轴性脊柱关节炎患者肠道炎症的特征是明显的 17 型偏倚黏膜固有样 T 细胞特征。

Gut Inflammation in Axial Spondyloarthritis Patients is Characterized by a Marked Type 17 Skewed Mucosal Innate-like T Cell Signature.

机构信息

Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University and Unit for Molecular Immunology and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.

Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium, Data Mining and Modeling for Biomedicine group, VIB-UGent Center for Inflammation Research, Ghent, Belgium, and Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

出版信息

Arthritis Rheumatol. 2023 Nov;75(11):1969-1982. doi: 10.1002/art.42627. Epub 2023 Oct 4.

DOI:10.1002/art.42627

PMID:37293832

Abstract

OBJECTIVE

Patients with spondyloarthritis (SpA) often present with microscopic signs of gut inflammation, a risk factor for progressive disease. We investigated whether mucosal innate-like T cells are involved in dysregulated interleukin-23 (IL-23)/IL-17 responses in the gut-joint axis in SpA.

METHODS

Ileal and colonic intraepithelial lymphocytes (IELs), lamina propria lymphocytes (LPLs), and paired peripheral blood mononuclear cells (PBMCs) were isolated from treatment-naive patients with nonradiographic axial SpA with (n = 11) and without (n = 14) microscopic gut inflammation and healthy controls (n = 15) undergoing ileocolonoscopy. The presence of gut inflammation was assessed histopathologically. Immunophenotyping of innate-like T cells and conventional T cells was performed using intracellular flow cytometry. Unsupervised clustering analysis was done by FlowSOM technology. Serum IL-17A levels were measured via Luminex.

RESULTS

Microscopic gut inflammation in nonradiographic axial SpA was characterized by increased ileal intraepithelial γδ-hi T cells, a γδ-T cell subset with elevated γδ-T cell receptor expression. γδ-hi T cells were also increased in PBMCs of patients with nonradiographic axial SpA versus healthy controls and were strongly associated with Ankylosing Spondylitis Disease Activity Score. The abundance of mucosal-associated invariant T cells and invariant natural killer T cells was unaltered. Innate-like T cells in the inflamed gut showed increased RORγt, IL-17A, and IL-22 levels with loss of T-bet, a signature that was less pronounced in conventional T cells. Presence of gut inflammation was associated with higher serum IL-17A levels. In patients treated with tumor necrosis factor blockade, the proportion of γδ-hi cells and RORγt expression in blood was completely restored.

CONCLUSION

Intestinal innate-like T cells display marked type 17 skewing in the inflamed gut mucosa of patients with nonradiographic axial SpA. γδ-hi T cells are linked to intestinal inflammation and disease activity in SpA.

摘要

目的

患有脊柱关节炎（SpA）的患者通常存在肠道炎症的微观迹象，这是疾病进展的一个危险因素。我们研究了黏膜固有样 T 细胞是否参与 SpA 肠道-关节轴中失调的白细胞介素 23（IL-23）/白细胞介素 17（IL-17）反应。

方法

我们从未经治疗的非放射性轴性 SpA 患者（有微观肠道炎症者 11 例，无微观肠道炎症者 14 例）和健康对照者（行结肠镜检查者 15 例）中分离出回肠和结肠上皮内淋巴细胞（IEL）、固有层淋巴细胞（LPL）和配对的外周血单核细胞（PBMC）。通过组织病理学评估肠道炎症的存在。使用细胞内流式细胞术对固有样 T 细胞和常规 T 细胞进行免疫表型分析。通过 FlowSOM 技术进行无监督聚类分析。通过 Luminex 测量血清 IL-17A 水平。

结果

非放射性轴性 SpA 的微观肠道炎症表现为回肠上皮内 γδ-hi T 细胞增加，这是一种具有高 γδ-T 细胞受体表达的 γδ-T 细胞亚群。与健康对照者相比，非放射性轴性 SpA 患者的 PBMC 中 γδ-hi T 细胞也增加，并且与强直性脊柱炎疾病活动评分密切相关。黏膜相关固有 T 细胞和固有自然杀伤 T 细胞的丰度没有改变。在炎症肠道中，固有样 T 细胞表现出更高的 RORγt、IL-17A 和 IL-22 水平，而 T-bet 减少，这种特征在常规 T 细胞中不那么明显。肠道炎症的存在与更高的血清 IL-17A 水平相关。在接受肿瘤坏死因子阻断治疗的患者中，血液中 γδ-hi 细胞的比例和 RORγt 的表达完全恢复。