Novel role of toll-like receptors in Helicobacter pylori-induced gastric malignancy

Helicobacter pylori(H.pylori)infects the human stomach during infancy and develops into chronic activeinflammation.The majority of H.pylori tend to colonize within the mucous gel layer of the stomach.Thestomach lacks its own immune function,thus innateimmunity as the first line of defense is vital for specificimmunity against H.pylori.We review recent discoveries in the pathophysiologic roles of toll-like receptors(TLRs),mainly TLR2 and TLR4,in H.pylori-induced inflammation.In addition,the TLR pathways activated byH.pylori-induced inflammation have been shown to beclosely associated not only with gastric carcinogenesis,but also with formation of the tumor microenvironmentthrough the production of pro-inflammatory cytokines,chemokines,and reactive oxygen species.Althoughthe correlation between single nucleotide polymorphisms of TLRs and gastric cancer risk remains unclear,a recent study demonstrated that STAT3-driven upregulation of TLR2 might promote gastric tumorigenesis independent of inflammation.Further research onthe regulation of TLRs in H.pylori-associated gastriccarcinogenesis will uncover diagnostic/predictive biomarkers and therapeutic targets for gastric cancer.

Toll like receptors and inflammatory factors in sepsis and differential expression related to age

In recent years, the incidence of systematic severe .infection in intensive care units （ICUs） has increased significantly. Sepsis is a＂ complex, multifactorial syndrome that can develop into conditions of different severity, described as severe sepsis or septic shock. The immunology of severe sepsis and septic shock is poorly defined, despite many studies investigating the pathogenesis of this syndrome. With mortality rates of up to 50%, greater understanding of the interactions between host and microbe is necessary to improve patient outcome. Given the rapid progression of sepsis and immediate recruitment of the inflammatory cytokine cascade, the early innate response of the immune system to the pathogen is likely to play a critical role.

Interrelationship between Toll-like receptors and infection after orthotopic liver transplantation

Early microbial recognition by the innate immune system is accomplished by Toll-like receptors(TLRs),with resultant initiation of a pro-inflammatory response against infecting organisms.In spite of presence of an abundance of Toll-like receptors on the surface of the liver,gut bacteria does not elicit an inflammatory reaction in healthy individuals due to tolerance to these TLRs,suggesting that the inflammatory responses seen in the liver are the result of breakdown of this tolerance.While orthotopic liver transplantation is often life saving in many instances,death following this procedure is most commonly due to infection that occurs in up to 80%of transplant recipients,most commonly due to microbial causes in up to 70%of cases and viral infections in 20%,while fungal infections affect only 8%of cases.The probability of acquiring infection following hepatic transplantation is heightened due to affection of the innate immune defense mechanisms of the host following this procedure.Single nucleotide polymorphisms of TLRs have been associated with increased likelihood of either development of post-transplant infection or eradication of infecting organism.However,conflicting reports from other studies reveal that prevalence of this single nucleotide polymorphism is not increased in infected patients.

Novel genetic markers in inflammatory bowel disease

Genetic factors play a significant role in determining inflammatory bowel disease(IBD)susceptibility.Epidemiologic data support genetic contribution to the pathogenesis of IBD,which include familial aggregation,twin studies,racial and ethnic differences in disease prevalence.Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9.Nucleotide oligomerization domain(NOD2)and human leukocyte antigen(HLA)genes are the most extensively studied genetic regions(IBD1 and IBD3 respectively)in IBD.Mutations of the NOD2 gene are associated with Crohn's disease(CD)and several HLA genes are associated with ulcerative colitis(UC)and CD.Toll like receptors(TLRs)have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns.Studying single-nucleotide polymorphisms(SNPs)in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD.Recently,numerous new genes have been identified to be involved in the genetic susceptibility to IBD:NOD1/Caspase-activation recruitment domains 4(CARD4),Chemokine ligand 20(CCL20),IL-11,and IL-18 among others.The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.

Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease

AIM To evaluate the inflammatory state in Crohn's disease(CD) patients and correlate it with genetic background and microbial spreading.METHODS By means of flow cytometry, production of tumor necrosis factor-alpha(TNF-α) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis(UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common NOD2 variants(R702W, G908 R and L1007Pfs*2) and basal production of TNF-α was correlated to NOD2 genotype. Also, production of TNF-α was correlated to plasmatic levels of LPS Binding Protein(LBP), soluble(s) CD14 and to the activity state of the disease.RESULTS The patients with CD were characterized by a significantly higher monocyte basal expression of TNF-αcompared with healthy subjects and UC patients, and after stimulation with Pam3CSK4(ligand of TLR2/1) and MDP-L18(ligand of NOD2) this difference was maintained, while other microbial stimuli(LPS, ligand of TLR4 and Poly I:C, ligand of TLR3) induced massive activation in CD monocytes as well as in UC and in healthy control cells. There was no significant difference in the production of TNF- α between patients who carried CD-associated heterozygous or homozygous variants in NOD2 and patients with wild type NOD2 genotype. Although serum LBP levels have been shown to correlate positively with the state of activity of the disease, TNF-α production did not show a clear correlation with either LBP or s CD14 levels in plasma. Moreover, no clear correlation was seen between TNF-α production and activity indices in either CD or UC.CONCLUSION Peripheral monocytes from CD express higher basal and stimulated TNF-α than controls, regardless of NOD2 genotype and without a clear correlation with disease activity.

Between Scylla and Charybdis:The role of the human immune system in the pathogenesis of hepatitis C

Hepatitis C virus(HCV)frequently elicits only mild immune responses so that it can often establish chronic infection.In this case HCV antigens persist and continue to stimulate the immune system.Antigen persistence then leads to profound changes in the infected host’s immune responsiveness,and eventually contributes to the pathology of chronic hepatitis.This topic highlight summarizes changes associated with chronic hepatitis C concerning innate immunity(interferons,natural killer cells),adaptive immune responses(immunoglobulins,T cells,and mechanisms of immune regulation(regulatory T cells).Our overview clarifies that a strong anti-HCV immune response is frequently associated with acute severe tissue damage.In chronic hepatitis C,however,the effector arms of the immune system either become refractory to activation or take over regulatory functions.Taken together these changes in immunity may lead to persistent liver damage and cirrhosis.Consequently,effector arms of the immune system will not only be considered with respect to antiviral defence but also as pivotal mechanisms of inflammation,necrosis and progression to cirrhosis.Thus,avoiding Scylla-a strong,sustained antiviral immune response with inital tissue damage-takes the infected host to virus-triggered immunopathology,which ultimately leads to cirrhosis and liver cancerthe realm of Charybdis.

Gut microbiome dysbiosis in the setting of solid organ transplantation:What we have gleaned from human and animal studies

The human gut microbiome refers to all of the microorganisms present throughout the length of the gastrointestinal tract.Gut flora influence host metabolic and immune processes in myriad ways.They also play an important role in maturation and modulation of the immune system.Dysbiosis or a pathologic alteration in gut flora has been implicated in a number of diseases ranging from metabolic,autoimmune and degenerative.Whether dysbiosis has similar implications in organ transplant has been the focus of a number of pre-clinical and clinical studies.Researchers have observed significant microbiome changes after solid organ transplantation in humans that have been associated with clinical outcomes such as post-transplant urinary tract infections and diarrhea.In this article,we will discuss the available data regarding pathologic alterations in gut microbiome(dysbiosis)in solid organ transplant recipients as well as some of challenges in this field.We will also discuss animal studies focusing on mouse models of transplantation that shed light on the underlying mechanisms that explain these findings.

General principles of developing novel radioprotective agents for nuclear emergency

With the rapid application of nuclear energy and radiological technology in national economy and military field,the risk of nuclear accidents increases as well.Exposure to irradiation causes severe damages to the human body,and radioprotective agents are required for medical protection.To find the safe and effective radioprotective agents is the key for nuclear emergency.Recently,Toll like receptors(TLRs)and PHD-HIF oxygen sensing signal pathway have been extensively studied for radioprotection.Great progress has been made in this field and a number of radioprotective agents have been found.In this review,we have summarized recent findings of radioprotective roles of TLRs signaling pathway and PHD-HIF signaling pathway and discussed the general principles of developing novel radioprotective agents.These findings will provide opportunities for developing new strategies to prevent IR-induced injuries in public health events.