黏膜相关恒定 T 细胞在中轴型脊柱关节炎患者血液中的特征分析，以及非中轴型脊柱关节炎对照患者附着点组织中固有黏膜相关恒定 T 细胞的特征分析。

Characterization of Blood Mucosal-Associated Invariant T Cells in Patients With Axial Spondyloarthritis and of Resident Mucosal-Associated Invariant T Cells From the Axial Entheses of Non-Axial Spondyloarthritis Control Patients.

机构信息

Institut Pasteur, Université de Paris, Immunoregulation Unit, Department of Immunology, Paris, France.

University of Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK.

出版信息

Arthritis Rheumatol. 2022 Nov;74(11):1786-1795. doi: 10.1002/art.42090. Epub 2022 Sep 22.

DOI:10.1002/art.42090

PMID:35166073

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9825958/

Abstract

OBJECTIVE

The importance of interleukin-17A (IL-17A) in the pathogenesis of axial spondyloarthritis (SpA) has been demonstrated by the success of IL-17A blockade. However, the nature of the cell populations that produce this important proinflammatory cytokine remains poorly defined. We undertook this study to characterize the major IL-17A-producing blood cell populations in the peripheral blood of patients with axial SpA, with a focus on mucosal-associated invariant T (MAIT) cells, a population known to be capable of producing IL-17.

METHODS

We evaluated IL-17A production from 5 sorted peripheral blood cell populations, namely, MAIT cells, γδ T cells, CD4+ T cells, CD8+ T cells, and neutrophils, before and after stimulation with phorbol myristate acetate, the calcium ionophore A23187, and β-1,3-glucan. Expression of IL-17A transcripts and protein were determined using nCounter and ultra-sensitive Simoa technology, respectively. MAIT cells from the axial entheses of non-axial SpA control patients (n = 5) were further characterized using flow cytometric immunophenotyping and quantitative polymerase chain reaction, and the production of IL-17 was assessed following stimulation.

RESULTS

On a per-cell basis, MAIT cells from peripheral blood produced the most IL-17A compared to CD4+ T cells (P < 0.01), CD8+ T cells (P < 0.0001), and γδ T cells (P < 0.0001). IL-17A was not produced by neutrophils. Gene expression analysis also revealed significantly higher expression of IL17A and IL23R in MAIT cells. Stimulation of peripheral blood MAIT cells with anti-CD3/CD28 and IL-7 and/or IL-18 induced strong expression of IL17F. MAIT cells were present in the normal, unaffected entheses of control patients who did not have axial SpA and showed elevated AHR, JAK1, STAT4, and TGFB1 transcript expression with inducible IL-17A protein. IL-18 protein expression was evident in spinal enthesis digests.

CONCLUSION

Both peripheral blood MAIT cells and resident MAIT cells in normal axial entheses contribute to the production of IL-17 and may play important roles in the pathogenesis of axial SpA.

摘要

目的

白细胞介素-17A（IL-17A）在轴性脊柱关节炎（SpA）发病机制中的重要性已被 IL-17A 阻断的成功所证明。然而，产生这种重要促炎细胞因子的细胞群体的性质仍未得到很好的定义。我们进行这项研究是为了描述轴性 SpA 患者外周血中主要的 IL-17A 产生血细胞群体，重点是黏膜相关不变 T（MAIT）细胞，已知这种细胞能够产生 IL-17。

方法

我们评估了 5 种外周血细胞群体（即 MAIT 细胞、γδ T 细胞、CD4+T 细胞、CD8+T 细胞和中性粒细胞）在佛波醇肉豆蔻酸酯、钙离子载体 A23187 和 β-1,3-葡聚糖刺激前后产生 IL-17A 的情况。使用 nCounter 和超灵敏 Simoa 技术分别测定 IL-17A 转录本和蛋白的表达。进一步通过流式细胞术免疫表型和定量聚合酶链反应对非轴性 SpA 对照组患者轴突附着点的 MAIT 细胞进行特征描述，并在刺激后评估 IL-17 的产生。

结果

以单个细胞为基础，外周血中的 MAIT 细胞比 CD4+T 细胞（P<0.01）、CD8+T 细胞（P<0.0001）和 γδ T 细胞（P<0.0001）产生更多的 IL-17A。中性粒细胞不产生 IL-17A。基因表达分析还显示 MAIT 细胞中 IL17A 和 IL23R 的表达明显更高。用抗 CD3/CD28 和 IL-7 以及/或 IL-18 刺激外周血 MAIT 细胞可诱导强烈的 IL17F 表达。在没有轴性 SpA 的对照组正常、未受影响的附着点中存在 MAIT 细胞，并表现出升高的 AHR、JAK1、STAT4 和 TGFB1 转录物表达，并伴有可诱导的 IL-17A 蛋白。在脊柱附着点消化物中可检测到 IL-18 蛋白表达。