H. by the mucosal epithelial layer. And this process

H. pylori
is a prevalent species which mainly present in human gastric region. More than
half of the human population is infected with H. pylori. This is present in the
filamentous epithelial region of antrum into the stomach and persist there for
a long period of time or lifelong. Due to persistence of H. pylori, causes
chronic inflammation and rise the chances of gastric cancer.

More than
half of the human population is infected with H. pylori and every infected
individual have gastritis but a very less amount of infected persons develops
cancer. And the development of gastric cancer is regulated by host pathogen
interaction and pathogenic ( H. pylori) virulence factors.

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H. pylori
strains are diversified on the basis of genomic diversification for example
point mutation and inter genomic recombination. Degree of pathogenicity is
regulated by these genomic variabilities.



responses against the H. pylori infection:

responses(WJG 20):

Gastric infection due to h.
pylori strain causes significantly rises the expression of IL-1, IL-6 and IL-8
in the antrum region. Cd4+ and cd8+ t-cells concentration also increases
compared to the pre infection state.
Concentrations of these cytokines interferon-? (IFN-?), tumor necrosis
factor-? (TNF-?), IL-1, IL-6, IL-7, IL-8, IL-10, and IL-18 are frequently
increases in the stomach of H. pylori-infected individuals compared to
uninfected individuals. B cells
and cd4+ t cells with dendritic cells  together
organise into lymphoid follicles but mainly these strain specific cd4+ t cells
present into gastric mucosa & peripheral blood of infected peoples but
these strain specific cells are absent in the non-infected person.



Mucosal epithelial of gastro
intestinal tract block the entrance or invasion of the pathogenic bacteria and
commensal pathogens. Because these pathogens have the ability to colonize there
and this process is inhibited by the mucosal epithelial layer. And this process
is regulated by forming tight junction with the cell and immunogenic protection
like secretion or diffusion of pro inflammatory chemokines, defensins and
immunoglobins (IgG/IgA/IgM) .

IgA : mainly in mucosal  epithelium comprises IgA and these IgA have
the ability to bind with the antigens with high affinity and low affinity. High-affinity IgA is thought to
emerge in Peyer’s Patches (PPs) and mesenteric lymph nodes (MLNs) from
follicular B cells stimulated via T cell-dependent pathways, whereas low
affinity IgA likely emerges in PPs, MLNs and lamina propria from B cells
stimulated via T cell-independent pathways.


How H.
pylori persist in the stomach: derived factors of H. pylori have capability to
inhibit T-cell proliferation.

-Using mortal T cells and immortal T cells (jurkat
cells), it was already illustrated that the VacA obstructed by
calcium-signalling pathway into the cell and interrupted activation
calcineurine. Calcineurine is a calcium dependant phosphatase. (PMID- 14676300,

-subsequently nuclear factor of activated T cell,
regulatory factors of immune responses, is phosphorylated. Due to this
phosphorylation this IL-2 secretion stopped and T cell proliferation is
inhibited. Similarly ?-glutamyl transpeptidase also have this inhibitory

– H. pylori arginase can use the addition of VacA and ?-glutamyl
transpeptidase for inhibition of T cells proliferation during infection. In a
wild type H. pylori strain, using mixture of jurkat cells and normal human
lymphatic cells, proliferation of T cells is inhibited by depletion of
L-arganine and CD3 chain is expressed on the T cell receptor.(78)

– Innate immune response is inhibited by H. pylori
strains because they have cag pathogenicity island. These island  have the ability to impair the efficient
phagocytosis of the H. pylori microbe.(81,82)



paper :Alison l every

Host factors:

Most of
the population on earth have H. pylori infection but very less of them can
develop gastric cancer. And this property based on host genetic factor that the
host can generate gastric cancer or remain asymptomatic. Toll like receptors
are the pattern recognition factor that can enhance


 Paper nihms-500119


virulence factor of H. pylori help in evading the immune response of the host
by disguising from the innate immune recognition. First line of defence for H.
pylori is the gastric mucosal layer which is produced by gastric epithelial
cells and the innate immune cells (dendritic cells, natural killing cells and
mast cells etc.) is localised in the gastric lamina propria. These cells
activated under pre infection stage. The recognition of pathogen associated
molecular patterns (PAMP) by innate immune cells via pathogen recognition
receptor (PRR). H. pylori have an efficient process to dodge those receptors
which are very specific for gram negative enteropathogens.



host sensor or PRRs have 4 main categories, in which 2 (TLRs and RLRs) are more
derived on nature. TLRs mainly present on the host dendritic cells and
macrophages. 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)

receptors mainly found on the cell membranes of the phagocytic cells and they
successfully bind with invasive pathogenic PAMPs.

All these
TLRs bind with their specific ligands, like TLR-1 bind with triacyl
lipopeptides 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 because
it use LPS as a ligand of the H. pylori for recognition and H. pylori dodges
this recognition. H. pylori mutated its LPS chain from lipid A and make it
incompatible for the TLRs binding. There is a removal or deletion of phosphate
group from the 1st and 4th position on lipid A chain.

studies says that the TLR-4 is the main receptor for the H. pylori but other
says that the TLR-2 is the main sensor for H. pylori. (PMID- 15240737,
11401977, 17645528, 21220698)  

example of dodging the TLRs for H. pylori PAMP sensor is TLR-5, which recognise
the flagella and this modification usually done on the N terminus of the TLR-5
recognition domain.(79)

already done on DCs cells in which they doesn’t have TLRs 2,4,7 and 9. After
this experiment they saw that H. pylori nucleic acid or DNA is recognized. This
delivery of DNA by lipofection process in DCs, which activate the TLR-9. (Pmid-19272387)

responsible for H. pylori RNA recognition as RIG-like receptor, belongs to
helicase 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)  

recognizes 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,


ligands have harbors which also known as CLR family DC-SIGN. (pmid-19718030)

the signalling complex which consist of LSP-1, KSR-1, CNK and kinase Raf-1.
DC-SIGN regulates the suppression of proinflammatory signalling. (pmid-19718030)

residue 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 mediated
acylation of NF-kappaB subunit p65 and this will increase the transcription of
IL-10 and that will increase anti-inflammatory cytokine responses.

H. pylori
need to persist in the host boy, so it will adapt this dodging process of CLRs
for persistence.


Forth and
the last group of PRRs is NOD like receptors. These receptors bind with
alarming complex or damage like associated molecular patterns (DAMPs), which are
the widest range of PAMPs. And these factors released in lamina propria due to
the tissue damages or tissue necrosis. (pmid-22258606)

divided into 2 classes- Nod1 and Nod2, and they recognizes the peptidoglycan of
H. pylori. That process is responsible for the activation of NF-kappa B.
NF-kappa B induces the immune response (innate and adaptive immune responses).

complex inflammasomes regulated by NLRs and this will activate the cysteine
protease Caspase-1.(pmid-21884176)

IL-18 is
responsible for the regulation of effecter T-cells (Treg) activation and this
helps in persistence. (pmid-21884176)      




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