GASTRIC ADAPTATION OF H.pylori AND PATHOGENIC MECHANISMS

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INTRODUCTION: Various diseases of the intestinal tract are closely related to infections caused by various micro-organisms. Diseases such as gastritis, peptic ulcers and even gastric cancer are related to specific bacteria: Helicobacter pylori. This bacteria was first isolated in the early 80s by Marshall and Warren (1) despite already having been previously described many years ago, and since then many advances in gastroenterology has been developed. H. pylori is a bacteria that is usually acquired in childhood and can remain in the body for life and usually is restricted to gastric mucosa without invading the region of the duodenum ( 2,3). It consists of gram-negative bacteria of varying length from 2 to 4 microns and 0.5 to 1 micron in diameter and has a spiral shape (4). Also presents a tuft of 5-7 flagella and approximately 3 microns in length that allow getting through viscose environment which they live (5).

GASTRIC ADAPTATION OF H.pylori AND PATHOGENIC MECHANISMS: There are several factors that combined confer the bacteria a great ability to withstand the protection of host factors and persist in our intestinal tract for many years. Several experiments in animal models have been conducted over the years to elucidate the main mechanisms of evasion of bacteria to our defense mechanisms. Firstly, the attachment of bacteria to the gastric tissue is extremely efficient and the specificity for binding to this epithelium suggests recognition of these cells by bacteria. This process is possible through the action of bacterial adhesins that are capable of recognize and bind to specific receptors expressed on the cell surface. This process of fixation may alter epithelial cell or activate certain bacterial functions that increase its toxicity. Other proteins are also related to bacterial adhesion as virulence factors. The best known are: BabA (blood group antigen binding adhesin), OipA (outer membrane inflammatory protein), sabA (sialic acid binding adhesin), AlpA, AlpB, and HopZ. Binding of H. pylori to epithelial cells influences the development of inflammation of the gastric mucosa, production of autoantibodies and loss of parietal cells. The BabA gene encodes an adhesin which mediates binding to Lewis b antigen expressed in gastric epithelial cells. The interaction between BabA and the Lewis b antigen is the best characterized adhesin-receptor interaction. Another way to achieve the successfully bacterium colonization of the gastric environment is binding to host proteins to confuse the immune system and not be tackled, as in the pgbA and pgbB proteins that bind to plasminogen. H. pylori secrete several enzymes that are essential for their survival and colonization of the gastric environment. One of the most important enzymes is urease which is the main factor of resistance to acidity of the environment. Urease act converting urea into ammonia and carbamate, and ammonia production is responsible for increasing the ph. Urease itself is able to activate the host immune system and indirectly produces damage through the stimulation of inflammatory cells. It is believed that ammonia has a cytotoxic effect on the gastric epithelial cells and bicarbonate can suppress the bactericidal effect of peroxynitrite, a metabolite of nitric oxide. Some other important enzymes: phospholipases, that can alter the phospholipid content of gastric mucosal barrier involving mainly its permeability and catalases which are responsible for protecting the bacteria from toxic metabolites derived from oxygen that are released by activated neutrophils. Another factor that make a successful adaptation of the bacteria is their synthesis of LPS that is less proinflammatory in comparison with other bacteria, so basically, is not a good activator of the innate immune response of our body. The bacteria also present antigens in its constitution that are very similar to human blood group antigens (Lewis antigens), so it helps in the bacterial evasion mechanism. The H. pylori bacteria have a rich genetic heterogeneity which gives a wide variety in how the strains will interact with our bodies, resulting from colonization without any symptoms until very serious diseases such as gastric cancer. One of the most important differences between strains is the expression of the CagA protein, an immunogenic protein encoded by the cagA gene present in more than half of the strains of H. pylori. This protein are related to more virulent and severe forms of infection by H. pylori. The cagA is a product of the cag PAI (pathogenicity island) and is involved in several alterations in cell signaling and morphological changes of epithelial cells through a process of translocation into host cells which is dependent on a functional type IV secretion system. CagA also is involved in stimulating the production of high levels of cytokines such as interleukin-8 (IL8). Some bacterial strains may also secretes a vacuolating cytotoxin VacA which may causes gastric mucosal damage through vacuolization, apoptosis and activationand proliferation of CD4 + T lymphocyte. The presence of these two factors in bacterial invasion is very important to predict the severity of immunological and inflammatory response of the body. Other virulence factors include the CAGE, which induces the release of cytokines including interleukin 8, iceA that was related to peptic ulcers and babA2 related to duodenal ulcers and gastric cancer.

IMMUNE RESPONSE: The human body uses various strategies to contain the harmful effect of the invasion of micro-organisms. In the case of an infection of the digestive tract, the first barrier that exists is the antimicrobial factors in saliva, which unfortunately are not as potent to eradicate the bacteria. The mucus lining the gastric epithelium also has antibodies and antimicrobial factors such as lactoferrin, which inhibits the growth of bacteria acting on the drop in iron availability in the environment and acting on the membrane permeability, lysozyme which can degrade the peptidoglycan of many bacterial species and defensins 1 and 2. Another important factor in protecting stomach mucosa is the presence of gastric acid (2,6). However, the bacteria have different mechanisms of evasion of these protective factors that already have been discussed. In addition to these nonspecific factors our body has an important inflammatory and immune reaction against the invasion of this bacterium from both cellular immune response and innate immune response. The Bacteria releases various antigenic substances that can be captured and processed by macrophages and activated T cells. This antigen presentation is increased when cellular disruption mainly near the epithelial tight junctions occurs and this facilitates an immune stimulation. This process results in an increased production of inflammatory cytokines such as IL-8 (main), IL-1, IL-6 and TNF alpha. In the immune reaction the CD4 + T cell usually are more present than the CD8 +T cells and based on the large amount of production of IFN-gamma in relation to production of IL-4, it can be concluded that the infection is based on a Th1-polarized response. Also there is an up-regulate expression of major histocompatibility complex (MHC) class II and costimulatory molecules by dendritic cells that increase the efficiency of antigen presentation. Perhaps one of the factors that causes the bacteria can maintain the infection for long periods of time is the presence of B7-H1, an associated inhibition of T cell protein justifying the hyporesponsiveness of these cells (10). In part, the regulation of the inflammatory response to H. pylori is taken by regulatory T cells. The CD4 + / CD25 + Tregs can suppress the production of cytokines and the proliferation of other T cells helping control the inflammation of the tissue (11). Another important factor is that the toll like receptors (TLRs) is not apparently the major inducers of immune response against Helicobacter pylori, for example in the recognition of bacterial heat shock protein Hsp60 there is no involvement of TLRs. However, Nod1 and Nod2 are involved in the recognition of the peptidoglycan of bacteria, and at least in the cag PAI positive strains that Nod1 signaling pathway is a crucial factor in the activation of the inflammatory response (12,13). The response of B cells to H. pylori occurs both locally and systematically. Although the role of local antibodies in producing tissue injury remains controversial, H.pylori specific IgA and IgM antibodies are observed in the gastric mucosa of patients with the bacteria. The H. pylori have several inhibitory effects on lymphocytes B. The bacterial VacA protein inhibits the ability of lymphocytes in stimulate CD4 T cells and CagA protein appears to be involved in inhibiting proliferation of interleucin-3-dependent B-cell through the inhibition of Jak-STAT signaling pathway, which can result in inefficient production of antibodies and reduced expression of cytokines (14,15). Is worth mentioning that besides the characteristics of the strain of bacteria the host genetics are fundamental in determining susceptibility, severity of disease and response to treatment. About half of patients infected with H. pylori have autoantibodies that are reactive against gastric mucosal antigens. Are clinically important in H. pylori-associated autoimmunity antigastric specific types of antibodies such as those directed against parietal cell canaliculi. Neutrophils and mast cells are also involved in the immune response against H. pylori. Mast cells are normally activated by VacA protein and neutrophil infiltration is usually mediated by neutrophil-activating Protein (HP-NAP) and outer membrane protein Saba.

CLINICAL FEATURES,DIAGNOSTIC AND TREATMENT: The H. pylori infection does not always will result in the development of diseases such as gastritis (clinical form) and peptic ulcer. The risk of development of these diseases depends upon a variety of factors both of the host (host susceptibility and genetics) as virulence factors and adaption of bacteria to the environment. There are not many cases of acute ingestion of H. pylori gastritis reported. In the cases studied, the involvement of the gastric antrum and body seem to be similar. The clinical features nonspecific gastrointestinal symptoms as fullness, nausea and vomiting. This acute phase is also accompanied by profound hypochlorhydria and can take months after infection to return to normal levels. In most patients the immune response can not completely eliminate the bacteria which would lead to a state of chronic gastritis. Importantly, despite the most times gastritis be related with Helicobacter pylori infection, there are several other causes of gastritis as viral infections, autoimmune inflammatory diseases such as Crohn's disease, abuse of nonsteroidal anti-inflammatory drug (NSAID) or other drugs that can cause tissue damage and lead to an inflammatory response. Another condition highly related to infection by Helicobacter pylori are the gastric and duodenal ulcers. They are more likely to occur in regions where mucosal inflammation is more severe. H. pylori eradication completely changes the natural course of ulcerative disease. The main complications of peptic ulcer disease are: bleeding (the most common complications), perforation, obstruction and formation of fistulas. The stomach over time loses glandular tissue damage caused by the progressive infection leading to a state of atrophy. The atrophy is caused both by direct damage of bacteria as the inflammatory and immune response of the host. During the regeneration of the tissue that was injured there may be a replacement of the gastric tissue by intestinal tissue, situation called intestinal metaplasia. This process of atrophy and dysplasia increases the risk of developing gastric cancer. Other association that is well established is the H. pylori MALT lymphoma. This association led to the hypothesis that bacteria are responsible for antigenic stimulus that sustains the growth of MALT lymphoma in the stomach. The prognosis of patients treated with antibiotics seems to be relatively similar to those patients treated with surgery, radiotherapy or chemotherapy. There are some methods for diagnosing the presence of Helicobacter pylori in the body. The main non-invasive method is the urea breath test based on bacterial urease activity. Another method is to biopsy the tissue by means of endoscopy and through it to make a histological study to assess quantitatively and qualitatively the extent of tissue damage caused by infection. Currently this method is considered the gold standard. Usually the most effective treatment currently used is a combination of two antibiotics (eg. amoxicillin and clarithromycin) and proton pump inhibitor (eg omeprazole or pantoprazole). In some cases a bismuth compound can be administered together. Normally therapeutic failures happen for antimicrobial resistance or difficulty in adherence of patients to treatment.

VACCINATION: Many studies and researches have been made ​​in the last two decades in an attempt to develop a viable vaccine for humans. Unfortunately, the vaccine is not yet ready and more knowledge about our immune response to H. pylori needs to be understood. As we know that our immune response is led by Th1 cells, it was thought that the most effective vaccine would induce a Th 2 response capable of preventing or curing H. pylori infection. Through some research with animal models it was found that this was the right way to develop the vaccine. Some studies showed that after immunization there was a Th2 CD4+ T cells response which was capable of eliminates a Helicobacter pylori infection. The immunization could be made with a variety of antigens including recombinant subunits of urease and catalase that would develop a response able to protect animals from exposure to bacteria. One of the challenges to develop a human vaccine is finding an effective adjuvant to be inoculated with the antigen, for animal studies is used in the adjuvant cholera toxin which can not be used in humans. The development of the vaccine would be extremely useful to reduce the use of antibiotics and consequently the development of antibiotic -resistant bacteria. Another important action to reduce infection by bacteria involves improvements in socio-economic aspects, living conditions and hygiene that have already been shown to be risk factors for this bacterial infection.

CONCLUSION: This report tried briefly talk about the gram-negative bacterium Helicobacter pylori and its relationship with man. H. pylori have a very clear role in various gastric diseases ranging from gastritis until histological gastric cancer. This variety will depend on genetic factors of the host and the virulence of different strains of bacteria that exist. Major virulence factors such as cagA and vacA protein are responsible for the great success of the bacteria to colonize and cause the inflammation.

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