IgG4-related disease (IgG4-RD) is a systemic autoimmune disease with an unknown etiology, affecting single/multiple organ(s). Pathological findings include the infiltration of IgG4-producing plasma cells, obliterative phlebitis, and storiform fibrosis. Although immunological studies have shed light on the dysregulation of lymphocytes in IgG4-RD pathogenesis, the role of non-immune cells remains unclear. This study aimed to investigate the demographics and characteristics of non-immune cells in IgG4-RD and explore potential biomarkers derived from non-immune cells in the sera. We conducted single-cell RNA sequence (scRNA-seq) on non-immune cells isolated from submandibular glands of IgG4-RD patients. We focused on fibroblasts expressing collagen type XV and confirmed the presence of those fibroblasts using immunohistochemistry. Additionally, we measured the levels of collagen type XV in the sera of IgG4-RD patients. The scRNA-seq analysis revealed several distinct clusters consisting of fibroblasts, endothelial cells, ductal cells, and muscle cells. Differential gene expression analysis showed upregulation of COL15A1 in IgG4-RD fibroblasts compared to control subjects. Notably, COL15A1-positive fibroblasts exhibited a distinct transcriptome compared to COL15A1-negative counterparts. Immunohistochemical analysis confirmed a significant presence of collagen type XV-positive fibroblasts in IgG4-RD patients. Furthermore, immune-suppressive therapy in active IgG4-RD patients resulted in decreased serum levels of collagen type XV. Our findings suggest that collagen type XV-producing fibroblasts may represent a disease-characterizing non-immune cell population in IgG4-RD and hold potential as a disease-monitoring marker.

中文翻译：

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颌下腺的单细胞 RNA 测序揭示 XV 型胶原蛋白阳性成纤维细胞是 IgG4 相关疾病的疾病特征细胞群

IgG4相关疾病（IgG4-RD）是一种病因不明的全身性自身免疫性疾病，影响单个/多个器官。病理结果包括产生 IgG4 的浆细胞浸润、闭塞性静脉炎和席纹状纤维化。尽管免疫学研究揭示了 IgG4-RD 发病机制中淋巴细胞的失调，但非免疫细胞的作用仍不清楚。本研究旨在调查 IgG4-RD 中非免疫细胞的人口统计和特征，并探索源自血清中非免疫细胞的潜在生物标志物。我们对从 IgG4-RD 患者下颌下腺分离的非免疫细胞进行了单细胞 RNA 序列 (scRNA-seq)。我们专注于表达 XV 型胶原蛋白的成纤维细胞，并使用免疫组织化学证实了这些成纤维细胞的存在。此外，我们还测量了 IgG4-RD 患者血清中 XV 型胶原蛋白的水平。scRNA-seq 分析揭示了由成纤维细胞、内皮细胞、导管细胞和肌肉细胞组成的几个不同的簇。差异基因表达分析显示，与对照受试者相比，IgG4-RD 成纤维细胞中 COL15A1 上调。值得注意的是，与 COL15A1 阴性成纤维细胞相比，COL15A1 阳性成纤维细胞表现出不同的转录组。免疫组织化学分析证实 IgG4-RD 患者中存在大量 XV 型胶原蛋白阳性成纤维细胞。此外，活动性 IgG4-RD 患者的免疫抑制治疗导致 XV 型胶原蛋白的血清水平降低。我们的研究结果表明，产生 XV 型胶原的成纤维细胞可能代表 IgG4-RD 中疾病特征性的非免疫细胞群，并具有作为疾病监测标记物的潜力。