PDF(Pubmed)
Abstract：
We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.
摘要：
我们描述了一种由常染色体隐性遗传引起的人类肺病，单核细胞趋化因子受体C-C基序趋化因子受体2（CCR2）完全缺乏。来自五个独立家族的9名儿童患有肺泡蛋白沉积症（PAP），进行性多囊肺病,和反复感染，包括卡介苗（BCG）病。CCR2变体在6名患者中是纯合的，在3名患者中是复合杂合的，都是表达缺失和功能缺失。它们消除了CCR2激动剂趋化因子C-C基序配体2（CCL-2）刺激的单核细胞中的Ca2信号传导和迁移。所有患者的血CCL-2水平都很高,为患有无法解释的肺部或分枝杆菌疾病的儿童提供诊断测试。血液骨髓和淋巴亚群以及干扰素（IFN）-γ-和粒细胞-巨噬细胞集落刺激因子（GM-CSF）介导的免疫不受影响。缺乏CCR2的单核细胞和肺泡巨噬细胞样细胞具有正常的基因表达谱和功能。相比之下,肺泡巨噬细胞计数约为一半。人类完全CCR2缺乏是PAP的遗传病因，多囊肺病,和由受损的CCL2依赖性单核细胞迁移到肺和感染组织引起的复发性感染。
