Department of Dermatology, University of Rochester Medical Center, Rochester, NY, United States.
Division of Allergy, Immunology, and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, United States.
Front Immunol. 2019 Dec 10;10:2881. doi: 10.3389/fimmu.2019.02881. eCollection 2019.
Common variable immunodeficiency (CVID) comprises a group of related disorders defined by defects in B cell function and antibody production. Concurrent autoimmune features are common, but the underlying pathogenic mechanisms of autoimmunity in CVID are poorly understood. Overlap in some clinical and laboratory features suggests a shared pathogenesis, at least in part, with systemic lupus erythematosus (SLE). One important part of SLE pathogenesis is loss of B cell tolerance, an aspect that warrants further study in CVID. The study of inherently autoreactive 9G4 B cells has led to a greater understanding of B cell tolerance defects in lupus. Study of these B cells in CVID has yielded conflicting results, largely due to differences in methodological approaches. In this study, we take a comprehensive look at 9G4 B cells throughout B cell development in CVID patients and compare patients both with and without autoimmune features. Using flow cytometry to examine B cell subpopulations in detail, we show that only those CVID patients with autoimmune features demonstrate significant expansion of 9G4 B cells, both in naïve and multiple memory populations. Examination of two autoreactive B cell subsets recently characterized in SLE, the activated naïve (aNAV) and double negative 2 (DN2) B cells, reveals an expanded 9G4 DN2 population to be common among CVID patients. These results reveal that both multiple central and peripheral B cell tolerance defects are related to autoimmunity in CVID. Furthermore, these data suggest that the autoreactive DN2 B cell population, which has not previously been examined in CVID, may play an important role in the development of autoimmunity in patients with CVID.
普通变异性免疫缺陷（CVID）是一组由 B 细胞功能和抗体产生缺陷定义的相关疾病。同时存在自身免疫特征很常见，但 CVID 中自身免疫的潜在发病机制仍了解甚少。一些临床和实验室特征的重叠表明存在共同的发病机制，至少部分与系统性红斑狼疮（SLE）相同。SLE 发病机制的一个重要部分是 B 细胞耐受丧失，这一方面值得在 CVID 中进一步研究。固有自身反应性 9G4 B 细胞的研究导致了对狼疮中 B 细胞耐受缺陷的更深入理解。在 CVID 中研究这些 B 细胞得出了相互矛盾的结果，主要是由于方法学方法的差异。在这项研究中，我们全面研究了 CVID 患者整个 B 细胞发育过程中的 9G4 B 细胞，并比较了有和没有自身免疫特征的患者。我们使用流式细胞术详细检查 B 细胞亚群，结果表明只有那些具有自身免疫特征的 CVID 患者表现出 9G4 B 细胞的显著扩增，无论是在幼稚和多个记忆群体中。最近在 SLE 中表征的两个自身反应性 B 细胞亚群，即活化的幼稚（aNAV）和双阴性 2（DN2）B 细胞的检查表明，9G4 DN2 群体的扩增在 CVID 患者中很常见。这些结果表明，多个中枢和外周 B 细胞耐受缺陷与 CVID 中的自身免疫有关。此外，这些数据表明，以前在 CVID 中未检查过的自身反应性 DN2 B 细胞群体可能在 CVID 患者自身免疫的发展中发挥重要作用。
