Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Institute of Immunology, Christian-Albrechts-University of Kiel, Michaelmass 5, 24105 Kiel, Germany.
J Autoimmun. 2017 Mar;78:79-91. doi: 10.1016/j.jaut.2016.12.004. Epub 2016 Dec 28.
Autoimmune diseases are initiated by a combination of predisposing genetic and environmental factors resulting in self-perpetuating chronic inflammation and tissue damage. Autoantibody production and an imbalance of effector and regulatory T-cells are hallmarks of autoimmune dysregulation. While expansion of circulating effector memory T-cells is linked to disease pathogenesis and progression, the causes driving alterations of the peripheral T-cell compartment have remained poorly understood so far. In granulomatosis with polyangiitis (GPA), a prototypical autoimmune disorder of unknown aetiology, we performed for the first time a combined approach using phenotyping, transcriptome and functional analyses of T-cell populations to evaluate triggers of memory T-cell expansion. In more detail, we found increased percentages of circulating CD4+CD28-, CD8+CD28- and CD4+CD161+ single-positive and CD4+CD8+ double-positive T-cells in GPA. Transcriptomic profiling of sorted T-cell populations showed major differences between GPA and healthy controls reflecting antigen- (bacteria, viruses, fungi) and cytokine-driven impact on T-cell populations in GPA. Concomitant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) - positivity was associated with a significant increase in the percentage of CD28- T-cells in GPA-patients compared to sole CMV- or EBV-positivity or CMV- and EBV-negativity. T-cells specific for other viruses (influenza A virus, metapneumovirus, respiratory syncytial virus) and the autoantigen proteinase 3 (PR3) were infrequently detected in GPA. Antigen-specific T-cells were not specifically enriched in any of the T-cell subsets. Altogether, on a genetic and cellular basis, here we show that alterations of the peripheral T-cell compartment are driven by inflammation and various environmental factors including concomitant CMV and EBV infection. Our study provides novel insights into mechanisms driving autoimmune disease and on potential therapeutic targets.
自身免疫性疾病是由易感遗传和环境因素共同作用引起的，导致自我持续的慢性炎症和组织损伤。自身抗体的产生和效应和调节性 T 细胞的失衡是自身免疫失调的标志。虽然循环效应记忆 T 细胞的扩增与疾病的发病机制和进展有关，但迄今为止，导致外周 T 细胞区室改变的原因仍知之甚少。在肉芽肿性多血管炎 (GPA) 中，我们首次采用表型、T 细胞群体转录组和功能分析相结合的方法，评估记忆 T 细胞扩增的触发因素。更详细地说，我们发现 GPA 患者循环 CD4+CD28-、CD8+CD28-和 CD4+CD161+单阳性和 CD4+CD8+双阳性 T 细胞的百分比增加。对分选 T 细胞群体的转录组分析显示，GPA 与健康对照组之间存在主要差异，反映了抗原（细菌、病毒、真菌）和细胞因子对 GPA 中 T 细胞群体的影响。同时的巨细胞病毒 (CMV) 和 Epstein-Barr 病毒 (EBV) 阳性与 GPA 患者 CD28-T 细胞百分比的显著增加相关，与单独的 CMV 或 EBV 阳性或 CMV 和 EBV 阴性相比。针对其他病毒（甲型流感病毒、副流感病毒、呼吸道合胞病毒）和自身抗原蛋白酶 3 (PR3) 的 T 细胞在 GPA 中很少被检测到。抗原特异性 T 细胞没有在任何 T 细胞亚群中特异性富集。总之，在遗传和细胞基础上，我们在这里表明，外周 T 细胞区室的改变是由炎症和各种环境因素驱动的，包括同时的 CMV 和 EBV 感染。我们的研究为驱动自身免疫性疾病的机制和潜在的治疗靶点提供了新的见解。
