Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada.
Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada.
J Exp Med. 2018 Dec 3;215(12):3151-3164. doi: 10.1084/jem.20180668.
Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSL mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSL diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSL also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human deficiency as a novel cause of a combined immunodeficiency.
原发性免疫缺陷是解析人类免疫生物学的天然实验模型。我们报告了一例联合免疫缺陷患者，其特征为反复呼吸道和基于 DNA 的病毒感染、低丙种球蛋白血症和全淋巴细胞减少症。他还出现了中度中性粒细胞减少症，但没有典型的化脓性感染。通过全外显子组测序，我们在诱导性 T 细胞共刺激配体基因中发现了一个纯合突变（; c.657C>G; p.N219K）。野生型 ICOSL 在细胞表面表达，而 ICOSL 突变则消除了表面定位：突变蛋白保留在内质网/高尔基体中，这预计是由于有害的构象和生化变化所致。ICOSL 减弱了 B 细胞对 T 细胞的共刺激作用，为观察到的抗体和记忆 B 细胞生成缺陷提供了有力依据。有趣的是，ICOSL 还损害了淋巴细胞和中性粒细胞穿过内皮细胞的迁移，而内皮细胞通常表达 ICOSL。这些缺陷可能分别导致了患者适应性免疫和中性粒细胞减少症的改变。我们的研究确定了人类 缺陷是一种新型联合免疫缺陷的原因。
