Melén Krister, Jalkanen Pinja, Kukkonen Jyrki P, Partinen Markku, Nohynek Hanna, Vuorela Arja, Vaarala Outi, Freitag Tobias L, Meri Seppo, Julkunen Ilkka
Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland.
Expert Microbiology Unit, Finnish Institute for Health and Welfare, Mannerheimintie 166, 00300, Helsinki, Finland.
J Transl Autoimmun. 2020 May 1;3:100055. doi: 10.1016/j.jtauto.2020.100055. eCollection 2020.
Narcolepsy type 1, likely an immune-mediated disease, is characterized by excessive daytime sleepiness and cataplexy. The disease is strongly associated with human leukocyte antigen (HLA) DQB1∗06:02. A significant increase in the incidence of childhood and adolescent narcolepsy was observed after a vaccination campaign with AS03-adjuvanted Pandemrix influenza vaccine in Nordic and several other countries in 2010 and 2011. Previously, it has been suggested that a surface-exposed region of influenza A nucleoprotein, a structural component of the Pandemrix vaccine, shares amino acid residues with the first extracellular domain of the human OX orexin/hypocretin receptor eliciting the development of autoantibodies. Here, we analyzed, whether H1N1pdm09 infection or Pandemrix vaccination contributed to the development of autoantibodies to the orexin precursor protein or the OX or OX receptors. The analysis was based on the presence or absence of autoantibody responses against analyzed proteins. Entire OX and OX receptors or just their extracellular N-termini were transiently expressed in HuH7 cells to determine specific antibody responses in human sera. Based on our immunofluorescence analysis, none of the 56 Pandemrix-vaccinated narcoleptic patients, 28 patients who suffered from a laboratory-confirmed H1N1pdm09 infection or 19 Pandemrix-vaccinated controls showed specific autoantibody responses to prepro-orexin, orexin receptors or the isolated extracellular N-termini of orexin receptors. We also did not find any evidence for cell-mediated immunity against the N-terminal epitopes of OX. Our findings do not support the hypothesis that the surface-exposed region of the influenza nucleoprotein A would elicit the development of an immune response against orexin receptors.
1型发作性睡病可能是一种免疫介导的疾病，其特征为日间过度嗜睡和猝倒。该疾病与人类白细胞抗原（HLA）DQB1∗06:02密切相关。2010年和2011年，北欧及其他几个国家开展了使用AS03佐剂的帕兰朵（Pandemrix）流感疫苗的接种活动后，儿童和青少年发作性睡病的发病率显著上升。此前有人提出，帕兰朵疫苗的一种结构成分甲型流感核蛋白的一个表面暴露区域与人类食欲素/下丘脑泌素受体的第一个细胞外结构域具有相同的氨基酸残基，从而引发自身抗体的产生。在此，我们分析了H1N1pdm09感染或帕兰朵疫苗接种是否会导致针对食欲素前体蛋白或食欲素受体OX1或OX2受体产生自身抗体。该分析基于针对所分析蛋白质的自身抗体反应的有无。将完整的OX1和OX2受体或仅其细胞外N端在HuH7细胞中瞬时表达，以确定人血清中的特异性抗体反应。基于我们的免疫荧光分析，56名接种帕兰朵疫苗的发作性睡病患者、28名实验室确诊感染H1N1pdm09的患者或19名接种帕兰朵疫苗的对照者中，均未显示出针对前食欲素原、食欲素受体或食欲素受体分离的细胞外N端的特异性自身抗体反应。我们也未发现任何针对OX1 N端表位的细胞介导免疫的证据。我们的研究结果不支持流感核蛋白A的表面暴露区域会引发针对食欲素受体的免疫反应这一假说。
