小柯机器人

法国巴黎城市大学Dusan Bugonovic等研究人员合作发现人类遗传性CCR2缺乏是进行性多囊性肺疾病的基础。这一研究成果于2023年12月28日在线发表在国际学术期刊《细胞》上。

研究人员描述了一种由常染色体隐性遗传、单核细胞趋化因子受体C-C模体趋化因子受体2（CCR2）完全缺乏引起的人类肺部疾病。来自五个独立血统的九名儿童患有肺泡蛋白沉着症（PAP）、进行性多囊肺病和反复感染，包括卡介苗（BCG）病。六名患者的CCR2变异体为同型杂合子，三名患者为复合杂合子，所有变异体均为表达缺失和功能缺失。这些变异体能抑制CCR2-激动剂趋化因子C-C马达配体2（CCL-2）刺激单核细胞的Ca²⁺信号转导和迁移。所有患者血液中的CCL-2水平都很高，这为筛查不明原因的肺病或霉菌病儿童提供了一种诊断测试。

血液中的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。CCR2缺陷单核细胞和肺泡巨噬细胞样细胞的基因表达谱和功能正常。相比之下，肺泡巨噬细胞的数量减少了一半左右。人类完全CCR2缺乏症是PAP、多囊肺病和反复感染的遗传病因，其原因是CCL2依赖性单核细胞向肺部和受感染组织迁移的能力受损。

附：英文原文

Title: Human inherited CCR2 deficiency underlies progressive polycystic lung disease

Author: Anna-Lena Neehus, Brenna Carey, Marija Landekic, Patricia Panikulam, Gail Deutsch, Masato Ogishi, Carlos A. Arango-Franco, Quentin Philippot, Mohammadreza Modaresi, Iraj Mohammadzadeh, Melissa Corcini Berndt, Darawan Rinchai, Tom Le Voyer, Jérémie Rosain, Mana Momenilandi, Marta Martin-Fernandez, Taushif Khan, Jonathan Bohlen, Ji Eun Han, Alexandre Deslys, Mathilde Bernard, Tania Gajardo-Carrasco, Camille Soudée, Corentin Le Floc’h, Mélanie Migaud, Yoann Seeleuthner, Mi-Sun Jang, Eirini Nikolouli, Simin Seyedpour, Hugues Begueret, Jean-Franois Emile, Pierre Le Guen, Guido Tavazzi, Costanza Natalia Julia Colombo, Federico Capra Marzani, Micol Angelini, Francesca Trespidi, Stefano Ghirardello, Nasrin Alipour, Anne Molitor, Raphael Carapito, Mohsen Mazloomrezaei, Hassan Rokni-Zadeh, Majid Changi-Ashtiani, Chantal Brouzes, Pablo Vargas, Alessandro Borghesi, Nico Lachmann, Seiamak Bahram, Bruno Crestani, Susanta Pahari, Larry S. Schlesinger, Nico Marr, Dusan Bugonovic

Issue&Volume: 2023-12-28

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.

DOI: 10.1016/j.cell.2023.11.036

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01323-5