University of Toronto, Krembil Research Institute, Toronto Western Hospital, and University Health Network, Toronto, Ontario, Canada.
University of Toronto, Krembil Research Institute, and University Health Network, Toronto, Ontario, Canada.
Arthritis Rheumatol. 2020 Mar;72(3):428-434. doi: 10.1002/art.41129. Epub 2020 Jan 22.
Ankylosing spondylitis (AS) is an inflammatory arthritis in which men have a higher risk of developing progressive axial disease than women. Transcriptomic studies have shown reduced expression of cytotoxic cell genes in the blood of AS patients. HLA-B27 contributes the greatest risk for AS, suggesting a role for CD8+ T cells. This study was undertaken to profile AS patient cytotoxic cells with the hypothesis that an alteration in CD8+ T cells might explain the aberrant cytotoxic profile observed in patients.
Whole blood was examined for GZM and PRF1 gene expression by quantitative polymerase chain reaction. Serum and synovial fluid (SF) were examined for granzyme and perforin 1 expression by bead array, and blood and SF mononuclear cells were examined for granzyme and perforin 1 expression by fluorescence-activated cell sorting (FACS).
GZM and PRF1 gene expression were both reduced in AS patients compared to healthy controls, especially in men. Perforin 1, but not granzyme, protein levels were reduced in AS patient serum. Granzymes were elevated in AS SF, but not in rheumatoid arthritis or osteoarthritis SF. FACS revealed a reduction in granzyme-positive and perforin 1-positive lymphocytes, but not an intrinsic defect in CD8+ T cell granzyme or perforin 1 production. CD8+ T cell frequency was reduced in the blood and increased in the SF of AS patients.
Our findings indicate that AS patients have an altered cytotoxic T cell profile. These data suggest that CD8+ T cells with a cytotoxic phenotype are recruited to the joints, where they exhibit an activated phenotype. Thus, a central role for CD8+ T cells in AS may have been overlooked and deserves further study.
强直性脊柱炎（AS）是一种炎症性关节炎，男性发生进行性中轴疾病的风险高于女性。转录组学研究表明，AS 患者血液中的细胞毒性基因表达降低。HLA-B27 对 AS 的贡献最大，提示 CD8+T 细胞起作用。本研究旨在分析 AS 患者的细胞毒性细胞，假设 CD8+T 细胞的改变可能解释了患者观察到的异常细胞毒性特征。
通过定量聚合酶链反应检测全血中 GZM 和 PRF1 基因的表达。通过珠阵列检测血清和滑液（SF）中的颗粒酶和穿孔素 1 表达，通过荧光激活细胞分选（FACS）检测血液和 SF 单核细胞中的颗粒酶和穿孔素 1 表达。
与健康对照组相比，AS 患者的 GZM 和 PRF1 基因表达均降低，尤其是男性。AS 患者血清中的穿孔素 1 蛋白水平降低，但颗粒酶没有降低。AS SF 中的颗粒酶升高，但类风湿关节炎或骨关节炎 SF 中没有升高。FACS 显示颗粒酶阳性和穿孔素 1 阳性淋巴细胞减少，但 CD8+T 细胞颗粒酶或穿孔素 1 产生没有内在缺陷。AS 患者的血液中 CD8+T 细胞频率降低，SF 中增加。
我们的研究结果表明，AS 患者存在改变的细胞毒性 T 细胞特征。这些数据表明，具有细胞毒性表型的 CD8+T 细胞被募集到关节，在那里它们表现出激活表型。因此，CD8+T 细胞在 AS 中的核心作用可能被忽视了，值得进一步研究。
