A comprehensive look at the psychoneuroimmunoendocrinology of spinal cord injury and its progression: mechanisms and clinical opportunities

Spinal cord injury(SCI)is a devastating and disabling medical condition generally caused by a traumatic event(primary injury).This initial trauma is accompanied by a set of biological mechanisms directed to ameliorate neural damage but also exacerbate initial damage(secondary injury).The alterations that occur in the spinal cord have not only local but also systemic consequences and virtually all organs and tissues of the body incur important changes after SCI,explaining the progression and detrimental consequences related to this condition.Psychoneuroimmunoendocrinology(PNIE)is a growing area of research aiming to integrate and explore the interactions among the different systems that compose the human organism,considering the mind and the body as a whole.The initial traumatic event and the consequent neurological disruption trigger immune,endocrine,and multisystem dysfunction,which in turn affect the patient's psyche and well-being.In the present review,we will explore the most important local and systemic consequences of SCI from a PNIE perspective,defining the changes occurring in each system and how all these mechanisms are interconnected.Finally,potential clinical approaches derived from this knowledge will also be collectively presented with the aim to develop integrative therapies to maximize the clinical management of these patients.

Role of inflammatory response in liver diseases: Therapeutic strategies

Inflammation and tumorigenesis are tightly linked pathways impacting cancer development. Inflammasomes are key signalling platforms that detect pathogenic microorganisms, including hepatitis C virus(HCV) infection, and sterile stressors(oxidative stress, insulin resistance, lipotoxicity) able to activate pro-inflammatory cytokines interleukin-1β and IL-18. Most of the inflammasome complexes that have been described to date contain a NOD-like receptor sensor molecule. Redox state and autophagy can regulate inflammasome complex and, depending on the conditions, can be either pro-or antiapoptotic. Acute and chronic liver diseases are cytokinedriven diseases as several proinflammatory cytokines(IL-1α, IL-1β, tumor necrosis factor-alpha, and IL-6) are critically involved in inflammation, steatosis, fibrosis, and cancer development. NLRP3 inflammasome gain of function aggravates liver disease, resulting in severe liver fibrosis and highlighting this pathway in the pathogenesis of non-alcoholic fatty liver disease. On the other hand, HCV infection is the primary catalyst for progressive liver disease and development of liver cancer. It is well established that HCV-induced IL-1β production by hepatic macrophages plays a critical and central process that promotes liver inflammation and disease. In this review, we aim to clarify the role of the inflammasome in the aggravation of liver disease, and how selective blockade of this main pathway may be a useful strategy to delay fibrosis progression in liver diseases.

Esophageal cancer: Risk factors,screening and endoscopic treatment in Western and Eastern countries

Esophageal cancer is one of the most unknown and deadliest cancers worldwide,mainly because of its extremely aggressive nature and poor survival rate.Esophageal cancer is the 6th leading cause of death from cancer and the 8th most common cancer in the world.The 5-year survival is around 15%-25%.There are clear differences between the risk factors of both histological types that affect their incidence and distribution worldwide.There are areas of high incidence of squamous cell carcinoma(some areas in China) that meet the requirements for cost-effectiveness of endoscopy for early diagnosis in the general population of those areas.In Europe and United States the predominant histologic subtype is adenocarcinoma.The role of early diagnosis of adenocarcinoma in Barrett's esophagus remains controversial.The differences in the therapeutic management of early esophageal carcinoma(high-grade dysplasia,T1 a,T1 b,N0) between different parts of the world may be explained by the number of cancers diagnosed at an early stage.In areas where the incidence is high(China and Japan among others) early diagnoses is more frequent and has led to the development of endoscopic techniques for definitive treatment that achieve very effective results with a minimum number of complications and preserving the functionality of the esophagus.

Bile-acid-induced cell injury and protection

Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids （BAs） in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyI-N- methylglycine or pharmacological properties. cholylsarcosine, interest owing have also aroused to their protective

Bile acids:Chemistry,physiology,and pathophysiology

The family of bile acids includes a group of molecular species of acidic steroids with very peculiar physical-chemical and biological characteristics.They are synthesized by the liver from cholesterol through several complementary pathways that are controlled by mechanisms involving finetuning by the levels of certain bile acid species.Although their best-known role is their participation in the digestion and absorption of fat,they also play an important role in several other physiological processes.Thus,genetic abnormalities accounting for alterations in their synthesis,biotransformation and/or transport may result in severe alterations,even leading to lethal situations for which the sole therapeutic option may be liver transplantation.Moreover,the increased levels of bile acids reached during cholestatic liver diseases are known to induce oxidative stress and apoptosis,resulting in damage to the liver parenchyma and,eventually,extrahepatic tissues.When this occurs during pregnancy,the outcome of gestation may be challenged.In contrast,the physical-chemical and biological properties of these compounds have been used as the bases for the development of drugs and as pharmaceutical tools for the delivery of active agents.

Hepatobiliary manifestations in inflammatory bowel disease: The gut,the drugs and the liver

Abnormal liver biochemical tests are present in up to30%of patients with inflammatory bowel disease(IBD),and therefore become a diagnostic challenge.Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn’s disease and ulcerative colitis(UC),and typically do not correlate with intestinal activity.Primary sclerosing cholangitis(PSC)is the most common hepatobiliary manifestation of IBD,and is more prevalent in UC.Approximately 5%of patients with UC develop PSC,with the prevalence reaching up to 90%.Cholangiocarcinoma and colon cancer risks are increased in these patients.Less common disorders include autoimmune hepatitis/PSC overlap syndrome,IgG4-associated cholangiopathy,primary biliary cirrhosis,hepatic amyloidosis,granulomatous hepatitis,cholelithiasis,portal vein thrombosis,liver abscess,and non-alcoholic fatty liver disease.Hepatitis B reactivation during immunosuppressive therapy is a major concern,with screening and vaccination being recommended in serologically negative cases for patients with IBD.Reactivation prophylaxis with entecavir or tenofovir for 6to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen(HBsAg)positive,independently from viral load.HBsAg negative and anti-HBc positive patients,with or without anti-HBs,should be closely monitored,measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy,and should be treated if the viral load increases.On the other hand,immunosuppressive therapy does not seem to promote reactivation of hepatitis C,and hepatitis C antiviral treatment does not influence IBD natural history either.Most of the drugs used for IBD treatment may induce hepatotoxicity,although the incidence of serious adverse events is low.Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant.Methotrexaterelated hepatotoxicity has been described in 14%of patients with IBD,in a dose-dependent manner.Liver biopsy is not routinely recommended.Biologics-related hepatotoxicity is rare,but has been shown most frequently in patients treated with infliximab.Thiopurines have been associated with veno-occlusive disease,regenerative nodular hyperplasia,and liver peliosis.Routine liver biochemical tests are recommended,especially during the first month of treatment.All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement.Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.

Colorectal cancer population screening programs worldwide in 2016: An update

Colorectal cancer(CRC)is the third most commonly diagnosed cancer in the world.The incidence and mortality show wide geographical variations.Screening is recommended to reduce both incidence and mortality.However,there are significant differences among studies in implementation strategies and detection.This review aimed to present the results and strategies of different screening programs worldwide.We reviewed the literature on national and international screening programs published in Pub Med,on web pages,and in clinical guidelines.CRC Screening programs are currently underway in most European countries,Canada,specific regions in North and South America,Asia,and Oceania.The most extensive screening strategies were based on fecal occult blood testing,and more recently,the fecal immunochemical test(FIT).Participation in screening has varied greatly among different programs.The Netherlands showed the highest participation rate(68.2%)and some areas of Canada showed the lowest(16%).Participation rates were highest among women and in programs that used the FIT test.Men exhibited the greatest number of positive results.The FIT test has been the most widely used screening program worldwide.The advent of this test has increased participation rates and the detection of positive results.

Prognostic factors and time-related changes influence results of colorectal liver metastases surgical treatment:A single-center analysis

AIM:To analyze the prognostic factors involved in survival and cancer recurrence in patients undergoing surgical treatment for colorectal liver metastases(CLM) and to describe the effects of time-related changes on survival and recurrence in these patients.METHODS:From January 1994 to January 2006,236 patients with CLM underwent surgery with the aim of performing curative resection of neoplastic disease at our institution and 189(80%) of these patients underwent resection of CLM with curative intention.Preoperative,intraoperative and postoperative data,including primary tumor and CLM pathology results,were retrospectively reviewed.Patients were divided into two time periods:a first period from January 1994 to January 2000(n = 93),and a second period from February 2000 to January 2006(n = 143).RESULTS:Global survival at 1,3 and 5 years in patients undergoing hepatic resection was 91%,54% and 47%,respectively.Patients with preoperative extrahepatic disease,carcinoembryonic antigen(CEA) levels over 20 ng/dL,more than four nodules or extrahepatic invasion at pathological analysis had worse survival.Tumor recurrence rate at 1 year was 48.3%,being more frequent in patients with preoperative and pathological extrahepatic disease and CEA levels over 20 ng/dL.Although patients in the second time period had more adverse prognostic factors,no differences in overall survival and recurrence were observed between the two periods.CONCLUSION:Despite advances in surgical technique and better adjuvant treatments and preoperative imaging,careful patient staging and selection is crucial to continue offering a chance of cure to patients with CLM.

Excretion of biliary compounds during intrauterine life

In adults,the hepatobiliary system,together with the kidney,constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine,respectively.However,during intrauterine life the biliary route of excretion for cholephilic compounds,such as bile acids and biliary pigments,is very poor.Although very early in pregnancy the fetal liver produces bile acids,bilirubin and biliverdin,these compounds cannot be efficiently eliminated by the fetal hepatobiliary system,owing to the immaturity of the excretory machinery in the fetal liver.Therefore,the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta.Owing to the presence of detoxifying enzymes and specifi c transport systems at different locations of the placental barrier,such as the endothe-lial cells of chorionic vessels and trophoblast cells,this organ plays an important role in the hepatobiliary-like function during intrauterine life.The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother.This may result in oxidative stress and apoptosis,mainly in the placenta and fetal liver,which might affect normal fetal development and challenge the fate of the pregnancy.The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem.

Anemia and inflammatory bowel diseases

Too often anemia is considered a rare or unimportant manifestation in inflammatory bowel disease (IBD). However, over the last 10 years a number of studies have been conducted and the most relevant conclusions obtained are: (1) anemia is quite common in IBD; (2) although in many cases anemia parallels the clinical activity of the disease, many patients in remission have anemia, and iron, vitamin B12 and/or folic acid deficiency; (3) anemia, and also iron def iciency without anemia, have important consequences in the clinical status and quality of life of the patient; (4) oral iron can lead to gastrointestinal intolerance and failure of treatment; (5) intravenous iron is an effective and safe way to treat iron deficiency; (6) erythropoietin is needed in a significant number of cases to achieve normal hemoglobin levels. Thus, the clinician caring for IBD patients should have a comprehensive knowledge of anemia, and apply recently published guidelines in clinical practice.

Steatosis and insulin resistance in hepatitis C: A way out for the virus?

The hepatitis C virus (HCV) induces lipid accumulation in vitro and in vivo. The pathogenesis of steatosis is due to both viral and host factors. Viral steatosis is mostly reported in patients with genotype 3a, whereas meta-bolic steatosis is often associated with genotype 1 and metabolic syndrome. Several molecular mechanisms responsible for steatosis have been associated with the HCV core protein, which is able to induce gene expres-sion and activity of sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activat-ed receptor γ (PPARγ), increasing the transcription of genes involved in hepatic fatty acid synthesis. Steatosis has been also implicated in viral replication. In infected cells, HCV core protein is targeted to lipid droplets which serve as intracellular storage organelles. These studies have shown that lipid droplets are essential for virus assembly. Thus, HCV promotes steatosis as an eff icient mechanism for stable viral replication. Chronic HCV in-fection can also induce insulin resistance. In patients with HCV, insulin resistance is more strongly associated with viral load than visceral obesity. HCV seems to lead to insulin resistance through interference of intracellular insulin signalling by HCV proteins, mainly, the serine phosphorylation of insulin receptor-1 (IRS-1) and im-pairment of the downstream Akt signalling pathway. The HCV core protein interferes with in vitro insulin signal-ling by genotype-specif ic mechanisms, where the role of suppressor of cytokine signal 7 (SOCS-7) in genotype 3aand mammalian target of rapamycin (mTOR) in geno-type 1 in IRS-1 downregulation play key roles. Steatosis and insulin resistance have been associated with f ibrosis progression and a reduced rate of sustained response to peginterferon plus ribavirin.

Hepatopulmonary syndrome: What we know and what we would like to know

Hepatopulmonary syndrome (HPS) is characterized by abnormalities in blood oxygenation caused by the presence of intrapulmonary vascular dilations (IPVD) in the context of liver disease, generally at a cirrhotic stage. Knowledge about the subject is still only partial. The majority of the information about the etiopathogenesis of HPS has been obtained through experiments on animals. Reported prevalence in patients who are candidates for a liver transplantation (LT) varies between 4% and 32%, with a predominance of mild or moderate cases. Although it is generally asymptomatic it does have an impact on their quality of life and survival. The diagnosis requires taking an arterial blood gas sample of a seated patient with alveolar-arterial oxygen gradient (AaO2) ≥ 15 mm Hg, or ≥ 20 mm Hg in those over 64 years of age. The IPVD are identified through a transthoracic contrast echocardiography or a macroaggregated albumin lung perfusion scan (99mTc-MAA). There is currently no effective medical treatment. LT has been shown to reverse the syndrome and improve survival rates, even in severe cases. Therefore the policy of prioritizing LT would appear to increase survival rates. This paper takes a critical and clinical look at the current understanding of HPS, as well as the controversies surrounding it and possible future research.

Association between vitamin D and hepatitis C virus infection: A meta-analysis

AIM:To evaluate the association between 25-hydroxyvitamin D[25(OH)D]and sustained virological response(SVR)in hepatitis C virus(HCV)infected individuals.METHODS:Relevant studies were identified by systematically searching MEDLINE databases up to March2012 and abstracts of the European and American Congress of Hepatology conducted in 2011.Studies must provide information on SVR and the levels of 25(OH)D3and/or 25(OH)D2[henceforth referred to as 25(OH)D]in sera samples from HCV infected individuals.The inclusion criteria were:clinical studies that included HCV infected patients aged older than 18 years regardless of HCV genotype or ethnic group;provided information on SVR rates;and were reported in the English languageas full papers.Due to the heterogeneity of studies in categorizing serum vitamin D levels,a cut-off value of30 ng/mL of serum 25(OH)D was used.Heterogeneity was assessed using I2statistics.The summary odds ratios with their corresponding 95%CI were calculated based on a random-effects model.RESULTS:Overall,11 studies(8 observational and 3interventional)involving 1575 individuals were included and 1117 HCV infected individuals(71%)showed low vitamin D levels.Most of the studies included monoinfected HCV individuals with the mean age ranging from 38 to 56 years.Four studies were conducted in human immunodeficiency virus/HCV infected individuals.Regarding vitamin D measurement,most of the studies employed radioimmunoassays(n=5)followed by chemiluminescence(n=4)and just one study employed high performance/pressure liquid chromatography(HPLC).Basal vitamin D levels varied from 17 to43 ng/mL in the studies selected,and most of the HCV infected individuals had genotype 1(1068/1575)with mean viral load varying from log 4.5-5.9 UI/mL.With regard to HCV treatment,most of the studies(n=8)included HCV individuals without previous treatment,where the pooled SVR rate was 46.4%.High rates of SVR were observed in HCV individuals with vitamin D levels above 30 ng/mL(OR=1.57;95%CI:1.12-2.2)and those supplemented with vitamin D(OR=4.59;95%CI:1.67-12.63)regardless of genotype.CONCLUSION:Our results demonstrated high prevalence of vitamin D deficiency and high SVR in individuals with higher serum vitamin D levels or receiving vitamin D supplementation.

Liver disease and erythropoietic protoporphyria:A concise review

The porphyries are a group of metabolic disorders characterized by deficiencies in the activity of enzymes involved in the biosynthesis of heme.In erythropoietic protoporphyria(EPP),in the majority of cases an autosomal dominant disease,there is a mutation of the gene that encodes ferrochelatase(FECH).FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes,plasma,skin and liver.The prevalence of this inherited disorder oscillates between 1:75 000 and 1:200 000.Clinical manifestations of EPP appear in early infancy upon first exposure to the sun.Nevertheless,approximately 5%-20% of patients with EPP develop liver manifestations.Retention of protoporphyrin in the liver is associated with cholestatic phenomena and oxidative stress that predisposes to hepatobiliary disease of varying degrees of severity,such as cholelithiasis,mild parenchymal liver disease,progressive hepatocellular disease with end-stage liver disease and acute liver failure.Liver damage is the major risk in EPP patients,so surveillance and frequent clinical and biochemical liver follow-up is mandatory.The diagnostic approach consists in detecting increased levels of protoporphyrin,decreased activity of FECH and genetic analysis of the FECH gene.A variety of nonsurgical therapeutic approaches have been adopted for the management of EPP associated with liver disease,but none of these has been shown to be unequivocally efficacious.Nevertheless,some may have a place in preparing patients for liver transplantation.Liver transplantation does not correct the constitutional deficiency of FECH.Consequently,there is a risk of recurrence of liver disease after liver transplantation as a result of continuing overproduction of protoporphyrin.Some authors recommend that bone marrow transplantation should be considered in liver allograft recipients to prevent recurrence of hepatic disease.

Helicobacter pylori infection as a cause of iron deficiency anaemia of unknown origin

AIM: To assess the aetiological role of Helicobacter pylori (H. pylori) infection in adult patients with ironrefractory or iron-dependent anaemia of previously unknown origin. METHODS: Consecutive patients with chronic irondeficient anaemia (IDA) with H. pylori infection and a negative standard work-up were prospectively evaluated. All of them had either iron refractoriness or iron dependency. Response to H. pylori eradication was assessed at 6 and 12 mo from follow-up. H. pylori infection was considered to be the cause of the anaemia when a complete anaemia resolution without iron supplements was observed after eradication. RESULTS: H. pylori was eradicated in 88 of the 89 patients. In the non-eradicated patient the four eradicating regimens failed. There were violations of protocol in 4 patients, for whom it was not possible to ascertain the cause of the anaemia. Thus, 84 H. pylori eradicated patients (10 men; 74 women) were available to assess the effect of eradication on IDA. H. pylori infection was considered to be the aetiology of IDA in 32 patients (38.1%; 95%CI: 28.4%-48.8%). This was more frequent in men/postmenopausal women than in premenopausal women (75% vs 23.3%; P < 0.0001) with an OR of 9.8 (95%CI: 3.3-29.6). In these patients, anaemia resolution occurred in the first follow-up visit at 6 mo, and no anaemia or iron deficiency relapse was observed after a mean follow-up of 21 ± 2 mo. CONCLUSION: Gastric H. pylori infection is a frequent cause of iron-refractory or iron-dependent anaemia of previously unknown origin in adult patients.

Infiltrative xanthogranulomatous cholecystitis mimicking aggressive gallbladder carcinoma: A diagnostic and therapeutic dilemma

Xanthogranulomatous cholecystitis(XGC) is an uncommon variant of chronic cholecystitis. The perioperative findings in aggressive cases may be indistinguishable from those of gallbladder or biliary tract carcinomas. Three patients presented mass lesions that infiltrated the hepatic hilum,provoked biliary dilatation and jaundice,and were indicative of malignancy. Surgical excision was performed following oncological principles and included extirpation of the gallbladder,extrahepatic bile duct,and hilar lymph nodes,as well as partial hepatectomy. Postoperative morbidity was minimal. Surgical pathology demonstrated XGC and absence of malignancy in all three cases. All three patients are alive and well after years of follow-up. XGC may have such an aggressive presentation that carcinoma may only be ruled out on surgical pathology. In such cases,the best option may be radical resection following oncological principles performed by expert surgeons,in order that postoperative complications may be minimized if not avoided altogether.

An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure

Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.

I.31, a new combination of probiotics, improves irritable bowel syndrome-related quality of life

AIM: To determine the dose-related effects of a novel probiotic combination, I.31, on irritable bowel syndrome (IBS)-related quality of life (IBS-QoL).

Interaction between Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs and/or low-dose aspirin use: Old question new insights

Previous reports clearly demonstrated that Helicobacter pylori(H.pylori)infection,nonsteroidal anti-inflammatory drugs(NSAID)or low dose aspirin(ASA)use significantly and independently increased the risk for the development of peptic ulcer disease.Today,the presence of H.pylori infection associated with low dose ASA and/or NSAID use in the same patient is becoming more frequent and therefore the potential interaction between these factors and the consequences of it has important implications.Whether NSAID intake in the presence of H.pylori infection may further increase the risk of peptic ulcer carried by the presence of only one risk factor is still a matter of debate.Studies on the interaction between the two risk factors yielded conflicting data and no consensus has been reached in the last years.In addition,the interaction between H.pylori infection and low-dose ASA remains even more controversial.In real clinical practice,we can find different clinical scenarios involving these three factors associated with the presence of different gastrointestinal and cardiovascular risk factors.These huge variety of possible combinations greatly hinder the decision making process of physicians.

Immunogenetic biomarkers in inflammatory bowel diseases:Role of the IBD3 region

Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn’s disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-α and -β, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tγδ and T CD8+ cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4+ T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells’ function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-α and -β also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-α inhibitors. Additionally, polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.