Fox David A, Lundy Steven K, Whitfield Michael L, Berrocal Veronica, Campbell Phillip, Rasmussen Stephanie, Ohara Ray, Stinson Alexander, Gurrea-Rubio Mikel, Wiewiora Evan, Spino Catherine, Bush Erica, Furst Daniel, Pillai Shiv, Khanna Dinesh
Division of Rheumatology, Department of Internal Medicine, Scleroderma Program, Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, USA.
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, USA.
Arthritis Res Ther. 2021 Jan 6;23(1):10. doi: 10.1186/s13075-020-02383-w.
Abnormalities in lymphocyte surface markers and functions have been described in systemic sclerosis (SSc), but conflicting results abound, and these studies often examined patients with heterogeneous disease duration, severity, clinical phenotype, and concurrent immunosuppressive agents. We studied a clinically homogeneous group of early diffuse cutaneous SSc patients not exposed to immunosuppressive drugs who were enrolled in a clinical trial and compared their immune parameters to healthy control subjects.
Lymphocyte subsets were enumerated by multi-parameter flow cytometry of peripheral blood mononuclear cells at baseline visit. Production of the cytokines IL-4 and IL-17 was measured by intracellular flow cytometry following T cell activation.
SSc patients had increased percentages of CD4+ T cells but lower percentages of CD8+ T cells versus controls. The CD28-negative population was expanded in SSc, in the CD4 subset. Striking expansion of CD319+ T cells was noted among the CD4+ cells, in which they were barely detectable in healthy subjects. Frequencies of IL-4 producing cells did not differ between SSc and controls, but expansion of IL-17 producing cells was observed in SSc. A higher proportion of CD319+ cells produced cytokines, compared to other CD4+ cells. Numbers of activated T cells, regulatory T cells, and B cells were similar in SSc and control groups. Circulating follicular helper but not peripheral helper T cells were slightly expanded in SSc.
In this carefully selected group of early diffuse cutaneous SSc patients, analysis of immune cell parameters has identified abnormalities that likely reflect disease pathogenesis and that are candidate biomarkers for sub-classification and targeted treatment. The CD4+CD319+ (SLAM-F7+) cells are cytotoxic and oligoclonal, were recently shown to be a dominant T cell population in perivascular lymphocytic infiltrates in SSc skin, actively secrete cytokines, and are emerging as a target for novel treatments of SSc.
系统性硬化症（SSc）患者存在淋巴细胞表面标志物和功能异常，但研究结果相互矛盾，且这些研究常纳入疾病病程、严重程度、临床表型各异以及同时使用免疫抑制剂的患者。我们研究了一组未接受免疫抑制药物治疗且临床特征均一的早期弥漫性皮肤型SSc患者，这些患者参与了一项临床试验，并将他们的免疫参数与健康对照者进行比较。
在基线访视时，通过多参数流式细胞术对外周血单个核细胞进行淋巴细胞亚群计数。T细胞活化后，通过细胞内流式细胞术检测细胞因子IL-4和IL-17的产生。
与对照组相比，SSc患者CD4+ T细胞百分比增加，但CD8+ T细胞百分比降低。在SSc患者中，CD4亚群的CD28阴性群体有所扩大。在CD4+细胞中，CD319+ T细胞显著扩增，而在健康受试者中几乎检测不到。SSc患者和对照组中产生IL-4的细胞频率无差异，但在SSc患者中观察到产生IL-17的细胞扩增。与其他CD4+细胞相比，较高比例的CD319+细胞产生细胞因子。SSc组和对照组中活化T细胞、调节性T细胞和B细胞的数量相似。SSc患者中循环滤泡辅助性T细胞略有扩增，但外周辅助性T细胞无扩增。
在这组经过精心挑选的早期弥漫性皮肤型SSc患者中，免疫细胞参数分析确定了可能反映疾病发病机制的异常，这些异常是亚分类和靶向治疗的候选生物标志物。CD4+CD319+（信号淋巴细胞激活分子家族成员7+）细胞具有细胞毒性且为寡克隆性，最近被证明是SSc皮肤血管周围淋巴细胞浸润中的主要T细胞群体，可积极分泌细胞因子，并正成为SSc新治疗靶点。
