There is some scientific controversial evidence in support or against the role of HP as a potential trigger of a great variety of autoimmune diseases, including various neurological disorders of the central nervous system, such as MS [23].
Autoimmune diseases result from environmental exposures to bacteria, viruses and parasites in addition to genetic susceptibility [23,24,25]. There are several mechanisms triggered by infectious agents involved in the development of autoimmune diseases: T-regulatory imbalance, molecular mimicry, bystander effect, high levels of proinflammatory cytokines, epitope spreading, direct inflammatory damage, microbial super antigens, MHC class II expression on non-immune cells and immune complex formation [23, 26,27,28].
HP presents itself as a prevalent microbe, according to the medical literature it is present in 50–80% of the population worldwide being clinically implicated in gastritis, peptic ulcers, and appears as an independent risk factor for gastric carcinoma [29, 30]. Although many studies point out the fact that persistent HP infection represents a chronic inflammatory stimulus and could be a potential cause of the MS pathogenesis [29, 31, 32]. Despite the scientific evidence shown so far, the relationship between these two entities has not been clear.
In general population, HP seroprevalence determined by IgG anti-HP titles ranges between 30 and 50% in high income countries (HIC) and between 85 and 95% in low- and middle-income countries (LMIC) [33, 34], The findings of the present study showed a low prevalence of IgG (14%), IgM (8.3%) and IgA (18%) HP antibodies in pwMS, these data differ from the worldwide prevalence and with a study by Long et al. [27] in which they report the presence of HP antibodies in 73% of the pwMS analyzed.
There are some other reports in which they found significative association between HP and MS, as seen in a study by Mohebi et al. [35]. They analyzed blood samples for IgG and IgM anti HP antibodies, but there was no significant difference in seropositivity with respect to age nor sex. In spite of these findings, they report a significant difference in EDSS value between seropositivity and seronegativity, concluding that HP infection could have a protective influence on MS pathogenesis [35]. This observation could be supported by our findings, since the prevalence of anti-HP antibodies in the cohort is substantially lower than that of the general population. Positive serology for anti-HP antibodies is higher in LMIC: In México, the prevalence of IgG anti-HP is 66–80%, figures that are higher than those found in this study, where most patients live in HIC [36]. Since the prevalence of MS is substantially higher in HIC as compared to LMIC [37], we could speculate that exposure to HP could be one of the possible explanations to this difference.
Since IgG against HP is the more used and accurate marker of previous exposure and none of the patients had significative titles of IgM and IgA nor clinical manifestations of HP infection at the moment of the study which indicates active infection, we decided to analyze IgG titles to compare seroprevalence of HP with the main demographic and clinical features in pwMS [34]. In contrast with the observations reported in the study by Mohebi et al. [35], we found significantly higher concentration of anti-HP IgG in SPMS in comparison with RRMS; however, we did not find significant association between seropositivity nor concentration of IgG against HP among inflammatory phenotype of MS, age, length of disease nor EDSS (Tables 2 and 3).
A meta-analysis performed by Yao et al. [3] addressed 9 prospective articles that included 1553 cases of MS, all these articles were case–control studies in which different diagnostic methods were employed to detect HP infection (ELISA, Western Blot, immunofluorescence and latex agglutination). They reported a lower prevalence of HP infection of almost 25% in patients with MS with no significant differences among the HP identification methods employed. The prevalence found by Yao et al. [3] is considerably higher to the observed prevalence reported in our study. The study reports important limitations such as the difficulty to distinguish previous and active infection employing serological tests and the lack of subgroup analysis of gender, MS phenotype and length of the disease [3]. This metanalysis concluded that HP infection and MS may have a negative correlation, but also suggests the existence of a potential protective factor against MS [3].
Some reports found a negative correlation on the laboratory method employed to the IgG anti HP detection [3], although other studies suggest high relevance on several specific IgG HP antigens which are important on the loss of immunological tolerance to myelin antigens particularly heat shock proteins (hsp), such as hsp60 and hsp70 [11]. In an Egyptian study Gerges et al. [11] reported a high correlation between anti HP hsp60 IgG level and SPMS and propose anti HP hsp60 IgG as a biomarker for progression of MS, being correlated to age and length of the disease in a moderate level and with EDSS in a strong level, moreover, low levels of HP infection in western countries.
However, these specific IgG antibodies have been poorly studied, partly because of the limited access and availability of these particular laboratory method in certain regions of the globe, being an issue that may represent a great disparity among studies which have tried to demonstrate a positive correlation with MS [11].
There are other recent studies that could support our results, such is the case of the study performed by Ranjbar et al. [38] in which authors determined the seroprevalence of HP in 387 pwMS vs 420 healthy subjects, which represents a larger patient cohort compared to other reports. The authors found a significantly lower seropositivity in pwMS than the healthy individuals, a lower EDSS in HP seropositive pwMS compared with seronegative pwMS, proinflammatory cytokines (IFN-y, TNF-a, IL-6, IL-7) significantly lower as compared to seronegative patients and increased levels of IL-4 and IL-10 compared to seronegative patients, concluding that HP infection has a negative correlation in MS and may act as a protective agent in MS [38]. The exact pathogenic mechanism remains unclear, although these findings could suggest that a poor HP exposition in persons predisposed to develop MS could trigger the onset and the clinical length of the disease.
Regarding the geographical location, we stratified the population according to the country of origin of all the pwMS detecting that the majority of them (99.3%) belongs to Western countries. This scenario made it impossible to perform a comparison between the eastern and western regions to contrast what was established in the current scientific literature. However, our data are consistent with the low prevalence in pwSM specially in Western countries reported in other studies and could support the hypothesis in which HP plays a role as a protective effect reducing the risk of MS [3, 38] (Fig. 2).
This study showed some limitations related to the heterogeneity of the sample: Since MS is a disease with higher latitudinal prevalence [39], all the patients included in the study and treated at our center were from different regions of the globe, in addition to these differences they coursed with aggressive and rapidly progressive forms of the disease. This scenario made it difficult to create a control group with homogeneous characteristics as compared with other studies in which authors analyzed pwMS from a single population. However, patients were studied, analyzed, and compared with the current scientific data.