Helicobacter Pylori Infection Might be a Potential Protective Factor against Classic Multiple Sclerosis in Guilan, Iran

DOI: 10.9734/ARRB/2014/9832 Editor(s): (1) George Perry, Dean and Professor of Biology, University of Texas at San Antonio, USA. Reviewers: (1) Anonymous, Nemours Bio Medical research,USA. (2) Anonymous, Kecioren Training and Research Hospital, Turkey. (3) Anonymous, Zhengzhou University, China. (4) Anonymous, Belgian Charcot Foundation, Belgium. (5) Anonymous, Louisiana State University, USA. Peer review History: http://www.sciencedomain.org/review-history.php?iid=582&id=32&aid=5858


INTRODUCTION
Multiple Sclerosis is an inflammatory demyelinating disease of the Central Nervous System (CNS). It seems that environmental and genetic factors are the predominant risk-determining elements and many other factors must be considered [1].
Most commonly H. pylori colonize the gastric mucosa in early childhood and can persist throughout life, if no antibiotic therapy is given. Its worldwide prevalence is variable, with highest prevalence in areas with overcrowding and poor sanitation. The outcome of H. pylori infection is dependent on host, environmental and bacterial factors [2,3]. This bacterium has been associated with many intestinal and extra intestinal diseases. A high H. pylori seroprevalance has been reported in different neurological disorders including cerebrovascular diseases, migraine, Alzheimer's disease, epilepsy, Parkinson's disease, multiple sclerosis [4]. Persistent Helicobacter pylori (H. pylori) infection is a chronic inflammatory stimulus to hosts with an inverse correlation to atopic disorders. H. pylori infection has been linked to multiple sclerosis (MS) and demyelinating peripheral neuropathies as it can trigger cellular and humoral immunity due to the sharing of similar epitopes present in the nervous tissue [5][6]. These antibodies cross-react with different components of central and peripheral nerves resulting in their damage [5,6]. Many other factors like platelet activation and aggregation; different vasoactive and inflammatory substances, stimulation of mononuclear cells to produce different tissue factor -like procoagulants, reactive oxygen species, and apoptotic processes may be important factors in the association of H. pylori infection with MS and peripheral neuropathies like Guillain-Barre syndrome [5,6].
In this cross sectional prospective study we attempted to determine the seroprevalence of anti-H. pylori antibodies (IgG and IgA) in sera of study group (patients with MS) comparing to control group to determine the role of H. pylori infection in pathogenesis of MS.

MATERIALS AND METHODS
This study is a analytical cross sectional one which was conducted with all clinical samples from MS patients who were under supervision of MS society of Guilan province, Northern Iran and also, healthy blood donors (they were matched with patients based on age and gender) who voluntarily submitted for Pars medical laboratory of Rasht, Iran for 8 months from April, 2012 to Dec, 2012. MS patients were diagnosed with magnetic resonance imaging (MRI) and Evoked Potential (EP) and also McDonald criteria were recruited. Serum samples were collected by standard methods. All Specimens were stored at -70ºC until the experiment was performed. Some demographical and other required data were collected by filling a questionnaire including: age, Gender, duration of the disease, number of crisis, duration of interferon intake, score of EDSS, result of MRI, result of Evoked Potential test and type of antiviral therapy(if prescribed).
A group of 46 subjects with classic multiple sclerosis (CMS) along with 46 healthy controls were examined with the serological test for the presence of antibodies against Helicobacter pylori surface antigen. Patients who were residents of the area (more than 6 months) with age range of 10-50 years had classic MS (not opticospinal MS) confirmed by MRI and Evoked Potential test. All patients were under supervision of MS society of Guilan.
Serological test was performed using commercial ELISA Tests (Anti H. Pylori IgG and Anti H. Pylori IgA kits, Euroimmune, Germany). Titers>100 Ru/ml were considered as high titer, Titers from 51 to 100Ru/ml were considered medium titer and titers lower than 50Ru/ml were considered low titer.
The Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA), version 16 was used for statistical analysis. Chi square and Spearman's rho correlation tests were applied to analyze all variables. All P-values were two-tailed and significant at P<0.05.
The study conformed to the Helsinki declaration and was reviewed and approved by the local research committee, it was approved by ethics committee, and written informed consent was obtained from all subjects and control group. We did not encounter important limitations in this study but taking samples that took a long time.

RESULTS AND DISCUSSION
Average age of patients (n=46) was 32 years with min-max 28-38(average 32.8%). Most patients were women (71.4%). Most individuals in study group had Expanded Disability Status Scale (EDSS) between 2.5 and 3.5(45.2%) and 28.6% of them had EDSS score lower than 2.5. Evoked potential test and MRI were positive in all study group.
About 33.3% of Patients had seropositivity to H. pylori IgG (16.8% with high titer, 9.6% with medium and 6.9% with low titers). Seropositivity rate to H. pylori IgG in control group was more than that in patients (67.4% versus 33.3%) (Fig. 1) and this difference was significant (Chi-Square=9.889 and P Chi-Square =0.002, correlation coefficient=-0.341 and P Spearman's rho correlation (Sig. 2-tailed) = 0.001) and odd. Ratio= 0.297 (Table 1). Frequency of high titer seropositivity to IgG in control group was also more than that in patients (46.5% versus 16.8%) (Fig. 1) and this difference was also significant (Chi-Square=9.668 and P Chi-Square =0.004, correlation coefficient=-0.323 and P Spearman's rho correlation (Sig. 2-tailed) = 0.002 and odd. Ratio= 0.255. Seropositivity with medium and lower titer to H. pylori IgG in control group was also more frequent than that in patients (11.5% versus 9.6% and 9.4% versus 6.9% consequently). H. pylori have extensive interactions with the immune system. Their role as a causative agent of autoimmune diseases in genetically susceptible host has been studied and it has been associated with a variety of autoimmune disorders [4].
H. pylori have acquired several unique attributes helping them escape clearance through the normal immune mechanisms [4]. This prolonged coexistence of H. pylori in human raises the possibility of a rather symbiotic relationship in which its persistence may at least in part be beneficial to humans [4].
There are some recent data suggestive of a protective effect of H. pylori against autoimmune and allergic diseases. A recent meta-analysis suggested a protective role of H. pylori in inflammatory bowel disease [7]. An inverse relationship between H. pylori infection and allergic conditions is also reported. Rate of asthma was found to be lower in children who were H. pylori positive when compared with those who were H. pylori negative [8]. In a Japanese cohort an inverse association of H. pylori seropositivity and MS was reported [9]. Based on a recent review of literature, it is concluded that in most autoimmune diseases the role of H. pylori remains inconclusive [10].
It seems that some viral and bacterial infections can precipitate, worsen or protect patients from MS [11,12] . It is a new hypothesis that some environmental factors might be suspected to have protective effects for MS. Some chronic infections such as Helicobacter pylori can modulate the immune system to prevent its hyperactivity causing allergies and autoimmune disorders. Results of three studies in Japan like the present study demonstrated that H. pylori infection had protective effects on MS [13][14][15]. Prevalence of H. pylori infection in developing countries is more than in developed ones, and it may reach 80% in some countries [16,17] but incidence rate of MS is lower. There are some descriptions that explain why allergic and autoimmune diseases are more prevalent in wealthy countries.
There are increasing evidences that H. Pylori can play a protective role in the development of multiple sclerosis, systemic lupus erythematosus and inflammatory bowel disease.
Ram M et al. tested various links between anti-H. pylori antibodies and a wide profile of autoimmune diseases and auto antibodies. In their study a total of 1290 patients diagnosed with 14 different autoimmune diseases from two geographical areas (Europe and Latin America) and two groups of healthy matching controls (n=385) were screened for the presence of H. pylori IgG antibodies. They reported that H. pylori does not play a causative role in the autoimmune diseases and the negative associations could possibly support the notion that in susceptible individuals, infections may protect them from the development of autoimmune diseases [4]. We found that frequency of IgG seropositivity and high titer of H. pylori IgG was significantly more in controls than that it was in patients, indicating that people who were more immune to H. pylori were less vulnerable to be affected with MS. We also found that frequency of IgA seropositivity and high titer of H. pylori IgA was significantly more in controls than that it was in patients, indicating that people who had chronic or persistent H. pylori infection were more protected against MS. Our findings are in consistent with other similar studies which are described as follow.   [20]. Mohebi et al. observed a Significant difference in seropositivity between these two groups (P<0.001) but no significant difference was seen in seropositivity between conventional and opticospinal MS (P=0.522) [21]. Like our study they found no significant difference in seropositivity among ages (P=0.075) and between genders (P=0.204). A significant difference was seen in EDSS value between seropositive and seronegative patients (P=0.017). They concluded that patients with H. pylori infection had lower incidence of multiple sclerosis and MS patients with H. pylori infection showed lower neurologic complications, which could demonstrate that H. pylori infection might have a protective influence on MS pathogenesis. That study was performed in the same country as we did but in two different region and it was the most current study which showed compatible results.

CONCLUSION
H. pylori seropositivity to IgG and IgA showed a significant inverse association with prevalence of MS. Findings of this study suggest that H. pylori infection is not a causative factor but might be a protective factor against classic MS. We suggest further studies for the association of H. pylori with MS and for more extensive understanding of H. pylori neurotropism and its association with the disease process and also more similar studies with higher sample sizes are recommended.