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Editorial commentary

Helicobacter pylori infection might prove the hygiene hypothesis in multiple sclerosis Jun-ichi Kira In many developed countries, the incidence of autoimmune diseases and allergic/atopic disorders are rapidly increasing. The former is regarded as a T helper (Th) 1/Th17 disease while the latter is considered a Th2 disease. It is curious that the incidence of Th1/Th17 and Th2 diseases have increased simultaneously, given that Th1/Th17 cells and Th2 cells counteract each other. This inconsistency is explained by the ‘hygiene hypothesis’.1 Frequent infections in poor sanitary conditions may facilitate the development of the immune effector and immune regulatory systems. Overactivation of effector lymphocytes, macrophages and neutrophils during infection should be removed rapidly once infectious pathogens are eradicated; otherwise, these immune cells can cause bystander destruction of the neighbouring uninfected tissues. As a result, repeated infection might shape immune regulatory systems. The underdevelopment of immune regulatory systems because of infrequent infections during early life might prevent activated Th1/Th17 cells and Th2 cells from being controlled, resulting in the increased frequency of autoimmune diseases and allergic/atopic diseases later in life.1 Multiple sclerosis (MS) is assumed to be an autoimmune disease targeting central nervous system (CNS) myelin, whose pathogenesis is thought to involve a complex interplay between genes and the environment. The prevalence of MS has increased worldwide in tandem with a modern lifestyle, as seen for other autoimmune diseases. However, the cause for such an increase in MS prevalence is illdefined. Epidemiological studies have directly or indirectly shown that frequent childhood infection decreases MS risk.2 3 For example, the observation that dwelling with younger siblings during early life significantly decreased MS occurrence, later in life,3 is explained by the ‘hygiene Correspondence to Dr Jun-ichi Kira, Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; [email protected]

hypothesis’; that is, exposure to infant siblings can increase the opportunity to encounter infection during early life leading to a robust development of the immune regulatory system that can suppress immune effector responses such as those mediated by Th1/Th17 cells. Helicobacter pylori are Gram-negative microaerophilic bacteria that reside in the stomachs of more than half of the entire human population.4 H. pylori infection occurs mainly before 2 years of age when the parietal cells, secreting gastric acids that hamper the survival of H. pylori, are not well maturated.5 Once infected, the H. pylori infection persists lifelong. Therefore, the frequency of H. pylori infection reflects an individual’s environment during childhood; low sanitary conditions have a higher likelihood of increasing the prevalence of H. pylori antibody seropositivity in the populations. Individuals infected with H. pylori were reported to be 30% less likely to have concomitant allergic/atopic diseases.6 This protective effect of H. pylori infection against allergy might be explained by exposure to generic pathogens, rather than a specific infection. Bacterial infection can augment Th1/Th17 responses while dampening the Th2 response. Therefore, the Th1 (Th17)/Th2 paradigm might explain the low prevalence of allergy in people from an area with a high frequency of H. pylori infection. However, this seems to be an oversimplification because Th1/Th17 type autoimmune diseases, such as rheumatoid arthritis, Crohn’s disease, and type 1 diabetes mellitus, have a higher incidence in patients with airway allergy.7 8 In developed countries with good sanitation, the incidence of allergic disorders and autoimmune diseases have increased in parallel, which cannot simply be explained by the Th1 (Th17)/Th2 paradigm, but might be explained by the ‘hygiene hypothesis’. H. pylori seropositivity rates have repeatedly been shown to be lower in MS than in healthy controls in Japan,9–13 where a rapid increase of MS prevalence has been observed.14 By contrast, there was no correlation or positive correlation

with H. pylori infection in other nations.15 In their JNNP paper, Pedrini et al16 report that H. pylori seropositivity was significantly lower in female patients with MS than in female healthy controls, while no such trend was found in male patients with MS. Interestingly, H. pylori seropositivity was significantly associated with lower disability scores in female patients with MS only, suggesting a protective effect of H. pylori infection. Collectively, such an inverse correlation of H. pylori infection with MS in developed countries, where MS and allergic disorders have increased, may support the ‘hygiene hypothesis’. Although why the protective effects of H. pylori against MS were observed in women only remains to be elucidated, but might explain the recent increase of female–male ratio of MS in developed countries. By contrast, chronic bacterial infections including H. pylori might be associated with antiaquaporin 4 (AQP4) antibody-positive neuromyelitis optica,12 17 in which Th17 and Th1 cytokines are elevated in the cerebrospinal fluid during relapse.18 19 It is interesting to note that chronic bacterial infection may differentially relate to human CNS demyelinating disorders. In addition, a recent genome-wide association study revealed that some genetic risk factors for MS are involved in the development of regulatory T cells. The CC genotype of the interleukin 7 receptor α chain (IL-7RA) rs6897932 single nucleotide polymorphism decreases the production of Foxp3+ regulatory T cells.20 Regulatory T cell dysfunction may be critical for the development of MS. It is therefore important to examine whether the number and function of regulatory T cells and other immune-regulatory cells is varied according to H. pylori serostatus in patients with MS, to further strengthen the ‘hygiene hypothesis’ in MS. Competing interests J-iK is a consultant for Biogen Idec Japan, and has received honoraria from Bayer Healthcare and funding for a trip from Bayer Healthcare and Biogen Idec Japan. He is funded by a research grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare, Japan, and grants from the Japan Science and Technology Agency and the Ministry of Education, Culture, Sports, Science and Technology, Japan. Provenance and peer review Commissioned; internally peer reviewed.

To cite Kira Jun-ichi. J Neurol Neurosurg Psychiatry 2015;86:591–592.

Kira Jun-ichi. J Neurol Neurosurg Psychiatry June 2015 Vol 86 No 6

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Editorial commentary Received 27 November 2014 Accepted 30 November 2014 Published Online First 19 January 2015

▸ http://dx.doi.org/10.1136/jnnp-2014-309495 J Neurol Neurosurg Psychiatry 2015;86:591–592. doi:10.1136/jnnp-2014-309759

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Kira Jun-ichi. J Neurol Neurosurg Psychiatry June 2015 Vol 86 No 6

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Helicobacter pylori infection might prove the hygiene hypothesis in multiple sclerosis Jun-ichi Kira J Neurol Neurosurg Psychiatry 2015 86: 591-592 originally published online January 19, 2015

doi: 10.1136/jnnp-2014-309759 Updated information and services can be found at: http://jnnp.bmj.com/content/86/6/591

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Supplementary Supplementary material can be found at: Material http://jnnp.bmj.com/content/suppl/2015/01/20/jnnp-2014-309759.DC1. html

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Helicobacter pylori infection might prove the hygiene hypothesis in multiple sclerosis.

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