Department of Rheumatology and Clinical Immunology.
Department of Medicine I.
Blood. 2020 Apr 23;135(17):1452-1457. doi: 10.1182/blood.2019003855.
Common variable immunodeficiency (CVID) is a disease characterized by increased susceptibility to infections, hypogammaglobulinemia, and immune dysregulation. Although CVID is thought to be a disorder of the peripheral B-cell compartment, in 25% of patients, early B-cell development in the bone marrow is impaired. Because poor B-cell reconstitution after hematopoietic stem cell transplantation has been observed, we hypothesized that in some patients the bone marrow environment is not permissive to B-cell development. Studying the differentiation dynamics of bone marrow-derived CD34+ cells into immature B cells in vitro allowed us to distinguish patients with B-cell intrinsic defects and patients with a nonpermissive bone marrow environment. In the former, immature B cells did not develop and in the latter CD34+ cells differentiated into immature cells in vitro, but less efficiently in vivo. In a further group of patients, the uncommitted precursors were unable to support the constant development of B cells in vitro, indicating a possible low frequency or exhaustion of the precursor population. Hematopoietic stem cell transplantation would result in normal B-cell repopulation in case of intrinsic B-cell defect, but in defective B-cell repopulation in a nonpermissive environment. Our study points to the importance of the bone marrow niche in the pathogenesis of CVID.
普通变异型免疫缺陷病（CVID）是一种以易感染、低丙种球蛋白血症和免疫失调为特征的疾病。尽管 CVID 被认为是外周 B 细胞区室的紊乱，但在 25%的患者中，骨髓中的早期 B 细胞发育受损。由于造血干细胞移植后 B 细胞重建不良，我们假设在某些患者中，骨髓环境不利于 B 细胞发育。研究骨髓来源的 CD34+细胞体外向未成熟 B 细胞的分化动力学，使我们能够区分具有 B 细胞内在缺陷的患者和具有非许可骨髓环境的患者。在前一种情况下，未成熟 B 细胞无法发育，在后一种情况下，CD34+细胞在体外分化为未成熟细胞，但在体内效率较低。在另一组患者中，未分化的前体细胞无法在体外支持 B 细胞的持续发育，表明前体细胞群体的频率可能较低或耗竭。在存在内在 B 细胞缺陷的情况下，造血干细胞移植会导致正常的 B 细胞再植入，但在非许可的环境中会导致 B 细胞再植入缺陷。我们的研究表明骨髓龛在 CVID 的发病机制中的重要性。
