在瑞典嗜睡症病例中，增加了β-溶血性 A 组链球菌 M6 血清型和链道酶 B 特异性细胞免疫反应。
Increased β-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases.
机构信息
Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Centre for Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
出版信息
J Intern Med. 2015 Sep;278(3):264-76. doi: 10.1111/joim.12355. Epub 2015 Mar 22.
BACKGROUND
Type 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin-positive neurons.
OBJECTIVE
The aim of this study was to investigate potential aetiological factors in Swedish cases of postvaccination (Pandemrix) narcolepsy defined by interferon-gamma (IFNγ) production from immune cells in response to molecularly defined targets.
METHODS
Cellular reactivity defined by IFNγ production was examined in blood from 38 (HLA-DQB106:02(+) ) Pandemrix-vaccinated narcolepsy cases and 76 (23 HLA-DQB106:02(+) and 53 HLA-DQB1*06:02(-) ) control subjects, matched for age, sex and exposure, using a variety of different antigens: β-haemolytic group A streptococcal (GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X-179A and A/H1N1/California/7/09 NYMC X-181 vaccine antigens, previous Flu-A and -B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), noninfluenza viral targets (CMVpp65, EBNA-1 and EBNA-3) and auto-antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue).
RESULTS
IFN-γ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 (P = 0.0065) and streptodornase B protein (P = 0.0050). T-cell recognition of M6 and streptodornase B was confirmed at the single-cell level by intracellular cytokine (IL-2, IFNγ, tumour necrosis factor-alpha and IL-17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly, higher (P = 0.02) titres of serum antistreptolysin O were observed in narcolepsy cases, compared to vaccinated controls.
CONCLUSION
β-haemolytic GAS may be involved in triggering autoimmune responses in patients who developed narcolepsy symptoms after vaccination with Pandemrix in Sweden, characterized by a Streptococcus pyogenes M-type-specific IFN-γ cellular immune response.
背景
1 型发作性睡病是一种以日间过度嗜睡和猝倒为特征的神经疾病，与 HLA 等位基因 DQB1*06:02 相关。遗传易感性和外部触发因素可能会引发自身免疫反应，最终导致下丘脑分泌素阳性神经元的选择性丧失。
目的
本研究旨在调查瑞典接种后（Pandemrix）发作性睡病病例中潜在的病因因素，这些病例通过免疫细胞对分子定义的靶标产生干扰素-γ（IFNγ）来定义。
方法
使用各种不同的抗原（β-溶血性 A 组链球菌（GAS）抗原（M5、M6 和链道酶 B）、流感（大流行性 A/H1N1/加利福尼亚/7/09 NYMC X-179A 和 A/H1N1/加利福尼亚/7/09 NYMC X-181 疫苗抗原、以前的 Flu-A 和 -B 疫苗靶标、A/H1N1/Brisbane/59/2007、A/H1N1/Solomon Islands/3/2006、A/H3N2/Uruguay/716/2007、A/H3N2/Wisconsin/67/2005、A/H5N1/Vietnam/1203/2004 和 B/Malaysia/2506/2004）、非流感病毒靶标（CMVpp65、EBNA-1 和 EBNA-3）和自身抗原（下丘脑分泌素肽、Tribbles 同源物 2 肽混合物和大鼠下丘脑组织提取物），检测了 38 例（HLA-DQB106:02(+)）接种了 Pandemrix 的发作性睡病病例和 76 例（23 例 HLA-DQB106:02(+)和 53 例 HLA-DQB1*06:02(-)）对照者的血液中由 IFNγ 产生定义的细胞反应。
结果
与接种疫苗的对照组相比，在对链球菌血清型 M6（P=0.0065）和链道酶 B 蛋白（P=0.0050）作出反应时，发作性睡病患者的全血中 IFN-γ 的产生显著增加。通过用合成的 M6 或链道酶 B 肽刺激后，在单细胞水平上通过细胞内细胞因子（IL-2、IFNγ、肿瘤坏死因子-α和 IL-17）的产生证实了 T 细胞对 M6 和链道酶 B 的识别。值得注意的是，与接种疫苗的对照组相比，发作性睡病患者的血清抗链球菌溶血素 O 滴度明显更高（P=0.02）。
结论
β-溶血性 GAS 可能参与了瑞典接种 Pandemrix 后出现发作性睡病症状的患者的自身免疫反应的触发，其特征是存在针对链球菌 M 型的特异性 IFN-γ 细胞免疫反应。
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