Division of Rheumatology, Department of Medicine.
Division of Neuroimmunology, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Rheumatology (Oxford). 2020 Jul 1;59(7):1651-1661. doi: 10.1093/rheumatology/kez509.
Infections have been suggested in the pathogenesis of primary SS (pSS). Systematic studies of immune responses to microbial antigens in vivo may be performed during vaccination. In the present study, we therefore longitudinally followed patients with pSS and controls during split-virion influenza vaccination to identify pSS-specific cellular, transcriptomic and serological responses.
Patients without treatment (pSSUntr, n = 17), on hydroxychloroquine-treatment (pSSHCQ, n = 8), and healthy controls (n = 16) were included. Antibody titres were determined by ELISA. Plasma proteins were measured by proximity extension assay. Monocyte gene expression was assessed by Nanostring. Routine laboratory tests were performed and clinical disease symptoms were registered by questionnaires.
pSSUntr developed higher vaccine-specific IgG titres compared with controls. Notably, anti-Ro52 autoantibody titres increased in pSSUntr but remained unchanged in pSSHCQ. No changes in disease symptoms including EULAR Sjögren's Syndrome Patient Reported Index score were registered. Twenty-four hours after vaccination, the leucocyte count in pSSUntr decreased, with a concomitant increase of CCL7 in plasma. Transcriptomic analysis in monocytes revealed differential vaccination-related expression of the NEMO/IKBKG gene, and its higher induced expression in pSSUntr associated with higher serological vaccine responses. Moreover, titres of vaccine-specific antibodies were associated with higher vaccination-induced NF-κB signalling and higher steady-state IFN signatures in monocytes, and with the levels of several plasma proteins with soluble PD-1 displaying the strongest association.
We observed augmented innate and adaptive immune responses in pSS following viral antigen exposure suggesting an underlying hyper-responsiveness to immune challenges, supporting a role for infections driving the immunopathology and acting as environmental risk factor for pSS.
已有研究提示原发性干燥综合征（pSS）的发病机制与感染有关。在疫苗接种期间，可进行针对体内微生物抗原的免疫反应的系统研究。因此，本研究通过对 pSS 患者和对照者进行流感病毒亚单位疫苗接种的纵向随访，以确定 pSS 特异性的细胞、转录组和血清学反应。
纳入未经治疗（pSSUntr，n=17）、接受羟氯喹治疗（pSSHCQ，n=8）的患者和健康对照者（n=16）。通过 ELISA 测定抗体滴度，通过邻近延伸分析（proximity extension assay）测定血浆蛋白，通过 Nanostring 评估单核细胞基因表达。进行常规实验室检查，并通过问卷登记临床疾病症状。
pSSUntr 产生了更高的疫苗特异性 IgG 滴度，与对照组相比。值得注意的是，pSSUntr 中的抗 Ro52 自身抗体滴度增加，但 pSSHCQ 中不变。未登记疾病症状的变化，包括 EULAR 干燥综合征患者报告指数评分。接种后 24 小时，pSSUntr 的白细胞计数下降，同时血浆中 CCL7 增加。单核细胞转录组分析显示，NEMO/IKBKG 基因的疫苗相关表达存在差异，其在 pSSUntr 中的诱导表达更高与更高的血清疫苗反应相关。此外，疫苗特异性抗体的滴度与接种诱导的 NF-κB 信号的增加以及单核细胞中 IFN 特征的稳态增加相关，并且与几种具有可溶性 PD-1 的血浆蛋白的水平具有最强的相关性。
我们观察到 pSS 在病毒抗原暴露后先天和适应性免疫反应增强，提示其对免疫挑战存在潜在的高反应性，支持感染在驱动免疫病理学方面的作用，并作为 pSS 的环境风险因素。
