Autoimmune extraintestinal manifestations of Helicobacter pylori infection : A bundle of conflicts

Introduction Helicobacter pylori chronically infects more than half of the world’s population and, one of the most frequent causes of gastrointestinal infections and it is estimated that the pathogen has co-evolved with its human host for at least 30.000 years (1-5). H. pylori infection fulfills each of Koch's postulates as an infectious agent inflicting chronic active gastritis and ulcer. It is related with a wide spectrum of gastrointestinal diseases, as well as gastroduodenal ulcers, mucosaassociated lymphatic tissue lymphoma (MALToma), and gastric adenocarcinoma. It is well-known that several microorganisms have an effect on particular region of the body might additionally have systemic sequelae like Campylobacter species Streptococcus pneumonia infections.


Introduction
Helicobacter pylori chronically infects more than half of the world's population and, one of the most frequent causes of gastrointestinal infections and it is estimated that the pathogen has co-evolved with its human host for at least 30.000 years (1)(2)(3)(4)(5).H. pylori infection fulfills each of Koch's postulates as an infectious agent inflicting chronic active gastritis and ulcer.It is related with a wide spectrum of gastrointestinal diseases, as well as gastroduodenal ulcers, mucosaassociated lymphatic tissue lymphoma (MALToma), and gastric adenocarcinoma.It is well-known that several microorganisms have an effect on particular region of the body might additionally have systemic sequelae like Campylobacter species Streptococcus pneumonia infections.Available online at www.jiacm.com

Helicobacter pylori, infections and possible pathophysiological mechanisms
The agent is a Gram-negative spiral shaped bacterium that has the unique ability to colonize the human gastric mucosa in spite of acid pH of the stomach.Virulence factors like urease enzyme and flagella are present in all infectious strains and are required for colonization of the gastric mucosa.The other major virulence factors associated with pathogenicity are: cytotoxin-associated gene A (CagA) and Vacuolating cytotoxin A (VacA) toxins (1).The cagA and s1/m1 vacA alleles have associated with a higher degree of gastric mucosal inflammation (6).H. pylori infection is one of the most common bacterial infections worldwide and its prevalence has been estimated to extend from 40 to 80% and it changes widely by geographic region, age, race, ethnicity, and socioeconomic factors (1)(2)(3).Gastroduodenal ulceration and carcinogenesis are exclusive results of this infection.Diversity in the clinic result of H. pylori-induced pathologies are multifactorial, involving a complex interplay between host immune responses and the pathogen virulence factors (1).Several mechanisms have been suggested in an effort to clarify the extraintestinal manifestations of H. pylori infections.One of them is; gastric vascular permeability increases during atrophic gastritis due to infection and might cause increased exposure to alimentary antigens.In addition, the gastric infection causes releasing of inflammatory mediators and molecular mimicry to systemic circulation.For example, antigastric autoantibodies have been found in more frequently in patients infected with H. pylori (7).After the gastric colonization by H. pylori, production of large amounts of various proinflammatory substances, like interleukins, eicosanoids, and several proteins of the acute phase occur (8).This inflammatory response may cause the development of Ag-Ab complexes or crossreactive antibodies due to molecular mimicry and may result in damage to other organs.Also, it has been suggested that H. pylori induces a remarkable development similar to that seen in the molecular mimicry between Streptococcus pyogenes antigens and host proteins, resulting in both humoral and cell mediated immunologic reactions and eventually causing rheumatic fever, arthritis and rheumatic heart disease (7).H. pylori infections bring out a remarkable immunomodulation, which are activated by chronic inflammation (9).Chronic infection results in a mainly Th1 response, resulting in the production of IL-2 and IFN-gamma as well as other inflammatory cytokines like TNF-α, IL-6, IL-10, and IL-8.(10).This chronic infection due to H. pylori can also cause anarchic growth and proliferation of CD5+ B lymphocytes that produce poly-and auto-reactive IgM and IgG3 antibodies (11).
Several studies have reported that Toll-like receptors (TLR) and Treg cells play roles in the immune pathogenesis of H. pylori infection and it is suggested in an experimental study there might be an interplay between TLR signaling and Treg cells which is significant for restricting H. pylori colonization and suppressing the inflammatory response (12).H. pylori have an ability of immunomodulatory effect.The immunomodulatory features of the bacterium reprogram the immune system towards immunological tolerance and help the bacteria in setting up a persistent infection (13).As a result, the products of the local immune responses could migrate to extra-gastric region and this might clarify the association between H. pylori infection and the diversity of extra gastric diseases, as well as autoimmune disorders (14).
In contrast, some epidemiological data suggests a protective effect of H. pylori infection against the development of various sicknesses with an autoimmune component.The proposed mechanism for this effect may define as H. pylori's ability to induce immune tolerance and restrict inflammatory processes (15).In view of these data, researchers have investigated the role of H. pylori as a pathogenic determinant for idiopathic extraintestinal diseases, in case of immune dysregulation.This paper reviews current literature on the role of H. pylori infection within the pathological process of extraintestinal diseases taking into account the recent literature.

Rheumatoid arthritis
Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disorder that causes irreversible joint deformities and functional impairment.As with many other connective tissue disorders, the etiopathology of RA is not clearly understood.A report from Turkey, Yula E. et al. ( 2016) researched active H. pylori infection rate and CagA virulence marker positivity in patients with various autoimmune diseases, including RA and SLE, and they suggested that in a similar manner to the some literature their first results recommended that active H. pylori infection rates are higher in patients with autoimmune diseases when compared with their routine laboratory data (16).Similarly, in a recent study, El-Hewala ASI, et al. ( 2015) was to assess the effect of H. pylori treatment on disease activity in patients with rheumatoid arthritis and the authors suggested that H. pylori treatment may induce a significant improvement of the disease activity over two months (17).On the other hand, a study of 1815 Japanese RA patients, 49.3% were reported to have H. pylori antibodies, which was lower compared with the healthy Japanese subjects (18).There are few data in the literature on this topic and the possible effect of H. pylori infection in the pathogenesis of RA remains controversial.

Parkinson's disease
Parkinson's disease is a chronic, progressive and degenerative disorder of the central nervous system and in most people is idiopathic.Recently, some studies have advised that chronic H. pylori infection may worsen the neurodegenerative process in Parkinson's disease.Tan et al. (2015) reported in a large cross-sectional study showed a link between H. pylori and worse Parkinson's disease motor severity (19).In addition, it has been suggested that eradication of H. pylori infection improves levodopa action, clinical symptoms and quality of life in patients with Parkinson's disease (20).Interestingly, Blaecher C, et al. ( 2013) declared that frequency of Helicobacter suis is significantly higher in patients with idiopathic parkinsonism than healthy subjects ( 21).
An another exciting assumption is that in case of H. pylori infection is not controlled by the immune system or not eradicated, H. pylori may causes the development of Parkinson's disease by damaging dopaminergic cells in central nervous system.(22).

Multiple sclerosis
Multiple sclerosis (MS) is a multifactorial, complex, chronic inflammatory and neurodegenerative disease of the central nervous system.Gavalas E. et al (2015), reported that H. pylori infection appears to be more frequent in MS patients (23).A recent report indicated the presence of immunomodulating features of "Sydney Strain-1 antigen" administration in an experimental model of MS, recommending the possible role of H. pylori infection in the mechanism of the disease (24).Long Y, et al. showed H. pylori seropositivity in patients with MS, though it did not differ considerably when compared with controls (25).In contrast, a recent metaanalysis reported that H. pylori infection and MS are negatively correlated, particularly in Western countries (26).These conflicting findings among the aforementioned reports may be due to ethnicity, and methodological dissimilarity.

Cardiovascular Disease
Cardiovascular disease, including coronary artery disease, peripheral artery disease and stroke are the leading causes of mortality and morbidity globally.The possible effect of H. pylori infection in the pathogenesis of cardiovascular disorders remains controversial.Many Available online at www.jiacm.comepidemiological researches have been performed to detect association between ischemic heart disease, lipid abnormalities and the pathogen (27).Recently, it has been reported that H. pylori may be present at the level of the carotid plaques.Because of the some strains elicit a strong local inflammatory response, particularly cagA gene positive strains; the presence of the bacteria may contribute to plaque instability and to the development of ischemic stroke (28).Despite of these studies, whether the association is still unclear.A study from Japanese population examined possible relationships between H. pylori infection and risk of death from coronary heart disease and stroke in a large prospective cohort study (29).They suggested that there is no link between H. pylori infection and coronary heart disease and stroke mortality risk.In contrast, Sagar V. et al. ( 2016) researched the prevalence and association of H. pylori infection in patients of ischemic cerebrovascular stroke and they suggested there is link between H. pylori infection and acute cerebral ischemia (28).But they found no considerably association between H. pylori seropositivity and carotid plaque instability.In a recent work from Korea, the authors investigated the relationship of current H. pylori infection with lipid profile and cardiovascular disease and its eradication effect (30).In a similar manner to the literature, they have declared that the current infection with the pathogen had a positive association with high LDL, low HDL, and cardiovascular disease.They also reported that successful H. pylori eradication decreased the risk of high LDL and low HDL.However, eradication of the bacteria did not reduce the risk of cardiovascular disease.

Skin diseases
Autoimmune based dermatological pathologies are characterized by dysregulation of the immune system that causes loss of self-tolerance to dermal antigens.Many studies have been reported an association between idiopathic chronic urticaria, acne rosacea, alopecia areata and H. pylori infection (31)(32)(33).Treatment of H. pylori infection has been reported to be effective in some patients with psoriasis, Schoenlein-Henoch purpura chronic autoimmune urticaria and alopecia areata (11).Some studies declared higher prevalence of H. pylori infection in patients with systemic sclerosis, than in healthy individuals (34).Despite that, there is conflicting data about the association of H. pylori infection with scleroderma, Behçet's disease and autoimmune bullous diseases.
One of the most researched skin diseases is immune thrombocytopenic purpura (ITP).Several reports have recommended a pathological link between ITP and H. pylori infection.Clinical experiences have described a spontaneous resolution of ITP symptoms in approximately half of chronic ITP patients taking after treatment against H. pylori infection (35).Also, a randomized controlled trial suggested that, H. pylori eradication plays significant role in the management of H. pylori infected chronic ITP children and adolescents (36).
It is well known that the prevalence of eczema is increasing, particularly in developed countries where the H. pylori seroprevelance is relatively low.The reported risk factors linked with increased prevalence of eczema include higher level of family education, higher socioeconomic status, smaller family size and urban environment.Opposite of these conditions is known as risk factors for higher prevalence of H. pylori positivity.
Similarly, in a recent work, Ali AM et al., reported that H. pylori infection is associated with childhood eczema in genetically predisposed atopic children and likewise a considerable inverse correlation between atopic dermatitis and positive H. pylori serology (37).In addition, a meta-analysis provides evidence that H. pylori infection is inversely associated with atopy (38).
Recent studies proposed a potential relationship between rosacea, psoriasis and H. pylori.Information from the literature involving the H. pylori infection in psoriasis are not clear; on the other hand, a recent study has recommended that H. pylori seems able to affect the clinical severity of psoriasis (39).However, several researches reported that the prevalence of H. pylori infection was considerably higher in patients with rosacea (40).

Migraine
Migraine is a common, multifactorial, disabling, an episodic, hereditary neurovascular headache disorder (41).The well-known vascular theory of migraine is that migraine headache is caused by the dilatation of blood vessels, while the aura of migraine resulted from vasoconstriction.It has been reported that C-reactive protein, which can increase blood-brain barrier permeability, and some pro-inflammatory cytokine levels rise in migraineurs (42,43), and likewise it has been suggested that single nucleotide polymorphisms in TNFα and IL-1 are associated with migraine may relevant to the etiology of the disease (44).Due to the high levels of IL-17, the cytokine most strongly associated with autoimmune disorders, it has been suspected that migraine may also be associated with autoimmune disorders (45).Several studies presented a positive correlation between H. pylori infection and migraine headache.It has been proposed that the pathogenic role of the bacterium in migraine, in light of a relationship between the host immune response against the H. pylori and the chronic release of vasoactive substances.The proposed factors of the relationship between migraine and H. pylori infection included inflammation, nitric oxide imbalance, oxidative stress, or virulence of cagA-positive strains (46,47).Similarly, in a recent study, it is reported that mean of H. pylori IgM antibody in migrainous patients showed a significant difference with a healthy control group (48).Nowadays, Mann, NS. et al. reported a meta-analysis about the possible relationship between H. pylori and migraine (49).They reported that 1084 cases of migraine associated with H. pylori and in some studies elimination of the bacteria resulted in amelioration of migraine symptoms.

Alzheimer's disease
Alzheimer's disease is a neurodegenerative disease which several causes have been suggested like relationship with known pathogens.Most of the infectious hypotheses are proposed by the alteration of the blood-brain barrier and the stimulation of neuroinflammation in the central nervous system that may play a role, particularly in the decrease of amyloid peptide clearance (50,51).Some bacterial or viral pathogens have been incriminated, including Chlamydia pneumonia, H. pylori and Herpes simplex virus-1 (52).Although, the direct laboratory evidence is lacking, H. pylori infection has been reported to be related to a high risk of Alzheimer's disease.In a recent study, researchers investigated the effect of H. pylori infection on tau phosphorylation due to abnormal hyperphosphorylation of microtubule-associated protein tau is involved in the pathogenesis of Alzheimer's disease (53).The authors, Xiu-Lian W. et al. reported evidence supporting the role of H. pylori infection in Alzheimer's disease-like tau pathology and they suggested that H. pylori eradication may be useful in the prevention of tauopathy.

Vitamin and mineral deficiency
It is reported that H. pylori infection was associated with an enhanced rate of iron deficiency anemia, cobalamin (vitamin B12), folic acid, alpha-tocopherol, beta-carotene and vitamin C deficiency (54).One of the suspected mechanisms for these deficiencies is that H. pyloriinduced gastritis leads to a functional inhibition of the parietal cells and causes hypochlorhydria.Thus, higher gastric pH causes iron malabsorption and also have a major role in the development of vitamin deficiencies like folate, vitamin B12 and vitamin A.

Diabetes mellitus
It is suggested that H. pylori infection may associated with insulin resistance, diabetes mellitus and metabolic syndrome.However, the relationship between H. pylori infection and type 2 diabetes mellitus is controversial, as some studies revealed a higher prevalence of infection in diabetic patients while others reported there is no significant difference (55)(56)(57).Some studies from Asia have reported on an relationship between H. pylori infection with insulin resistance in normal-weight individuals.Recently, Nasif WA. et al. (2016), reported that infection with H. pylori in type 2 diabetes mellitus was higher when compared to non-diabetic population and seems no link with glycemic control (58); Likewise, they proposed that diabetes seems to be associated with increased oxidative stress in H. pylori infection and they reported that significantly raised serum Oxidized lowdensity lipoprotein (Ox-LDL) levels in diabetes patients with positive H. pylori infection, proposing hypothesis that high serum level of Ox-LDL levels in diabetes patients with positive H. pylori infection considered as a risk factor for atherosclerotic vascular disease.One recent study has shown obese patients do not provide evidence for an enhanced insulin resistance state associated with gastric H. pylori infection, but they suggested that the presence of the bacterium in gastric biopsies is associated with an adverse lipid profile (59).In addition, it was suggested that eradication rate of H. Available online at www.jiacm.compylori is significantly lower in patients with obese nondiabetic than healthy subjects (60).

Oral pathologies and Sjögren Syndrome
Several studies indicated that H. pylori can be isolated from the oral cavity, salivary secretions and dental plaque.The presence of the pathogen in some oral lesions like burning, halitosis and lingual dorsum hyperplasia has been reported with high frequency (61).Alireza Monsef Esfahani et al. (2015) reported that H. pylori infection plays important role in the pathogenesis of Sjögren Syndrome a chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands (62).Recurrent aphthous stomatitis is one of the common oral mucosal diseases with unknown etiology.Gülseren D. et al. (2016) researched possible link between recurrent aphthous stomatitis, and periodontal disease and H. pylori infection in a cross-sectional study and they suggested that H. pylori might have played an etiological role in recurrent aphthous stomatitis and might have caused periodontal disease and eradicating H. pylori may be useful to prevent the disease (63).

Obesity
In developed countries, the prevalence of overweight and obese individuals has substantially increased, but the prevalence of H. pylori has decreased.It has been speculated that decreasing prevalence of H. pylori might represent a risk or contributing factor to the endemic of obesity in western countries.But, the relationship between gastric H. pylori infection and body mass index (BMI) is controversial.While several cross-sectional studies have reported a link between H. pylori infection with BMI, others did not find an association (64).Arslan E, et al. has shown an increased prevalence of gastric H. pylori infection in obese individuals when compared to normal-weight counterparts (65).Interestingly, Lender N. et al., reported that the prevalence of gastric H. pylori colonization in various countries is inversely related to the prevalence of obesity (64).

Bronchial asthma and chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is considered the fourth leading cause of death worldwide.Controversial results of H. pylori seroprevalence have been achieved in patients with bronchial asthma, sarcoidosis, pulmonary tuberculosis, cystic fibrosis, chronic bronchitis and lung cancer (66).For example, a recent systematic review has reported that there is a relationship between H. pylori infection and extra-gastric diseases like bronchiectasis, asthma, COPD, lung cancer, and lung tuberculosis (67).It is well known that H. pylori prevalence in developed countries has been declining simultaneously with increases in childhood asthma and other allergic diseases.Thus, several studies have linked these phenomena.Lim JH et al. (2016) have declared an inverse association between H. pylori infection and asthma among young adult, and they proposed that the underlying immune mechanism induced by H. pylori infection may affect allergic reactions associated with asthma in young adults due to its low prevalence (15).Also, they supposed that, H. pylori infection may inhibit development of asthma in some way in young adults due to effects on the immune system.On the other hand, den Hollander WJ et al. reported that colonization of a European child with a CagA negative strains at age 6 was associated with an increased prevalence of asthma, but they declared no link for non-European children (68).We think that the underlying mechanisms for the relationship between asthma and H. pylori infection requires further research like the other diseases.

Inflammatory bowel diseases (Crohn's disease, ulcerative colitis)
Interestingly, some epidemiological data suggest a protecting effect of H. pylori infection against the development of autoimmune diseases and, additionally, there are laboratory data illustrating H. pylori's ability to induce immune tolerance and limit inflammatory responses (69).Inflammatory bowel disease is an important growing health problem, globally.In last decades, a lot of developing countries have experienced a spectacular climb in the incidence of the disease.Recently, a meta-analysis indicated a significant negative link between H. pylori infection and inflammatory bowel diseases that supports a possible protective profit of H. pylori infection against the development of the disease (69).The researchers also reported that further prospective studies determining the role of H. pylori and its eradication in the evolvement of inflammatory bowel Available online at www.jiacm.comdiseases are required by taking into account the role of confounders like environmental factors.

Conclusion
The distinctive ability of H. pylori to inveterately infect the gastric tissue to activate inflammation and host immunological response recommends its role in various autoimmune diseases.Although there are conflicting and controversy data in some diseases, in the light of mentioned reports, it is currently accepted; that the presence or absence of H. pylori infection might influence the chance of developing of many autoimmune diseases.Despite extensive medical advancement many questions still remain unanswered and, further studies analyzing the supposed causality of the observed relationship between H. pylori infection and extraintestinal diseases are clearly in need.think that, if such causality is confirmed, this could have a great effect on clinical practice as it will probably goes to the recommendation of H. pylori screening and eradication in various diseases as a clinical standard therapy.Although, lots amount of studies are required to address the role of H. pylori in pathogenesis of various autoimmune diseases, some reports give a hope that eradication of the bacteria could be a cure or to reduce the severity of some diseases.

Table 1 .
Extraintestinal manifestations with a proven or suspected pathophysiological role in H. pylori infection.