Lin Wei, Zhang Panpan, Chen Hua, Chen Yu, Yang Hongxian, Zheng Wenjie, Zhang Xuan, Zhang Fengxiao, Zhang Wen, Lipsky Peter E
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
Department of Rheumatology, Hebei General Hospital, Shijiazhuang, China.
Arthritis Res Ther. 2017 Feb 10;19(1):25. doi: 10.1186/s13075-017-1231-2.
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multisystem fibroinflammatory disease. We previously reported that a circulating cell population expressing CD19CD24CD38 was increased in patients with IgG4-RD. In this study, we aimed to document that this cell population represented circulating plasmablasts/plasma cells, to identify the detailed phenotype and gene expression profile of these IgG4-secreting plasmablasts/plasma cells, and to determine whether this B-cell lineage subset could be a biomarker in IgG4-related disease (IgG4-RD).
A total of 42 untreated patients with IgG4-RD were evaluated. Peripheral B-cell subsets, including CD19CD24CD38 plasmablasts/plasma cells, CD19CD24CD38 memory B cells, CD19CD24CD38 naïve B cells, and CD19CD24CD38 regulatory B cells, were assessed and sorted by flow cytometry. Microarray analysis was used to measure gene expression of circulating B-cell lineage subsets. Further characterization of CD19CD24CD38 plasmablasts/plasma cells was carried out by evaluating additional surface markers, including CD27, CD95, and human leukocyte antigen (HLA)-DR, by flow cytometric assay. In addition, various B-cell lineage subsets were cultured in vitro and IgG4 concentrations were measured by cytometric bead array.
In untreated patients with IgG4-RD, the peripheral CD19CD24CD38 plasmablast/plasma cell subset was increased and positively correlated with serum IgG4 levels, the number of involved organs, and the IgG4-related Disease Responder Index. It decreased after treatment with glucocorticoids. Characterization of the plasmablast/plasma cell population by gene expression profiling documented a typical plasmablast/plasma cell signature with higher expression of X-box binding protein 1 and IFN regulatory factor 4, but lower expression of paired box gene 5 and B-cell lymphoma 6 protein. In addition, CD27, CD95, and HLA-DR were highly expressed on CD19CD24CD38 plasmablasts/plasma cells from patients with IgG4-RD. Furthermore, CD19CD24CD38 plasmablasts/plasma cells secreted more IgG4 than other B-cell populations.
Circulating CD19CD24CD38 plasmablasts/plasma cells are elevated in active IgG4-RD and decreased after glucocorticoid treatment. This IgG4-secreting plasmablast/plasma cell population might be a potentially useful biomarker for diagnosis and assessing response to treatment.
免疫球蛋白G4（IgG4）相关疾病（IgG4-RD）是一种多系统纤维炎性疾病。我们之前报道过，IgG4-RD患者中表达CD19CD24CD38的循环细胞群体有所增加。在本研究中，我们旨在证明该细胞群体代表循环浆母细胞/浆细胞，确定这些分泌IgG4的浆母细胞/浆细胞的详细表型和基因表达谱，并确定该B细胞谱系亚群是否可能成为IgG4相关疾病（IgG4-RD）的生物标志物。
共评估了42例未经治疗的IgG4-RD患者。通过流式细胞术评估并分选外周血B细胞亚群，包括CD19CD24CD38浆母细胞/浆细胞、CD19CD24CD38记忆B细胞、CD19CD24CD38幼稚B细胞和CD19CD24CD38调节性B细胞。利用微阵列分析测量循环B细胞谱系亚群的基因表达。通过流式细胞术检测评估包括CD27、CD95和人类白细胞抗原（HLA）-DR在内的其他表面标志物，对CD19CD24CD38浆母细胞/浆细胞进行进一步表征。此外，将各种B细胞谱系亚群进行体外培养，并通过细胞计数珠阵列测量IgG4浓度。
在未经治疗的IgG4-RD患者中，外周血CD19CD24CD38浆母细胞/浆细胞亚群增加，且与血清IgG4水平、受累器官数量及IgG4相关疾病反应指数呈正相关。糖皮质激素治疗后其数量减少。通过基因表达谱对浆母细胞/浆细胞群体进行表征，发现其具有典型的浆母细胞/浆细胞特征，X盒结合蛋白1和干扰素调节因子4表达较高，而配对盒基因5和B细胞淋巴瘤6蛋白表达较低。此外，IgG4-RD患者的CD19CD24CD38浆母细胞/浆细胞上CD27、CD95和HLA-DR高度表达。此外，CD19CD24CD38浆母细胞/浆细胞分泌的IgG4比其他B细胞群体更多。
循环CD19CD24CD38浆母细胞/浆细胞在活动性IgG4-RD中升高，糖皮质激素治疗后降低。这种分泌IgG4的浆母细胞/浆细胞群体可能是诊断及评估治疗反应的潜在有用生物标志物。
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