Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
J Allergy Clin Immunol. 2018 May;141(5):1831-1843.e10. doi: 10.1016/j.jaci.2017.07.024. Epub 2017 Aug 19.
IgG-related disease (IgG-RD) is a systemic fibroinflammatory condition affecting various organs and has a diverse clinical presentation. Fibrosis and accumulation of IgG plasma cells in tissue are hallmarks of the disease, and IgG-RD is associated with increased IgG serum levels. However, disease pathogenesis is still unclear, and these cellular and molecular parameters are neither sensitive nor specific for the diagnosis of IgG-RD.
Here we sought to develop a flow cytometric gating strategy to reliably identify blood IgG B cells to study their cellular and molecular characteristics and investigate their contribution in disease pathogenesis.
Sixteen patients with histologically confirmed IgG-RD, 11 patients with sarcoidosis, and 30 healthy subjects were included for 11-color flow cytometric analysis of peripheral blood for IgG-expressing B cells and T subsets. In addition, detailed analysis of activation markers and chemokine receptors was performed on IgG-expressing B cells, and IgG transcripts were analyzed for somatic hypermutations.
Cellular and molecular analyses revealed increased numbers of blood IgG memory B cells in patients with IgG-RD. These cells showed reduced expression of CD27 and CXCR5 and increased signs of antibody maturation. Furthermore, patients with IgG-RD, but not patients with sarcoidosis, had increased numbers of circulating plasmablasts and CD21 B cells, as well as T2 and regulatory T cells, indicating a common disease pathogenesis in patients with IgG-RD.
These results provide new insights into the dysregulated IgG response in patients with IgG-RD. A specific "peripheral lymphocyte signature" observed in patients with IgG-RD, could support diagnosis and treatment monitoring.
IgG 相关疾病（IgG-RD）是一种影响多种器官的系统性纤维炎症性疾病，具有多种临床表现。组织中纤维蛋白和 IgG 浆细胞的积累是该疾病的标志，并且 IgG-RD 与 IgG 血清水平升高有关。然而，疾病的发病机制仍不清楚，这些细胞和分子参数既不敏感也不特异于 IgG-RD 的诊断。
本研究旨在开发一种流式细胞术门控策略，以可靠地鉴定血液 IgG B 细胞，研究其细胞和分子特征，并探讨其在疾病发病机制中的作用。
纳入 16 例组织学证实的 IgG-RD 患者、11 例结节病患者和 30 名健康对照者，进行外周血 11 色流式细胞术分析，以鉴定 IgG 表达 B 细胞和 T 亚群。此外，对 IgG 表达 B 细胞进行了详细的活化标志物和趋化因子受体分析，并对 IgG 转录本进行了体细胞高频突变分析。
细胞和分子分析显示，IgG-RD 患者血液中的 IgG 记忆 B 细胞数量增加。这些细胞表现出 CD27 和 CXCR5 表达减少，以及抗体成熟的迹象增加。此外，只有 IgG-RD 患者而不是结节病患者具有循环浆母细胞和 CD21 B 细胞以及 T2 和调节性 T 细胞数量增加，表明 IgG-RD 患者存在共同的疾病发病机制。
这些结果为 IgG-RD 患者中失调的 IgG 反应提供了新的见解。在 IgG-RD 患者中观察到的特定“外周淋巴细胞特征”可以支持诊断和治疗监测。
