Helicobacter pylori and Type 1 Diabetes Mellitus

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Helicobacter pylori and Type 1 Diabetes Mellitus: Possibility of Modifying Chronic Disease. Susceptibility with Vaccinomics at the Anvil. Tiruvayipati Suma ...
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Review Article

OMICS A Journal of Integrative Biology Volume 15, Number 00, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2010.0138

Helicobacter pylori and Type 1 Diabetes Mellitus: Possibility of Modifying Chronic Disease Susceptibility with Vaccinomics at the Anvil Tiruvayipati Suma Avasthi1 and Niyaz Ahmed1,2,3

Abstract

The human gastric pathogen, Helicobacter pylori, colonizes more than 50% of the world population and is a wellknown cause of peptic ulcer disease. H. pylori has been epidemiologically linked to various other diseases, among which its putative link with certain complex diseases such as type 1 diabetes mellitus (T1DM) is of interest. Although antibiotic resistance is a significant clinical problem in H. pylori infection control, the exact cause and much of the underlying mechanisms of T1DM are not clearly understood. In addition, commensal microflora, gut-adapted microbial communities, and plausible roles of some of the chronic human pathogens add an important dimension to the control of T1DM. Given this, the present review attempts to analyze and examine the confounding association of H. pylori and T1DM and the approaches to tackle them, and how the emerging field of vaccinomics might help in this pursuit.

development of duodenal and gastric ulcers, lymphoma, and primary gastric nonHodgkin’s lymphoma. It is also associated with the development of gastric mucosa-associated lymphoid tissue lymphoma (MALT) (Wotherspoon et al., 1993). H. pylori-induced inflammation may not be confined solely to the digestive tract but could be a link to several other extragastric diseases involving the cardiovascular, hepatobiliary, pulmonary, dermatological, immunologic, and hematologic niches/ systems (Franceschi and Gasbarrini, 2007). Among the above links, H. pylori’s possible association with T1DM is the focus of the present discussion. Characterized by hyperglycemia, diabetes mellitus is a group of metabolic diseases whose basic aetiology is at the base of insulin deficiency attributed to different degrees of either decreased insulin secretion (as seen in T1DM) or resistance to insulin action (as seen in T2DM). Patients could experience a rise in glycemia, which requires additional doses of insulin to control their glucose metabolism. In its most lifethreatening form this condition manifests as a diabetic ketoacidosis primarily seen among T1DM. The exact etiology of T1DM is not fully understood, but it is believed to be of certain immunological consequences of antigenic responses. It is often stated that T1DM results from a combination of varying degrees of genetic susceptibility and environmental factors. The understanding on H. pylori’s association with certain endocrine disorders is growing. Therefore, if it is indeed

Introduction

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he rise in the rates of morbidity and mortality due to certain chronic diseases of humans has created an urge for devising proper vaccination regimens. However, the situation is largely illusive in many cases. It is noteworthy to consider the scenario of two such diseases, gastric/duodenal ulcers caused by Helicobacter pylori and type 1 diabetes mellitus (T1DM), which appear to be linked to each other according to current understanding and could possibly be tackled through vaccinomics. H. pylori is a Gram-negative, microaerophilic, spiral bacterium that infects more than half of the world’s population. The infection rates vary from >20% in industrialized countries to >90% in the developing countries of the world where up to 80% of children younger than the age of 10 years (Das and Paul, 2007; Khalifa et al., 2010) and more than 90% of adults are infected by this pathogen. H. pylori causes chronic gastritis, peptic ulcer disease, and gastric malignancies. It thrives mainly in the mucous lining of the stomach without attaching to the host cells, where it neutralizes the stomach acidity by the production of urease. As many as 70–90% of ulcers are associated with H. pylori, which could be worsened by drugs such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Contrary to the general belief, many peptic ulcers arise in the duodenum rather than in the stomach. The infection is also significant in the

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Pathogen Biology Laboratory, Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, India. Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, India. Institute of Biological Sciences, University of Malaya, Kuala Lumpur, Malaysia.

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2 associated with T1DM then two logical questions arise: is the control of T1DM negatively affected by H. pylori infection, or does occurrence of diabetes facilitates escalation of the infection (or simply hinders its eradication)? The onset of infection is during childhood, which tends to persist unless accurately treated. As eradication of H. pylori requires treatment with multidrug cocktails, prevention in earlier stages with a suitable vaccine is advisable. New approaches including delivery of Helicobacter antigens in the form of DNA vaccines, nanoparticles, or live vectors are being developed. Several questions about what, how, and when a feasible prophylactic and therapeutic vaccine will be developed against Helicobacter are yet to be answered appropriately. Herein, we review and examine the possible factors, existing treatments, vaccines, and approaches to tackle infectious and microbial triggers of T1DM and how the emerging field of vaccinomics might help us in this pursuit, with special reference to H. pylori. By studying the factors, immune responses, vaccines, and treatments of T1DM and peptic ulcer disease, we define the most probable approaches that might form the core of such vaccinomics iniF1 c tiative (Fig. 1). Toward the end, we also refer to how the omics-guided vaccine development might help us bring in new hopes to tackle the collective scourge of T1DM and H. pylori.

AVASTHI AND AHMED Peptic Ulcer Disease and T1DM: How Significant is the Link? The plausible association between H. pylori and T1DM is at the moment perplexing if not very controversial. Some studies indeed bring forward interesting data whereby such an association is evident as a function of high rates of H. pylori infection in cases with either type 1 or type 2 diabetes (Bener et al., 2007; Ojetti et al., 2002). It is certainly not clear which of the two occur first. The evidence in this direction is not very convincing due to either a small number of individuals/ cohorts studied or elucidation of a clear association was hindered because of methodological barriers or confounding interpretations. Nevertheless, as reviewed earlier (Papamichael et al., 2009) there is one issue, across which all the studies converge, and which seems to be the fact that success of H. pylori eradication by triple therapy is much reduced in diabetics than those with a normal pancreatic function. Also, the recurrence of infection seems frequent in diabetics, posteradication. In other observations, children with T1DM plus H. pylori infection posed a higher daily requirement of insulin when compared to their noncolonized counterparts (Begue et al., 1999). At the base of pathogenesis, increase in production of cytokines due to Helicobacter infection could have worsening

FIG. 1. A systematic juxtaposition of the events and parameters that link the two chronic diseases, T1DM and peptic ulcer disease/H. pylori infection. The two are compared with reference to triggers of inflammation, underlying immune responses, available control strategies, and the signaling events that underline the overlapping susceptibilities or cellular determinants of comorbidity.

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H. PYLORI, TYPE I DIABETES, AND NEW VACCINOMICS affects on glycemia. Given this, reduced success of therapeutic based control or management of these two diseases clearly underlines the proposition that an effective vaccine is the only way forward to tackle the two. However, because the two diseases are complex by nature in terms of their progression and outcome as dictated by the individual host immune responses, a universal vaccine preparation may perhaps not be appropriate. This also makes sense from the pathogen point of view given the prevailing strain diversity among the global H. pylori populations and that not all H. pylori strains lead to serious outcomes. Immune Response to H. pylori Infection and Type 1 Diabetes Mellitus Antibody responses Earlier, studies have demonstrated that not only mucosal IgA antibodies, but to some extent, even serum IgA antibodies, have a role in immunity. Various studies have even shown the role of IgG antibodies, which though increase after immunization, were suggested to have a protective activity (Ferrero et al., 1997). Because H. pylori is a mucosa-associated organism, it was initially thought that an IgA type antibody response would be essential for protective immunity. Studies provide clue that a humoral response is actually required for protective immunity against H. pylori infection. When prophylactic immunization was done in mMT mice (deficient in Btype lymphocytes and challenged with H. pylori and Helacobacter felis), it was observed that an antibody independent immunity was possible against H. pylori with an excellent protection (Sutton, 2001). H. pylori infection can persist despite increased production of IgA, although protection can possibly be achieved even in the absence of antibodies (Agarwal and Agarwal, 2008; Wyatt et al., 1986). Promotion of bacterial colonization and prevention of protective immune mechanisms have been shown by some specific IgG and IgA antibodies (Akhiani et al., 2004). Further, crossreactivity with some host antigens in an H. pylori precipitated autoimmune process could be damaging because of the antibody response (D’Elios et al., 2004). Cell-mediated immunity Secretory IgA antibodies might be expected to be protective as H. pylori colonize the epithelial surface and the mucous layer of the stomach. Neutrophil trafficking has been shown in the gastric epithelium and gastric glands in response to H. pylori infection. However, lymphocytes were found in abundant numbers throughout the lamina propria, which are usually absent in the stomach tissue. In vitro studies have shown that H. pylori infected individuals respond to stimulation by H. pylori antigens with the production of cytokines such as interferon (IFN)-g with the help of the peripheral blood mononuclear cells and the lamina propria-derived mononuclear cells (Blanchard et al., 2004). This observation suggests that H. pylori induce a TH1-mediated proinflammatory response recruiting CD4þ T cells resulting in the increased local production of cytokines such as IFN-g and interleukin-12. However, TH1 response is just not enough to cure the infection (Pappo et al., 1999). H. pylori infection has also been associated with an increased production of cytokines such as tumor necrosis factor (TNF)-a, INF-g, and in-

3 terleukin-1, 6, and 8 (Genta et al., 1997). Gastric parietal cell autoantibodies have been identified more frequently in T1DM patients with concomitant H. pylori infection compared to uninfected patients (Barrio et al., 1997). Theoretically, the inflammation and increased production of cytokines could be deleterious for the control of glycemia of patients with diabetes. The gastric mucosa in naturally infected people is predominated by helper T cells type 1 (TH1), but, given the persistence of natural infection in the body, this response can be presumed to be largely ineffective (Sutton and Lee, 2000). Studies show that systemic immunization of mice using adjuvants induce either a TH1 or TH2 response leading to reduced colonization after bacterial challenge. Hence, we can infer that cell-mediated immunity is important in protecting against H. pylori infection (Gottwein et al., 2001). CD4þ T cells and major histocompatibility complex class II expression were also established to be essential (Pappo et al., 1999). This must trigger an immune response in the upper digestive tract and probably is directed toward a TH2 type response and would be able to prevent the initial colonization of the gastric mucosa without any harmful effects on the host. CD4þ T cells and mast cells have also been suggested to be protective (Velin et al., 2005). Vaccines Developed to Date for H. pylori and T1DM Prophylactic approaches for H. pylori H. pylori proteins as vaccine candidates. The most critical step in H. pylori vaccination is the selection of antigenic targets. Previous studies on Urease, CagA, VacA, and PldA have been carried out with fairly good results, although a majority of them did not result in 100% clearance of H. pylori from the gastric mucosa or from reinfection cases depending on the antigenic proteins and the delivery system. Urease is an important factor needed for virulence and colonization of gastric mucosa. It has the ability to hydrolyze urea to carbon dioxide and ammonia thereby neutralizing the immediate microenvironment of H. pylori in the stomach (Ha et al., 2001). A conformational epitope that involves the two urease subunits UreA (265 kDa) and UreB (61 kDa) at a stoichiometric ratio (1:1) is recognized and neutralized of its enzymatic activity by immunoglobulin A (IgA) antibodies. H. pylori urease particularly stimulates human gastric epithelial cells and induces proinflammatory cytokines, particularly interleukin-6 (IL-6) and TNF-a (Tanahasi et al., 2000). These are mainly associated with mucosal damage and tissue inflammation. However, it was most likely that individual subunits of urease with other defined H. pylori antigens could produce even more effective antibody response (Chinn and Nedrud, 1999). Mice immunized with both heat-shock protein A (HspA) and UreB or even the engineered heat-shock protein GroES and UreB along with the vacuolating cytotoxin (VacA) and urease were found to be highly protective (Ferrero et al., 1994, 1995). The feasibility of both the prophylactic and therapeutic vaccination in mice with a mixture of three H. pylori toxins CagA, VacA, and NAP was shown to be relevant in pathogenesis. Parenteral administration of these in the Beagle dog model has given a good protection against subsequent experimental challenges with H. pylori (Rossi et al., 2004). Presently, many of the above coordinates are considered to be true virulence factors due to their ability to enhance disease risk through the induction of cytokines, especially the

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4 interleukin-8 (Lu et al., 2005; Robinson et al., 2007). Some of the other relevant proteins in peptic ulcer disease are the outer inflammatory protein A, duodenal ulcer promoting gene (dupA) and the blood group binding antigen A. RNA polymerase b-subunit has recently been shown to be the risk factor for the development of the infection in some populations (Lee et al., 2004). The type IV secretion system leads to increased gastric inflammation and neoplastic risk through the stimulation of proinflammatory cytokine expression by epithelial cells. It is through this pathogenicity island-encoded type IV secretion (Backert and Selbach, 2008; Backert et al., 2010) that the CagA protein is injected into the gastric epithelial cells. This cytotoxin-associated gene (Cag) pathogenicity island is the most essential virulence factor associated with peptic ulcer in the host. Although neutrophil-activating protein (NAP) results in injury to human gastric mucosal tissue by the release of active oxygen radicals from neutrophils. Flagellin, another important pathogenic factor of H. pylori, takes part in colonization, persistent infection, and inflammatory reaction (Ottemann and Lowenthal, 2002). VacA, which has been first described by Leunk and colleagues (1988) has the ability to cause vacuolar degeneration in epithelial cell lines such as Hela cells. Regulation of T and B lymphocytes and disease pathogenesis with the role of VacA and CagA has not yet been establishes in vivo (Leunk et al., 1988). Protein vaccines tested in animal models. Protein vaccines have been extensively studied in animal models but minimally in humans. Earlier, repetitive oral immunizations of rodents with cholera toxin (CT) were shown to induce mucosal immunity (Elson and Ealding, 1984; Lycke and Holmgren, 1986; Nedrud et al., 1987). Cholera toxin inclusion as a mucosal adjuvant in the immunization protocol has shown an enhanced antibody response (Czinn and Nedrud, 1991). Other proteins such as CagA, VacA, NAP, catalase, and lipoprotein 20 have also been extensively studied proving to be effective candidate vaccines. The rodent model used in such studies is not ideal for the reasons that (1) it is not a natural host for H. pylori and (2) the duration of observation is limited by the lifespan compared to humans (Dubois et al., 1996). Escherichia coli heat-labile toxin (LT) was able to protect against H. pylori infection without causing any adverse effects in studies carried out on rhesus monkeys, a more human-like model of H. pylori infection (Dubois et al., 1998). Humans were also used in some studies as models, whereby LT when used with rUre showed a decrease in bacterial density but caused diarrhoea in two-thirds of the volunteers (Michetti et al., 1999). Salmonella typhimurium was also used in some studies showing a good antibody response (Angelakopoulos and Holmann, 2000; Bumann et al., 2001). CagA, VacA, and NAP when injected as a multicomponent prophylactic vaccine intramuscularly along with aluminium hydroxide as adjuvant induced good immune response with lesser adverse effects (Malfertheiner et al., 2002). Live vectors. The most effective human vaccines against the infectious pathogens are those consisting of a living organism and have often proven to be the most effective ones. Vaccine preparations have involved the use of bacterial and viral vectors successfully. A reduction in H. pylori colonization in the stomach was observed in two murine studies where vaccination was carried out with strains of S. typhimurium

AVASTHI AND AHMED expressing the A and B subunits of urease (Corthesy-Theulaz et al., 1998; Gomez-Duarte et al., 1998). In contrast, there was no prompt development of antibodies to H. pylori in humans when a similar attenuated S. typhi Ty800 strain expressing urease A and B was used (Dipetrillo et al., 1999). However, the expression of urease from H. pylori in S. enterica serovar Typhimurium was associated with a modest antibody response (Angelakopoulos et al., 2000). This suggests that the delivery of antigens expressed in Salmonella can induce a humoral immune response in humans. DNA vaccines. DNA vaccines offer considerable technical advantage over conventional protein immunization and are considered to be easier and safer for neonates (Tighe et al., 1998). The only cautionary step that must be dealt with regarding DNA vaccination is that it tends to drive TH1 mediated responses. As TH1-mediated response is not desirable for controlling H. pylori infection, and as a TH2-type response might help in a more safer and effective DNA based vaccination, the latter approach could be harnessed to trigger the desired TH2-dominant response. The DNA vaccines are generally held as safe, stable, and induce both humoral and cell-mediated immune responses (Schalk et al., 2006). These vaccines are constructed by the insertion of DNA encoding a pathogen’s antigen into a bacterial plasmid and can be delivered either as naked DNA or by an attenuated carrier such as Salmonella, to provide a heterologous crossprotection and can be easily prepared as polyvalent vaccines (LondonoArcila et al., 2002). When administered to mice, a constructed live attenuated S. typhimurium strain harboring the H. pylori NAP generated humoral and mucosal immune responses (Sun et al., 2006). A good immunogenic response in an animal model was observed with a recombinant S. typhimurium DNA vaccine expressing urease B and interleukin-2 (Xu et al., 2007). DNA vaccines have not yet reached a level to be released as a potential vaccine, but could become feasible to control H. pylori infection in near future. Microparticles. The potential of mucosal vaccines of encapsulated antigens in microparticles for oral delivery has been of much interest in recent years. Attempts have been made to induce systemic and local immune responses after oral immunization to demonstrate the efficacy of biocompatible and biodegradable microspheres and vaccine adjuvant candidates (Challacombe et al., 1992; Maloy et al., 1994). These microparticles not only protect the antigen against degradation during passage through the highly acidic environment of the stomach, but also delivers the antigen by preferential uptake at the Payer’s patches to the mucosal immune system. Stimulation of Helicobacter specific secretory IgA and IgG antibody production was observed when H. pylori lysate encapsulated in poly (D,L-latide-co-glycolide) was orally delivered to BALB/c mice (Kim et al., 1999). Similarly, high immunogenesis was shown in mice with poly (D, L-lactide)-polyethylene glycol copolymer microspheres. Those methods that show a certain degree of protection to an H. pylori challenge need to be further evaluated. H. pylori ghost vaccines. Bacterial ghosts (BG) are empty cell envelopes generated by the expression of lysis gene E from the bacteriophage PhiX174 in Gram-negative bacteria. They are devoid of cytoplasmic contents, but retain their

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H. PYLORI, TYPE I DIABETES, AND NEW VACCINOMICS cellular morphology with native antigenic structures. Not only due to their ability in carriage of immunogenic antigens are bacterial ghosts used as vaccine candidates, but also because of the adjuvant properties of bacterial membrane components such as lipopolysaccharides, peptidoglycans, and lipid A. A study shows that prophylactic oral vaccination experiments using H. pylori ghosts in BALB/c mouse models revealed a lesser reduction of bacterial load. Further coadministration along with CT as mucosal adjuvant resulted in complete protection of all mice (Hoffelner and Haa, 2004). The most recent study in which H. pylori ghosts were loaded with recombinant Omp18 and were then applied in therapeutic immunization of H. pylori-infected C57BL-6 mice, the recombinant Omp18-loaded HPBG plus cholera toxin stimulated serum anti-Hp, and Omp18-specific antibodies that resulted in significant reduction of gastric H. pylori colonization (Talebkhan et al., 2010). T1DM management and control strategies Several studies are ongoing to achieve a biochemical mechanism to prevent the immune system from attacking beta cells thereby preventing the onset of T1DM. This would be possible by causing the activation state of the immune system to change from TH1 state (‘‘attack’’ by killer T cells) to TH2 state (development of new antibodies). The change in the type of cytokine signalling molecules being released by regulatory Tcells would help in this TH1–TH2 shift. The regulatory T-cells begin to release cytokines that inhibit inflammation instead of pro-inflammatory cytokines. This phenomenon is commonly known as ‘‘acquired immune tolerance.’’ Being less invasive and more rapid than subcutaneous injections, nasal insulin administration is a potential route for intensive insulin management. A TH1–TH2 shift can be induced by administration of insulin directly onto the immune tissue in the nasal cavity. This has been shown as a preclinical evidence (Overbergh et al., 2000). Studies have shown that gelified nasal insulin is as efficient as subcutaneous regular insulin in T1DM (Bennis et al., 2001). Further investigation needs to be performed to improve nasal tolerance and bioavailability. Pancreatic beta cells are selectively destroyed in T1DM. Insulin substitution becomes necessary ultimately when hyperglycemia develops. DiaPep277 is a peptide fragment of a larger protein called HSP60 or could be explained as the major T-cell epitope, which has been shown to be an effective modulator of the immune system in T1DM (Fischer et al., 2010). This substance is designed to prevent lymphocytes from attacking beta cells whose mechanism of action involves a TH1– TH2 shift when administered as a subcutaneous infection. As T1DM patients are deficient in TNF-a, which is a part of the immune system, it is suggested that administering Bacillus Calmette-Guerin (BCG), an inexpensive generic preparation used to immunize against Mycobacterium tuberculosis, would have the same impact as injecting diabetic mice with Freund’s Adjuvant, which stimulates TNF-a production. TNF-a helps the immune system distinguish self from nonself. In nonobese diabetic (NOD) mice, it has been shown that TNF-a limits white blood cells (WBCs) responsible for destroying beta cells, and thus prevents, or reverses diabetes (Ryu et al., 2001). In humans, there have been sporadic reports of preserving b-cell function when BCG vaccination is administered soon after

5 diabetes onset, and it has been suggested that BCG vaccination early in childhood could reduce the incidence of T1DM (Begue et al., 1999). Further research is needed to support the use of immunostimulatory effects of neonatal BCG vaccination to prevent T1DM (Huppmann et al., 2005). Diamyd (GAD65), is an alum-formulation from a full-length recombinant human glutamic acid decarboxylase 65. This vaccine is presently under study, which shows higher levels of regulatory cytokines, thought to protect the beta cells. GAD65, an autoantigen involved in T1DM, when given to patients, has shown delay of b-cell destruction for at least 30 months in clinical trials. Diamyd was indicated to be safe and well tolerated in patients with T1DM in the Phase II clinical trials (Hinke, 2008). Followed by a wider spectrum of cytokines at 3 and 9 months treatment with GAD-alum in T1DM children, it induced an early TH2 immune enhanced response to GAD(65) (Fischer et al., 2010). Treatment with Diamyd has not only been shown to preserve residual beta cell function in type 1 diabetes, but it might prove to be a new concept of treatment and perhaps even preventing autoimmune diseases (Ludvigsson, 2010). Vaccinomics of H. pylori and T1DM It appears from the above discussion that the two, H. pylori and T1DM, are perhaps interdependent, and therefore, two questions emerge: (1) does everyone really need multidrug cocktail treatment regimens such as a clarithromycin-based triple therapy or bismuth quadruple therapy to get rid of H. pylori, or (2) does everyone need a pancreas replacement therapy or a nanotechnology based vaccine to shut down the autoimmune attack that destroys beta cells? These questions at an individual level can only be answered with advances in genetics, that is, through individualized therapy/ personalized vaccine or vaccinomics. One of the main reasons that reinforce the need for effective vaccine against H. pylori is the emergence of drug resistance. Some of the known mechanisms of antibiotic resistance in H. pylori are mainly due to the mutations in the chromosomal genes and, the organism has evolved several mechanisms or pathways of resistance to antimicrobial compounds, such as the modification of drugs, regulation of uptake and efflux, alteration and protection of target sites, and horizontal genetic exchanges culminating in acquisition of resistance genes from extraneous sources (Wang et al., 2001). Several causes for the development of resistance of H. pylori to antibiotics have been studied with respect to ciprofloxacin, clarithromycin, metronidazole, and rifampicin, and have been reviewed (Wang et al., 2001). Given the rampant emergence of resistance, vaccination is perhaps the most desirable approach in controlling H. pylori infection. Although immunizations induce an effective immune response, they do not produce sterile immunity, and therefore, a decrease in bacterial burden is observed rather than complete clearance. As the ideal situation would be bacterial eradication, there is a clear case for the development of new, efficient Helicobacter vaccines. The net result would also be protection against the development of peptic ulcer if immunization could be used to invoke a condition by which the host immune system did not overreact to the Helicobacter infection. Given the association of H. pylori and T1DM, proper vaccination against H. pylori could actually help treat T1DM. Eradication of the H. pylori infection could result in improved

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6 insulin requirement, but only if the insulin secreting cells are not yet depleted. Various studies reviewed in this article show the importance of a shift from TH1 to a TH2 response in both peptic ulcer/H. pylori infection as well as T1DM. This shift, as a major target, could help develop appropriate and effective vaccines against H. pylori, which could be the best possible approach to tackle peptic ulcers in diabetics. H. pylori vaccination could be of further help in dealing with the development of vaccines for T1DM (Fig. 1). This possibility, although still hatching, is very likely to help develop personalized vaccines based on the data on interindividual immune response variations and would therefore enable the much awaited application of vaccinomics, which entails the convergence of classical vaccine development platforms with data intensive 21st century omics sciences (Poland et al., 2007, 2008; Thomas and Moridani, 2009). This intersection of omics sciences with vaccine research and development offers a number of important opportunities in the context of discerning the complex links between H. pylori and T1DM. Vaccinomics as a new field of study is poised to make immunization tailored to individual genetic profiles. This is a necessity as the presently available vaccines show significant differences in the levels of immune response and toxicity in individuals undergoing vaccination. Recent studies (Poland et al., 2007) show how some factors or molecules have a critical role in the regulation of immune response. There are several approaches to treat Helicobacter infection and T1DM as discussed in the above sections of the article. One of the important approaches to identify vaccine or drug targets against H. pylori could be through functional genomics (Seib et al., 2009) wherein the roles of genes and proteins are analyzed in order to identify genes required for survival under some specific conditions. The proposed methods utilize DNA signature tags (molecular barcodes) (Mazurkiewicz et al., 2006). Signature-tagged mutagenesis (STM), when applied to Helicobacter has shown 47 genes essential for its colonization in the stomach (Rinaudo et al., 2009). This was the first STM approach that helped identify a set of previously unknown H. pylori colonization factors that might in near future help target Helicobacter infection (Kavermann et al., 2003). On the other hand, a recent sophisticated nanotechnology based vaccine showed successful cure of T1DM in mice (Tsai et al., 2010). Although vaccines provide immunity through immune stimulation, the roles played by candidate gene polymorphisms in pathogenesis could regulate the success of protective immune responses. Other than this, baseline data for the overlapping diseases such as T1DM and H. pylori infection need to be established particularly in relation to cosusceptibility, comorbidity, immune surveillance, and prognosis. Such overlapping diseases pose complex problems during the testing and validation of a vaccine because at the base of the desired immune responses operates a complexity of interactions, interdependencies, and regulation of key HLA (human leukocyte antigen) alleles and the genes that determine the repertoire of cytokines and cytokine receptor functions leading to specific immune responses. These functional hierarchies are possibly dependent on the single nucleotide polymorphisms (SNPs) or haplotypes that are variable in relation to genetic descent, selection, and different environmental forces. Given this, the vaccinomics of complex diseases such as T1DM are likely to pose bountiful challenges. As stated, there exist no significant studies that have examined

AVASTHI AND AHMED association of SNPs or haplotypes of the genes encoding important effector molecules and their target receptors in the context of T1DM and H. pylori. Unless such studies are in place, it will be difficult to predict with certainty as to how the vaccine responses related to one will be impacted by the other and vice versa. Nevertheless, we are very optimistic about the future course of events, especially the technology revolution that will enable a ‘‘prevaccination genome-wide screen’’ of individuals having T1DM and an almost simultaneous predictive vaccine response profiling in juxtaposition with the inventory of H. pylori’s virulence arsenal determined by direct sequencing from the stomach biopsies. This will be possible mostly by the single molecule sequencing technologies that are at the anvil and public health impact of such screening platforms shall be tremendous. Acknowledgments H. pylori-related research in our laboratories is funded through a matching grant by the University of Hyderabad/ UGC (India) under the aegis of a German Research Foundation (DFG) sponsored international research training group entitled Internationales graduiertenkolleg-functional molecular infection epidemiology-GRK1673 (Berlin-Hyderabad). We thank Prof. Seyed E. Hasnain for discussion and encouragement. Author Disclosure Statement The authors declare that they have no competing interests. References Agarwal, K., and Agarwal, S. (2008). Helicobacter pylori vaccine: from past to future. Mayo Clinic Proc 83, 169–175. Akhiani, A.A., Schon, K., Franzen, L.E., Pappo, J., and Lycke, N. (2004). H. pylori-specific antibodies impair the development of gastritis, facilitate bacterial colonization, and counteract resistance against infection. J Immunol 172, 5024–5033. Angelakopoulos, H., and Hohmann, E.L. (2000). Pilot study of phoP/phoQ-deleted Salmonella enterica serovar typhimurium expressing Helicobacter pylori urease in adult volunteers. Infect Immun 68, 2135–2141. Backert, S., and Selbach M. (2008). Role of type IV secretion in Helicobacter pylori pathogenesis. Cell Microbiol 10, 1573–1581. Backert, S., Tegtmeyer, N., and Selbach, M. (2010). The versatility of Helicobacter pylori CagA effector protein functions: the master key hypothesis. Helicobacter 15, 163–176. Barrio, R., Roldan, M.B., Alonso, M., Canton, R., and Camarero, C. (1997). Helicobacter pylori infection with parietal cell antibodies in children and adolescents with insulin dependent diabetes mellitus. J Pediatr Endocrinol Metab 10, 511–516. Begue, R.E., Mirza, A., Compton, T., Gomez, R., and Vargas, A. (1999). Helicobacter pylori infection and insulin requirement among children with type 1 diabetes mellitus. Pediatrics 103, e83. Bener, A., Micallef, R., Afifi, M., Derbala, M., Al-Mulla, H.M., and Usmani, M.A. (2007). Association between type 2 diabetes mellitus and Helicobacter pylori infection. Turk J Gastroenterol 18, 225–229. Bennis, L.D., Boillot, J., Bardin, C., Zirinis, P., Coste, A., Escudier, E., et al. (2001). Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance. Diabetes Metab 27, 372–377.

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Address correspondence to: Niyaz Ahmed LS-296, Pathogen Biology Laboratory Department of Biotechnology School of Life Sciences University of Hyderabad Prof. C. R. Rao Road Gachibowli, Hyderabad—500046, India E-mail: [email protected] or [email protected]