Department of Clinical Immunology and Allergology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic;
St. Anne's University Hospital, 656 91 Brno, Czech Republic.
J Immunol. 2019 Jan 1;202(1):93-104. doi: 10.4049/jimmunol.1800102. Epub 2018 Nov 28.
Common variable immunodeficiency disorders (CVID) represent a group of primary immunodeficiency diseases characterized by hypogammaglobulinemia and impaired specific Ab response, resulting in recurrent infections due to dysfunctional immune response. The specific mechanisms mediating immune deficiency in CVID remain to be determined. Previous studies indicated that immune dysregulation in CVID patients is associated with chronic microbial translocation, systemic immune activation, and altered homeostasis of lymphocytic and myeloid lineages. A detailed phenotypic, functional characterization of plasma markers and immune cell populations was performed in 46 CVID patients and 44 healthy donors. CVID patients displayed significantly elevated plasma levels of a marker of neutrophil activation neutrophil gelatinase-associated lipocalin. Neutrophils from CVID patients exhibited elevated surface levels of CD11b and PD-L1 and decreased levels of CD62L, CD16, and CD80, consistent with a phenotype of activated neutrophils with suppressive properties. Neutrophils from CVID patients actively suppressed T cell activation and release of IFN-γ via the production of reactive oxygen species. Furthermore, CVID was associated with an increased frequency of low-density neutrophils (LDNs)/granulocytic myeloid-derived suppressor cells. LDN/granulocytic myeloid-derived suppressor cell frequency in CVID patients correlated with reduced T cell responsiveness. Exogenous stimulation of whole blood with bacterial LPS emulated some but not all of the phenotypic changes observed on neutrophils from CVID patients and induced neutrophil population with LDN phenotype. The presented data demonstrate that neutrophils in the blood of CVID patients acquire an activated phenotype and exert potent T cell suppressive activity. Specific targeting of myeloid cell-derived suppressor activity represents a novel potential therapeutic strategy for CVID.
普通变异性免疫缺陷病（CVID）代表一组以低丙种球蛋白血症和特异性 Ab 反应受损为特征的原发性免疫缺陷病，导致免疫功能障碍导致反复感染。介导 CVID 免疫缺陷的具体机制仍有待确定。先前的研究表明，CVID 患者的免疫失调与慢性微生物易位、全身免疫激活和淋巴细胞和髓样谱系的平衡失调有关。对 46 例 CVID 患者和 44 名健康供体进行了血浆标志物和免疫细胞群的详细表型和功能特征分析。CVID 患者的血浆标志物中性粒细胞激活的标志物中性粒细胞明胶酶相关脂质运载蛋白水平显著升高。CVID 患者的中性粒细胞表面 CD11b 和 PD-L1 水平升高，CD62L、CD16 和 CD80 水平降低，与具有抑制特性的活化中性粒细胞表型一致。CVID 患者的中性粒细胞通过产生活性氧主动抑制 T 细胞激活和 IFN-γ的释放。此外，CVID 与低密度中性粒细胞（LDN）/粒细胞髓系来源的抑制细胞的频率增加有关。CVID 患者的 LDN/粒细胞髓系来源的抑制细胞频率与 T 细胞反应性降低相关。用细菌 LPS 对全血进行外源性刺激模拟了 CVID 患者中性粒细胞中观察到的一些但不是所有的表型变化，并诱导具有 LDN 表型的中性粒细胞群体。所呈现的数据表明，CVID 患者血液中的中性粒细胞获得活化表型并发挥强大的 T 细胞抑制活性。髓样细胞来源的抑制活性的特异性靶向代表了 CVID 的一种新的潜在治疗策略。
