Erasmus Medical Center, Rotterdam, The Netherlands.
Academic Medical Center, Amsterdam, The Netherlands.
Arthritis Rheumatol. 2020 Aug;72(8):1303-1313. doi: 10.1002/art.41271. Epub 2020 Jul 8.
Interleukin-17A (IL-17A) and tumor necrosis factor (TNF) contribute to the pathogenesis of psoriatic arthritis (PsA). However, their functional relationship in PsA synovitis has not been fully elucidated. Additionally, although CD8+ T cells in PsA have been recognized via flow cytometry as a source of IL-17A production, it is not clear whether CD8+ T cells secrete IL-17A under more physiologically relevant conditions in the context from PsA synovitis. This study was undertaken to clarify the roles of IL-17A and TNF in the synovial fluid (SF) from patients with PsA and investigate the impact of CD8+ T cells on IL-17A production.
IL-17A+ T cells were identified by flow cytometry in SF samples from 20 patients with active PsA, blood samples from 22 treatment-naive patients with PsA, and blood samples from 22 healthy donors. IL-17A+ T cells were sorted from 12 PsA SF samples and stimulated using anti-CD3/anti-CD28 or phorbol myristate acetate (PMA) and ionomycin ex vivo, alone (n = 3) or together with autologous monocytes (n = 3) or PsA fibroblast-like synoviocytes (FLS) (n = 5-6). To evaluate the differential allogeneic effects of neutralizing IL-17A and TNF, SF CD4+ T cells and PsA FLS cocultures were also used (n = 5-6).
Flow cytometry analyses of SF samples from patients with PsA showed IL-17A positivity for CD4+ and CD8+ T cells (IL-17A, median 0.71% [interquartile range 0.35-1.50%] in CD4+ cells; median 0.44% [interquartile range 0.17-1.86%] in CD8+ T cells). However, only CD4+ T cells secreted IL-17A after anti-CD3/anti-CD28 activation, when cultured alone and in cocultures with PsA monocytes or PsA FLS (each P < 0.05). Remarkably, CD8+ T cells only secreted IL-17A after 4- or 72-hour stimulation with PMA/ionomycin. Anti-IL-17A and anti-TNF treatments both inhibited PsA synovitis ex vivo. Neutralizing IL-17A strongly inhibited IL-6 (P < 0.05) and IL-1β (P < 0.01), while anti-TNF treatment was more potent in reducing matrix metalloproteinase 3 (MMP-3) (P < 0.05) and MMP-13.
CD8+ T cells, in contrast to CD4+ T cells, in SF specimens obtained from PsA patients did not secrete IL-17A following T cell receptor activation. Overlapping, but distinct, effects at the level of inflammatory cytokines and MMPs were found after neutralizing IL-17A or TNF ex vivo in a human model of PsA synovitis.
白细胞介素-17A（IL-17A）和肿瘤坏死因子（TNF）有助于银屑病关节炎（PsA）的发病机制。然而，它们在 PsA 滑膜炎中的功能关系尚未完全阐明。此外，尽管通过流式细胞术已经在 PsA 中识别出 CD8+T 细胞是 IL-17A 产生的来源，但在 PsA 滑膜炎的背景下，CD8+T 细胞是否在更生理相关的条件下分泌 IL-17A 尚不清楚。本研究旨在阐明 IL-17A 和 TNF 在 PsA 患者滑液（SF）中的作用，并研究 CD8+T 细胞对 IL-17A 产生的影响。
通过流式细胞术鉴定 20 例活动期 PsA 患者 SF 样本、22 例未经治疗的 PsA 患者血液样本和 22 例健康供者血液样本中的 IL-17A+T 细胞。从 12 例 PsA SF 样本中分离出 IL-17A+T 细胞，并使用抗 CD3/抗 CD28 或佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）和离子霉素在体外单独（n=3）或与自体单核细胞（n=3）或 PsA 成纤维样滑膜细胞（FLS）（n=5-6）一起刺激。为了评估中和 IL-17A 和 TNF 的差异同种异体效应，还使用 SF CD4+T 细胞和 PsA FLS 共培养物（n=5-6）。
对 PsA 患者 SF 样本的流式细胞术分析显示 CD4+和 CD8+T 细胞的 IL-17A 阳性（CD4+细胞中 IL-17A 的中位数为 0.71%[四分位距 0.35-1.50%]；CD8+T 细胞中 IL-17A 的中位数为 0.44%[四分位距 0.17-1.86%]）。然而，只有在单独培养和与 PsA 单核细胞或 PsA FLS 共培养时，抗 CD3/抗 CD28 激活后 CD4+T 细胞才会分泌 IL-17A（均 P<0.05）。值得注意的是，只有在用 PMA/离子霉素刺激 4 或 72 小时后，CD8+T 细胞才会分泌 IL-17A。抗 IL-17A 和抗 TNF 治疗均可抑制体外 PsA 滑膜炎。中和 IL-17A 强烈抑制白细胞介素-6（P<0.05）和白细胞介素-1β（P<0.01），而抗 TNF 治疗在降低基质金属蛋白酶 3（MMP-3）（P<0.05）和基质金属蛋白酶 13 方面更为有效。
与 CD4+T 细胞相比，来自 PsA 患者 SF 标本的 CD8+T 细胞在 T 细胞受体激活后并未分泌 IL-17A。在 PsA 滑膜炎的人类模型中，体外中和 IL-17A 或 TNF 后，发现炎症细胞因子和 MMPs 水平存在重叠但不同的作用。
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