Wang Guojue, Sun Ying, Jiang Yongshuai, Li Shengzhe, Liu Yunhui, Yuan Yuanyang, Nie Hong
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Mol Immunol. 2023 Apr;156:39-47. doi: 10.1016/j.molimm.2023.02.009. Epub 2023 Mar 6.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a high level of autoantibody production. T follicular helper (Tfh) cells and B cells participate in the development of SLE. Several studies have shown that CXCR3 cells are increased in SLE patients. However, the mechanism through which CXCR3 influences lupus development remains unclear. In this study, we established lupus models to determine the role of CXCR3 in lupus pathogenesis. The concentration of autoantibodies was detected using the enzyme-linked immunosorbent assay (ELISA), and the percentages of Tfh cells and B cells were measured using flow cytometry. RNA sequencing (RNA-seq) was performed to detect the differentially expressed genes in CD4 T cells from wild-type (WT) and CXCR3 knock-out (KO) lupus mice. Migration of CD4 T cells in spleen section was assessed using immunofluorescence. CD4 T cell function in helping B cells produce antibodies was determined using a co-culture experiment and supernatant IgG ELISA. Lupus mice were treated with a CXCR3 antagonist to confirm the therapeutic effects. We found that the expression of CXCR3 was increased in CD4 T cells from lupus mice. CXCR3 deficiency reduced autoantibody production with decreased proportions of Tfh cells, germinal center (GC) B cells, and plasma cells. Expression of Tfh-related genes was downregulated in CD4 T cells from CXCR3 KO lupus mice. Migration to B cell follicles and T-helper function of CD4 T cells were reduced in CXCR3 KO lupus mice. CXCR3 antagonist AMG487 decreased the level of serum anti-dsDNA IgG in lupus mice. We clarify that CXCR3 may play an important role in autoantibody production by increasing the percentages of aberrant activated Tfh cells and B cells and promoting the migration and T-helper function of CD4 T cells in lupus mice. Thus, CXCR3 may be a potential target for lupus therapy.
系统性红斑狼疮（SLE）是一种以自身抗体高水平产生为特征的自身免疫性疾病。滤泡辅助性T（Tfh）细胞和B细胞参与SLE的发病过程。多项研究表明，SLE患者体内CXCR3细胞增多。然而，CXCR3影响狼疮发病的机制仍不清楚。在本研究中，我们建立狼疮模型以确定CXCR3在狼疮发病机制中的作用。采用酶联免疫吸附测定（ELISA）检测自身抗体浓度，并用流式细胞术检测Tfh细胞和B细胞的百分比。进行RNA测序（RNA-seq）以检测野生型（WT）和CXCR3基因敲除（KO）狼疮小鼠CD4 T细胞中的差异表达基因。用免疫荧光法评估脾脏切片中CD4 T细胞的迁移。通过共培养实验和上清液IgG ELISA确定CD4 T细胞在帮助B细胞产生抗体方面的功能。用CXCR3拮抗剂治疗狼疮小鼠以确认其治疗效果。我们发现狼疮小鼠CD4 T细胞中CXCR3的表达增加。CXCR3缺陷减少了自身抗体的产生，同时Tfh细胞、生发中心（GC）B细胞和浆细胞的比例降低。CXCR3基因敲除狼疮小鼠的CD4 T细胞中Tfh相关基因的表达下调。CXCR3基因敲除狼疮小鼠中CD4 T细胞向B细胞滤泡的迁移和辅助功能降低。CXCR3拮抗剂AMG487降低了狼疮小鼠血清抗双链DNA IgG的水平。我们阐明，CXCR3可能通过增加异常活化的Tfh细胞和B细胞的百分比以及促进狼疮小鼠中CD4 T细胞的迁移和辅助功能，在自身抗体产生中发挥重要作用。因此，CXCR3可能是狼疮治疗的一个潜在靶点。
