Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba, 260-8670, Japan.
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Arthritis Res Ther. 2024 Feb 20;26(1):55. doi: 10.1186/s13075-024-03289-7.
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.
IgG4 相关疾病（IgG4-RD）是一种病因不明的系统性自身免疫性疾病，影响单一/多个器官。病理表现包括 IgG4 产生浆细胞浸润、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。本研究旨在探讨 IgG4-RD 中非免疫细胞的特征和分布，并探索血清中非免疫细胞衍生的潜在生物标志物。
我们对 IgG4-RD 患者下颌下腺分离的非免疫细胞进行了单细胞 RNA 测序（scRNA-seq）。我们专注于表达胶原 XV 型的成纤维细胞，并通过免疫组织化学证实了这些成纤维细胞的存在。此外，我们测量了 IgG4-RD 患者血清中胶原 XV 型的水平。
scRNA-seq 分析揭示了由成纤维细胞、内皮细胞、导管细胞和肌细胞组成的几个不同簇。差异基因表达分析显示，与对照组相比，IgG4-RD 成纤维细胞中 COL15A1 上调。值得注意的是，COL15A1 阳性成纤维细胞的转录组与 COL15A1 阴性成纤维细胞明显不同。免疫组织化学分析证实 IgG4-RD 患者存在大量胶原 XV 阳性成纤维细胞。此外，在活动性 IgG4-RD 患者中进行免疫抑制治疗可导致血清中胶原 XV 型水平降低。
我们的研究结果表明，胶原 XV 型产生的成纤维细胞可能代表 IgG4-RD 中具有疾病特征的非免疫细胞群体，并可能作为疾病监测的标志物。
