University of Queensland, Brisbane, Queensland, Australia.
Queensland University of Technology and Translational Research Institute, Brisbane, Queensland, Australia.
Arthritis Rheumatol. 2020 Aug;72(8):1289-1302. doi: 10.1002/art.41252. Epub 2020 Jul 13.
Ankylosing spondylitis (AS) is a common spondyloarthropathy primarily affecting the axial skeleton and strongly associated with HLA-B27 carriage. Genetic evidence implicates both autoinflammatory processes and autoimmunity against an HLA-B27-restricted autoantigen in immunopathology. In addition to articular symptoms, up to 70% of AS patients present with concurrent bowel inflammation, suggesting that adverse interactions between a genetically primed host immune system and the gut microbiome contribute to the disease. Accordingly, this study aimed to characterize adaptive immune responses to antigenic stimuli in AS.
The peripheral CD4 and CD8 T cell receptor (TCR) repertoire was profiled in AS patients (n = 47) and HLA-B27-matched healthy controls (n = 38). Repertoire diversity was estimated using the Normalized Shannon Diversity Entropy (NSDE) index, and univariate and multivariate statistical analyses were performed to characterize AS-associated clonal signatures. Furthermore, T cell proliferation and cytokine production in response to immunogenic antigen exposure were investigated in vitro in peripheral blood mononuclear cells from AS patients (n = 19) and HLA-B27-matched healthy controls (n = 14).
Based on the NSDE measure of sample diversity across CD4 and CD8 T cell repertoires, AS patients showed increased TCR diversity compared to healthy controls (for CD4 T cells, P = 7.8 × 10 ; for CD8 T cells, P = 9.3 × 10 ), which was attributed to a significant reduction in the magnitude of peripheral T cell expansions globally. Upon in vitro stimulation, fewer T cells from AS patients than from healthy controls expressed interferon-γ (for CD8 T cells, P = 0.03) and tumor necrosis factor (for CD4 T cells, P = 0.01; for CD8 T cells, P = 0.002). In addition, the CD8 TCR signature was altered in HLA-B27+ AS patients compared to healthy controls, with significantly expanded Epstein-Barr virus-specific clonotypes (P = 0.03) and cytomegalovirus-specific clonotypes (P = 0.02). HLA-B27+ AS patients also showed an increased incidence of "public" CD8 TCRs, representing identical clonotypes emerging in response to common antigen encounters, including homologous clonotypes matching those previously isolated from individuals with bacterial-induced reactive arthritis.
The dynamics of peripheral T cell responses in AS patients are altered, suggesting that differential antigen exposure and disrupted adaptive immunity are underlying features of the disease.
强直性脊柱炎（AS）是一种常见的脊柱关节病，主要影响轴向骨骼，并与 HLA-B27 携带密切相关。遗传证据表明，免疫病理学中既存在自身炎症过程，也存在针对 HLA-B27 限制性自身抗原的自身免疫。除了关节症状外，多达 70%的 AS 患者同时存在肠道炎症，这表明遗传致敏的宿主免疫系统与肠道微生物组之间的不良相互作用导致了疾病的发生。因此，本研究旨在描述 AS 患者对抗原刺激的适应性免疫反应。
对 47 例 AS 患者（n=47）和 38 例 HLA-B27 匹配的健康对照者（n=38）的外周血 CD4 和 CD8 T 细胞受体（TCR）谱进行了分析。使用归一化 Shannon 多样性熵（NSDE）指数估计了 repertoire 多样性，并进行了单变量和多变量统计分析，以描述与 AS 相关的克隆特征。此外，还在 AS 患者（n=19）和 HLA-B27 匹配的健康对照者（n=14）的外周血单个核细胞中，研究了针对免疫原性抗原暴露的 T 细胞增殖和细胞因子产生情况。
基于 CD4 和 CD8 TCR repertoire 样本多样性的 NSDE 衡量标准，与健康对照组相比，AS 患者的 TCR 多样性增加（CD4 T 细胞，P=7.8×10-5；CD8 T 细胞，P=9.3×10-5），这归因于外周 T 细胞扩增幅度的显著降低。体外刺激后，AS 患者的 T 细胞表达干扰素-γ的数量少于健康对照组（CD8 T 细胞，P=0.03）和肿瘤坏死因子（CD4 T 细胞，P=0.01；CD8 T 细胞，P=0.002）。此外，与健康对照组相比，HLA-B27+AS 患者的 CD8 TCR 特征发生了改变，明显扩大了 EBV 特异性克隆型（P=0.03）和巨细胞病毒特异性克隆型（P=0.02）。HLA-B27+AS 患者还表现出“公共”CD8 TCR 的发生率增加，这些 TCR 代表了对共同抗原反应中出现的相同克隆型，包括与先前从细菌诱导性反应性关节炎患者中分离出的同源克隆型相匹配的克隆型。
AS 患者外周 T 细胞反应的动力学发生改变，提示差异抗原暴露和适应性免疫破坏是疾病的潜在特征。
