the human DC lineage remains largely unknown. We previously reported that cord blood CD34+ stem cell-derived DCs generated in vitro originate specifically from CSF1R expressing precursors. In this study, we examined the DC lineage of four unrelated patients with late-onset CSF1R-RD who carried heterozygous missense CSF1R variants (c.2330G>A, c.2375C>A, c.2329C>T, and c.2381T>C) affecting different amino acids in the protein tyrosine kinase domain of CSF1R. CD34+ stem cells and CD14+ monocytes were isolated from peripheral blood and subjected to an in vitro culture protocol to differentiate towards conventional DCs and monocyte-derived DCs, respectively. Flow cytometric analysis revealed that monocytes from patients with late-onset CSF1R-RD were still able to differentiate into monocyte-derived DCs in vitro, whereas the ability of CD34+ stem cells to differentiate into conventional DCs was impaired. Strikingly, the peripheral blood of patients contained all naturally occurring DC subsets. We conclude that the in vitro abrogation of DC-development in patients with heterozygous pathogenic missense CSF1R variants does not translate to an impairment in DC development in vivo and speculate that CSF1R signalling in vivo is compensated, which needs further study.
集落刺激因子 1 受体（CSF1R）是单核细胞前体和髓样细胞（包括单核细胞、树突状细胞（DC）和小胶质细胞）上表达的集落刺激因子 1（CSF1）和白细胞介素（IL）34 信号的必需受体。在人类中，CSF1R 中的显性杂合致病性变异导致一种称为 CSF1R 相关疾病（CSF1R-RD）的神经疾病，通常为迟发性，以前称为成人发病的伴轴突球体和色素性神经胶质的脑白质病（ALSP）。CSF1R-RD 的特征是小胶质细胞减少和单核细胞功能改变；然而，致病性 CSF1R 变异对人类 DC 谱系的影响在很大程度上仍然未知。我们之前报道过，体外生成的脐带血 CD34+干细胞衍生的 DC 专门源自表达 CSF1R 的前体。在这项研究中，我们检查了四名具有迟发性 CSF1R-RD 的无关患者的 DC 谱系，他们携带杂合错义 CSF1R 变异（c.2330G>A、c.2375C>A、c.2329C>T 和 c.2381T>C），影响 CSF1R 蛋白酪氨酸激酶结构域中的不同氨基酸。从外周血中分离出 CD34+干细胞和 CD14+单核细胞，并进行体外培养方案，分别分化为常规 DC 和单核细胞衍生的 DC。流式细胞术分析表明，迟发性 CSF1R-RD 患者的单核细胞仍能够在体外分化为单核细胞衍生的 DC，而 CD34+干细胞分化为常规 DC 的能力受损。引人注目的是，患者的外周血中包含所有自然存在的 DC 亚群。我们得出结论，杂合致病性错义 CSF1R 变异患者中体外 DC 发育的阻断不会转化为体内 DC 发育的损害，并推测体内 CSF1R 信号被代偿，这需要进一步研究。
