H. pyloriis a prevalent species which mainly present in human gastric region. More thanhalf of the human population is infected with H. pylori.
This is present in thefilamentous epithelial region of antrum into the stomach and persist there fora long period of time or lifelong. Due to persistence of H. pylori, causeschronic inflammation and rise the chances of gastric cancer.More thanhalf of the human population is infected with H. pylori and every infectedindividual have gastritis but a very less amount of infected persons developscancer.
And the development of gastric cancer is regulated by host pathogeninteraction and pathogenic ( H. pylori) virulence factors.H. pyloristrains are diversified on the basis of genomic diversification for examplepoint mutation and inter genomic recombination. Degree of pathogenicity isregulated by these genomic variabilities. Hostresponses against the H. pylori infection:Immunologicalresponses(WJG 20):Gastric infection due to h.
pylori strain causes significantly rises the expression of IL-1, IL-6 and IL-8in the antrum region. Cd4+ and cd8+ t-cells concentration also increasescompared to the pre infection state.Concentrations of these cytokines interferon-? (IFN-?), tumor necrosisfactor-? (TNF-?), IL-1, IL-6, IL-7, IL-8, IL-10, and IL-18 are frequentlyincreases in the stomach of H.
pylori-infected individuals compared touninfected individuals. B cellsand cd4+ t cells with dendritic cells togetherorganise into lymphoid follicles but mainly these strain specific cd4+ t cellspresent into gastric mucosa & peripheral blood of infected peoples butthese strain specific cells are absent in the non-infected person. GASTRO-INESTINALIMMUNOLOGICAL RESPONSE AGAINST THE H. PYLORI:Mucosal epithelial of gastrointestinal tract block the entrance or invasion of the pathogenic bacteria andcommensal pathogens.
Because these pathogens have the ability to colonize thereand this process is inhibited by the mucosal epithelial layer. And this processis regulated by forming tight junction with the cell and immunogenic protectionlike secretion or diffusion of pro inflammatory chemokines, defensins andimmunoglobins (IgG/IgA/IgM) .IgA : mainly in mucosal epithelium comprises IgA and these IgA havethe ability to bind with the antigens with high affinity and low affinity. High-affinity IgA is thought toemerge in Peyer’s Patches (PPs) and mesenteric lymph nodes (MLNs) fromfollicular B cells stimulated via T cell-dependent pathways, whereas lowaffinity IgA likely emerges in PPs, MLNs and lamina propria from B cellsstimulated via T cell-independent pathways. How H.pylori persist in the stomach: derived factors of H. pylori have capability toinhibit T-cell proliferation.
-Using mortal T cells and immortal T cells (jurkatcells), it was already illustrated that the VacA obstructed bycalcium-signalling pathway into the cell and interrupted activationcalcineurine. Calcineurine is a calcium dependant phosphatase. (PMID- 14676300,12934009)-subsequently nuclear factor of activated T cell,regulatory factors of immune responses, is phosphorylated. Due to thisphosphorylation this IL-2 secretion stopped and T cell proliferation isinhibited. Similarly ?-glutamyl transpeptidase also have this inhibitoryquality.(77)- H.
pylori arginase can use the addition of VacA and ?-glutamyltranspeptidase for inhibition of T cells proliferation during infection. In awild type H. pylori strain, using mixture of jurkat cells and normal humanlymphatic cells, proliferation of T cells is inhibited by depletion ofL-arganine and CD3 chain is expressed on the T cell receptor.(78)- Innate immune response is inhibited by H. pyloristrains because they have cag pathogenicity island. These island have the ability to impair the efficientphagocytosis of the H. pylori microbe.
(81,82) Reviewpaper :Alison l everyHost factors:Most ofthe population on earth have H. pylori infection but very less of them candevelop gastric cancer. And this property based on host genetic factor that thehost can generate gastric cancer or remain asymptomatic. Toll like receptorsare the pattern recognition factor that can enhance Paper nihms-500119HOST INNATE IMMUNE SYSTEM DODGING: Multiplevirulence factor of H. pylori help in evading the immune response of the hostby disguising from the innate immune recognition. First line of defence for H.
pylori is the gastric mucosal layer which is produced by gastric epithelialcells and the innate immune cells (dendritic cells, natural killing cells andmast cells etc.) is localised in the gastric lamina propria. These cellsactivated under pre infection stage. The recognition of pathogen associatedmolecular patterns (PAMP) by innate immune cells via pathogen recognitionreceptor (PRR).
H. pylori have an efficient process to dodge those receptorswhich are very specific for gram negative enteropathogens.MANUPULATION OF PRRs:TOLL LIKE RECEPTOR AND RIG-I-LIKERECEPTORS RECOGNITION:Germline-encodedhost sensor or PRRs have 4 main categories, in which 2 (TLRs and RLRs) are morederived on nature. TLRs mainly present on the host dendritic cells andmacrophages. Main categories of TLRs are TLR-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12 and 13, but TLR-12 and TLR-13 is not found in human. (PMID-24032031)Thesereceptors mainly found on the cell membranes of the phagocytic cells and theysuccessfully bind with invasive pathogenic PAMPs.All theseTLRs bind with their specific ligands, like TLR-1 bind with triacyllipopeptides and TLR-4 bind with LPS of the pathogenic cell.
(lippincots p-17,ISBN 0-7817-9543-5) TLR-4 is the perfect example for this becauseit use LPS as a ligand of the H. pylori for recognition and H. pylori dodgesthis recognition. H.
pylori mutated its LPS chain from lipid A and make itincompatible for the TLRs binding. There is a removal or deletion of phosphategroup from the 1st and 4th position on lipid A chain.(PMID-22216004)Moststudies says that the TLR-4 is the main receptor for the H. pylori but othersays that the TLR-2 is the main sensor for H.
pylori. (PMID- 15240737,11401977, 17645528, 21220698) Anotherexample of dodging the TLRs for H. pylori PAMP sensor is TLR-5, which recognisethe flagella and this modification usually done on the N terminus of the TLR-5recognition domain.(79)Experimentsalready done on DCs cells in which they doesn’t have TLRs 2,4,7 and 9. Afterthis experiment they saw that H. pylori nucleic acid or DNA is recognized. Thisdelivery of DNA by lipofection process in DCs, which activate the TLR-9.
(Pmid-19272387)TLR-8responsible for H. pylori RNA recognition as RIG-like receptor, belongs tohelicase family (RIG-I). RIG-I recognise the H. pylori RNA which is 5’triophophorylated and then forthcoming interferon regulatory factors (IRF 3/7)dependent induction of type-1 interferons, secreted by DCs.
(pmid-19272387) TLR-2recognizes the non-LPS ligands of H. pylori and then this will activate the MyD88-dependent expression.MyD88-dependent expression regulates the anti-inflammatory gens regulation. H.pylori suppress this expression by deletion of TLR-2 genes. (Pmid-19272387,21149607)CLRs and DC-SIGN- Fucosylatedligands have harbors which also known as CLR family DC-SIGN.
(pmid-19718030)DC-SIGN isthe signalling complex which consist of LSP-1, KSR-1, CNK and kinase Raf-1.DC-SIGN regulates the suppression of proinflammatory signalling. (pmid-19718030)Fucoseresidue on H. pylori activate the DC-SIGN and then regulation will stimulated.H. pylori and other specific microbes modify the PRRs by DC-SIGN/Raf-1 mediatedacylation of NF-kappaB subunit p65 and this will increase the transcription ofIL-10 and that will increase anti-inflammatory cytokine responses.(pmid-17462920)H. pylorineed to persist in the host boy, so it will adapt this dodging process of CLRsfor persistence.
NLRs:-Forth andthe last group of PRRs is NOD like receptors. These receptors bind withalarming complex or damage like associated molecular patterns (DAMPs), which arethe widest range of PAMPs. And these factors released in lamina propria due tothe tissue damages or tissue necrosis. (pmid-22258606)NLRsdivided into 2 classes- Nod1 and Nod2, and they recognizes the peptidoglycan ofH. pylori.
That process is responsible for the activation of NF-kappa B.NF-kappa B induces the immune response (innate and adaptive immune responses).(pmid-18261938)Multiproteincomplex inflammasomes regulated by NLRs and this will activate the cysteineprotease Caspase-1.(pmid-21884176)IL-18 isresponsible for the regulation of effecter T-cells (Treg) activation and thishelps in persistence. (pmid-21884176)