Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
J Neuroimmunol. 2019 Apr 15;329:14-19. doi: 10.1016/j.jneuroim.2018.06.017. Epub 2018 Jun 30.
Helicobacter pylori (H. pylori) colonize >50% of the entire human population. Generally, H. pylori infect the human stomach in infancy when parietal cells secreting gastric acids, which reduce the survival of H. pylori, are not well matured. Once acquired, the bacterium persists for life. Thus, H. pylori infection reflects sanitary conditions during childhood. >10 studies performed in various Eastern and Western countries as well as two meta-analyses collectively indicated the H. pylori infection rate is significantly lower in patients with multiple sclerosis (MS) than in healthy controls. Thus, the bacterium might be a protective factor for MS, especially in low prevalence countries and younger generations that grew up in the low prevalence era. The protective effects of H. pylori might be explained by the hygiene hypothesis-encountering generic infection early in life facilitates development of the immunoregulatory system, which suppresses overactivity of autoimmune T cells later in life. However, no influence of common childhood infections on MS risk was reported by large MS cohort studies. Direct attenuation of autoreactive Th1 and Th17 cells by H. pylori infection was found in experimental autoimmune encephalomyelitis, an animal model of MS. These observations may underscore the direct protective effects of H. pylori on MS rather than generic infection in childhood. By contrast, several studies reported that H. pylori infection rates are significantly higher in anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) than in healthy controls. H. pylori strongly activate Th17 cells via the induction of IL-23, resulting in neutrophil mobilization and activation. H. pylori neutrophil-activating protein (NAP) is a major proinflammatory protein responsible for the pathology of H. pylori-related gastric inflammatory diseases. Anti-H. pylori-NAP antibody levels were positively correlated with final EDSS scores and myeloperoxidase levels in anti-AQP4 antibody-positive NMOSD patients. Given that spinal cord lesions of NMOSD are heavily infiltrated with myeloperoxidase-positive neutrophils, H. pylori-NAP, which can be absorbed and presented to the host immune system, may exacerbate NMOSD. Thus, H. pylori infection and its proinflammatory proteins, such as NAP, may contribute to the pathology of anti-AQP4 antibody-related neural damage, by activating neutrophils. It is interesting that two representative demyelinating diseases of the central nervous system are differentially modulated by chronic H. pylori infection. The direct effects of H. pylori infection on MS and NMOSD warrant future studies.
幽门螺杆菌（H. pylori）定植于超过 50%的全人类。通常，当胃酸分泌的壁细胞尚未成熟时，H. pylori 会在婴儿时期感染人类胃部。一旦被感染，这种细菌就会终生存在。因此，H. pylori 感染反映了儿童时期的卫生条件。在不同的东方和西方国家进行的 10 多项研究以及两项荟萃分析表明，多发性硬化症（MS）患者的 H. pylori 感染率明显低于健康对照组。因此，这种细菌可能是 MS 的保护因素，尤其是在低流行率国家和在低流行率时代成长起来的年轻一代。H. pylori 的保护作用可以用卫生假说来解释——在生命早期接触普通感染有助于免疫调节系统的发展，从而抑制生命后期自身免疫性 T 细胞的过度活跃。然而，大型 MS 队列研究并未报道常见儿童感染对 MS 风险的影响。在多发性硬化症的动物模型——实验性自身免疫性脑脊髓炎中，发现 H. pylori 感染直接抑制了自身反应性 Th1 和 Th17 细胞。这些观察结果可能强调了 H. pylori 对 MS 的直接保护作用，而不是儿童时期的普通感染。相比之下，几项研究报道，抗水通道蛋白 4（AQP4）抗体阳性视神经脊髓炎谱系障碍（NMOSD）患者的 H. pylori 感染率明显高于健康对照组。H. pylori 通过诱导 IL-23 强烈激活 Th17 细胞，导致中性粒细胞的动员和激活。H. pylori 中性粒细胞激活蛋白（NAP）是一种主要的促炎蛋白，负责 H. pylori 相关胃炎症性疾病的病理学。抗 H. pylori-NAP 抗体水平与抗 AQP4 抗体阳性 NMOSD 患者的最终 EDSS 评分和髓过氧化物酶水平呈正相关。鉴于 NMOSD 的脊髓病变严重浸润髓过氧化物酶阳性中性粒细胞，因此可以被吸收并呈递给宿主免疫系统的 H. pylori-NAP 可能会加重 NMOSD。因此，H. pylori 感染及其促炎蛋白，如 NAP，可能通过激活中性粒细胞，导致抗 AQP4 抗体相关神经损伤的病理学发生。有趣的是，中枢神经系统的两种代表性脱髓鞘疾病受慢性 H. pylori 感染的不同调节。H. pylori 感染对 MS 和 NMOSD 的直接影响值得进一步研究。
