甲型 H1N1 流感增强型 T 细胞表位识别和对潘那利珠单抗相关 1 型发作性睡病蛋白-O-甘露糖基转移酶 1 的交叉反应性
Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1.
机构信息
Clinicum, University of Helsinki, Helsinki, Finland.
Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
出版信息
Nat Commun. 2021 Apr 16;12(1):2283. doi: 10.1038/s41467-021-22637-8.
Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175-189 (NA) and nucleoprotein 214-228 (NP), but also respond to a NA-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA or POMT1. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.
发作性睡病 1 型(NT1)是一种慢性神经疾病,与 HLA-DQB1*0602 强烈相关,提示其具有免疫起源。接种含 AS03 佐剂的季节性 H1N1 流感 A 疫苗(Pandemrix)的儿童或青少年中,NT1 的风险增加。我们在此表明,与儿科 Pandemrix 相关的 NT1 患者对病毒表位、神经氨酸酶 175-189(NA)和核蛋白 214-228(NP)具有增强的 T 细胞免疫,但也对 NA 模拟物、脑自身表位、蛋白-O-甘露糖基转移酶 1(POMT1)产生反应。流感病毒特异性 T 细胞的致病作用和 T 细胞交叉反应性在 NT1 中得到支持,表现为 IFN-γ、穿孔素 1 和颗粒酶 B 的上调,以及 TRAV10/TRAJ17 和 TRAV10/TRAJ24 T 细胞受体克隆型的趋同选择,对肽 NA 或 POMT1 的刺激均有反应。此外,接种 Pandemrix 的儿童或青少年的抗 POMT1 血清自身抗体增加。这些结果因此确定 POMT1 是 NT1 中 T 细胞和 B 细胞识别的潜在自身抗原。