The immune response as a therapeutic target in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a complex and heterogeneous disorder considered a liver-damaging manifestation of metabolic syndrome. Its prevalence has increased in the last decades due to modern-day lifestyle factors associated with overweight and obesity, making it a relevant public health problem worldwide. The clinical progression of NAFLD is associated with advanced forms of liver injury such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). As such, diverse pharmacological strategies have been implemented over the last few years, principally focused on metabolic pathways involved in NAFLD progression. However, a variable response rate has been observed in NAFLD patients, which is explained by the interindividual heterogeneity of susceptibility to liver damage. In this scenario, it is necessary to search for different therapeutic approaches. It is worth noting that chronic low-grade inflammation constitutes a central mechanism in the pathogenesis and progression of NAFLD, associated with abnormal composition of the intestinal microbiota, increased lymphocyte activation in the intestine and immune effector mechanisms in liver. This review aims to discuss the current knowledge about the role of the immune response in NAFLD development. We have focused mainly on the impact of altered gut-liver-microbiota axis communication on immune cell activation in the intestinal mucosa and the role of subsequent lymphocyte homing to the liver in NAFLD development. We further discuss novel clinical trials that addressed the control of the liver and intestinal immune response to complement current NAFLD therapies.

Elucidating the Role of Innate and Adaptive Immune Responses in the Pathogenesis of Canine Chronic Inflammatory Enteropathy-A Search for Potential Biomarkers.

Canine chronic inflammatory enteropathy (CIE) is one of the most common chronic gastrointestinal diseases affecting dogs worldwide. Genetic and environmental factors, as well as intestinal microbiota and dysregulated host immune responses, participate in this multifactorial disease. Despite advances explaining the immunological and molecular mechanisms involved in CIE development, the exact pathogenesis is still unknown. This review compiles the latest reports and advances that describe the main molecular and cellular mechanisms of both the innate and adaptive immune responses involved in canine CIE pathogenesis. Future studies should focus research on the characterization of the immunopathogenesis of canine CIE in order to advance the establishment of biomarkers and molecular targets of diagnostic, prognostic, or therapeutic utility.

Síndrome de intestino irritable en la enfermedad inflamatoria intestinal. ¿Sinergia en las alteraciones del eje cerebro-intestino? / Irritable bowel syndrome in inflammatory bowel disease. Synergy in alterations of the gut-brain axis?

La presencia de síntomas digestivos asociados al síndrome de intestino irritable (SII) en pacientes con enfermedad inflamatoria intestinal (EII) en remisión es un tema de interés creciente. Si bien existe una heterogeneidad de los estudios clínicos en relación con el uso de criterios de remisión de la EII y del diagnóstico de SII, los datos disponibles indican que la superposición EII-SII afectaría hasta un tercio de los pacientes en remisión, y coinciden en el hallazgo de un impacto negativo en la salud mental y calidad de vida de los individuos que la padecen. Las bases fisiopatológicas que explicarían esta potencial superposición no están completamente dilucidadas, sin embargo, la alteración en el eje cerebro-intestino asociada al aumento en la permeabilidad intestinal, la activación neuroinmune y la disbiosis serían fenómenos comunes a ambas condiciones. La hipótesis de una nueva entidad clínica o síndrome de «enfermedad inflamatoria intestinal irritable» o «SII postinflamatorio» con un perfil de microinflamación distintivo del SII, es motivo de intensa investigación. El reto clínico supone certificar la remisión de la actividad de la EII y descartar otras causas no inflamatorias de síntomas digestivos funcionales persistentes potencialmente tratables. En el caso de síntomas asociados a SII, a falta de evidencia suficiente, se debe realizar un control integral y personalizado del cuadro clínico (medidas dietéticas, farmacológicas y psicoterapéuticas), similar a un SII genuino.

The presence of digestive symptoms associated with irritable bowel syndrome (IBS) in patients with inflammatory bowel disease (IBD) in remission is a topic of growing interest. Although there is heterogeneity in clinical studies regarding the use of IBD remission criteria and the diagnosis of IBS, the available data indicate that the IBD-IBS overlap would affect up to one third of patients in remission, and they agree on the finding of a negative impact on the mental health and quality of life of the individuals who suffer from it. The pathophysiological bases that would explain this potential overlap are not completely elucidated; however, an alteration in the gut-brain axis associated with an increase in intestinal permeability, neuroimmune activation and dysbiosis would be common to both conditions. The hypothesis of a new clinical entity or syndrome of “Irritable Inflammatory Bowel Disease” or “Post-inflammatory IBS” is the subject of intense investigation. The clinical approach is based on certifying the remission of IBD activity and ruling out other non-inflammatory causes of potentially treatable persistent functional digestive symptoms. In the case of symptoms associated with IBS and in the absence of sufficient evidence, comprehensive and personalized management of the clinical picture (dietary, pharmacological and psychotherapeutic measures) should be carried out, similar to a genuine IBS.

Irritable bowel syndrome in inflammatory bowel disease. Synergy in alterations of the gut-brain axis? / Síndrome de intestino irritable en la enfermedad inflamatoria intestinal. ¿Sinergia en las alteraciones del eje cerebro-intestino?

The presence of digestive symptoms associated with irritable bowel syndrome (IBS) in patients with inflammatory bowel disease (IBD) in remission is a topic of growing interest. Although there is heterogeneity in clinical studies regarding the use of IBD remission criteria and the diagnosis of IBS, the available data indicate that the IBD-IBS overlap would affect up to one third of patients in remission, and they agree on the finding of a negative impact on the mental health and quality of life of the individuals who suffer from it. The pathophysiological bases that would explain this potential overlap are not completely elucidated; however, an alteration in the gut-brain axis associated with an increase in intestinal permeability, neuroimmune activation and dysbiosis would be common to both conditions. The hypothesis of a new clinical entity or syndrome of "Irritable Inflammatory Bowel Disease" or "Post-inflammatory IBS" is the subject of intense investigation. The clinical approach is based on certifying the remission of IBD activity and ruling out other non-inflammatory causes of potentially treatable persistent functional digestive symptoms. In the case of symptoms associated with IBS and in the absence of sufficient evidence, comprehensive and personalized management of the clinical picture (dietary, pharmacological and psychotherapeutic measures) should be carried out, similar to a genuine IBS.

Sertraline and Citalopram Actions on Gut Barrier Function.

INTRODUCTION: Disruption of intestinal barrier is a key component to various diseases. Whether barrier dysfunction is the cause or effect in these situations is still unknown, although it is believed that translocation of luminal content may initiate gastrointestinal or systemic inflammatory disorders. Since trauma- or infection-driven epithelial permeability depends on Toll-like receptor (TLR) activity, inhibition of TLR signaling has been proposed as a strategy to protect intestinal barrier integrity after infection or other pathological conditions. Recently, selective serotonin recapture inhibitors including sertraline and citalopram were shown to inhibit TLR-3 activity, but the direct effects of these antidepressant drugs on the gut mucosa barrier remain largely unexplored. MATERIALS AND METHODS: To investigate this, two approaches were used: first, ex vivo studies were performed to evaluate sertraline and citalopram-driven changes in permeability in isolated intestinal tissue. Second, both compounds were tested for their preventive effects in a rat model of disrupted gut barrier, induced by a low protein (LP) diet. RESULTS: Only sertraline was able to increase transepithelial electrical resistance in the rat colon both when used in an ex vivo (0.8 µg/mL, 180 min) or in vivo (30 mg/kg p.o., 20 days) fashion. However, citalopram (20 mg/kg p.o., 20 days), but not sertraline, prevented the increase in phospho-IRF3 protein, a marker of TLR-3 activation, in LP-rat ileum. Neither antidepressant affected locomotion, anxiety-like behaviours or stress-induced defecation. CONCLUSION: Our data provides evidence to support the investigation of sertraline as therapeutic strategy to protect intestinal barrier function under life-threatening situations or chronic conditions associated with gut epithelial disruption.

Primary infection by Pneumocystis induces Notch-independent Clara cell mucin production in rat distal airways.

Clara cells are the main airway secretory cells able to regenerate epithelium in the distal airways through transdifferentiating into goblet cells, a process under negative regulation of the Notch pathway. Pneumocystis is a highly prevalent fungus in humans occurring between 2 and 5 months of age, a period when airways are still developing and respiratory morbidity typically increases. Pneumocystis induces mucus hyperproduction in immunocompetent host airways and whether it can stimulate Clara cells is unknown. Markers of Clara cell secretion and Notch1 activation were investigated in lungs of immunocompetent rats at 40, 60, and 80 days of age during Pneumocystis primary infection with and without Valproic acid (VPA), a Notch inducer. The proportion of rats expressing mucin increased in Pneumocystis-infected rats respect to controls at 60 and 80 days of age. Frequency of distal airways Clara cells was maintained while mRNA levels for the mucin-encoding genes Muc5B and Muc5ac in lung homogenates increased 1.9 and 3.9 times at 60 days of infection (P. = 0.1609 and P. = 0.0001, respectively) and protein levels of the Clara cell marker CC10 decreased in the Pneumocystis-infected rats at 60 and 80 days of age (P. = 0.0118 & P. = 0.0388). CC10 and Muc5b co-localized in distal airway epithelium of Pneumocystis-infected rats at day 60. Co-localization of Muc5b and Ki67 as marker of mitosis in distal airways was not observed suggesting that Muc5b production by Clara cells was independent of mitosis. Notch levels remained similar and no transnucleation of activated Notch associated to Pneumocystis infection was detected. Unexpectedly, mucus was greatly increased at day 80 in Pneumocystis-infected rats receiving VPA suggesting that a Notch-independent mechanism was triggered. Overall, data suggests a Clara to goblet cell transdifferentiation mechanism induced by Pneumocystis and independent of Notch.

Progression of Type 2 Helper T Cell-Type Inflammation and Airway Remodeling in a Rodent Model of Naturally Acquired Subclinical Primary Pneumocystis Infection.

Subclinical primary Pneumocystis infection is the most common pulmonary infection in early infancy, making it important to determine whether it damages the lung. Pneumocystis peaks at 2 to 5 months of age, when respiratory morbidity coincidently increases. We have documented that Pneumocystis increases mucus production in infant lungs, and animal models reveal lung lesions that warrant characterization. Herein, immunocompetent rats infected at birth with Pneumocystis by cohabitation, to resemble community-acquired infection, underwent lung assessments at 45, 60, and 75 days of age. Lungs fixed by vascular perfusion to prevent collapse during necropsy were used for morphometry evaluations of mucus production, airway epithelial thickening, perivascular and peribronchiolar inflammation, and structural airway remodeling. Changes in these histologic features indicate lung disease. Selected immune markers were assessed in parallel using fresh-frozen lung tissue from sibling rats of the same cages. Sequential activation of NF-κB and an increased Gata3/T-bet mRNA level ratio, consistent with a type 2 helper T-cell-type inflammatory response, and subacute fibrosis were recognized. Therefore, documenting subclinical Pneumocystis infection induces lung disease in the immunocompetent host. Taken together with the peak age of primary Pneumocystis infection, results warrant investigating the clinical impact of this often subclinical infection on the severity of respiratory diseases in early infancy. This model can also be used to assess the effects of airway insults, including coinfections by recognized respiratory pathogens.

Protein Malnutrition During Juvenile Age Increases Ileal and Colonic Permeability in Rats.

Protein malnutrition can lead to morphological and functional changes in jejunum and ileum, affecting permeability to luminal contents. Regarding the large intestine, data are scarce, especially at juvenile age. We investigated whether low-protein (LP) diet could modify ileal and colonic permeability and epithelial morphology in young rats. Isocaloric diets containing 26% (control diet) or 4% protein were given to male rats between postnatal days 40 and 60. LP-diet animals failed to gain weight and displayed decreased plasma zinc levels (a marker of micronutrient deficiency). In addition, transepithelial electrical resistance and occludin expression were reduced in their ileum and colon, indicating increased gut permeability. Macromolecule transit was not modified. Finally, LP diet induced shortening of colonic crypts without affecting muscle thickness. These data show that protein malnutrition increases not only ileum but also colon permeability in juvenile rats. Enhanced exposure to colonic luminal entities may be an additional component in the pathophysiology of protein malnutrition.

[Parasitosis and irritable bowel syndrome]. / Parasitosis y síndrome de intestino irritable.

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterised by multi-factorial aetiology. In IBS physiopathology are involved diverse factors between them biological, psychosocial, and environmental components which affect the immune activation status of gut mucosa. Among these factors is recognized the intestinal parasitosis. Post-infection IBS (PI-IBS) is recognised as a subgroup of functional disorders whose symptoms onset appear after a symptomatic intestinal infection caused by microbial agents. There are few studies regarding of relationship between IBS and intestinal parasitosis in Chile. However, is has been well described a positive association between IBS and Blastocystis hominis infections, one of prevalent parasites in Chile. In other countries, is also described a relationship between IBS and amebiasis and giardiasis. Both, characterized by a common mode of transmission through water as well as contaminated food. Because the high prevalence of parasitosis in our country it is necessary to expand the association studies to clarify the strength of the parasites ethiology in IBS.

Parasitosis y síndrome de intestino irritable / Parasitosis and irritable bowel syndrome

El síndrome de intestino irritable (SII) es un trastorno funcional digestivo de etiología multifactorial. En su fisiopatología se describen diversos factores, tanto biológicos, como psicológicos y ambientales, que afectan el estado de activación de células inmunes en la mucosa intestinal. Entre los factores ambientales se incluye la presencia de alguna parasitosis intestinal. El síndrome de intestino irritable post-infeccioso (SII-PI) es reconocido como un subgrupo de estos trastornos, cuya aparición de los síntomas es posterior a una infección intestinal provocada por agentes microbianos. A pesar de que en Chile hay pocos estudios respecto a la relación entre SII y parasitosis intestinal, se ha descrito la existencia de una asociación positiva entre SII e infecciones por Blastocistis hominis, uno de los parásitos prevalentes en Chile. En otros países, se ha descrito además una relación entre SII, amebiasis y giardiasis. Por la alta prevalencia de parasitosis en nuestro país, existe la necesidad de ampliar los estudios para clarificar la fuerza de la asociación entre parasitosis y SII.

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterised by multi-factorial aetiology. In IBS physiopathology are involved diverse factors between them biological, psychosocial, and environmental components which affect the immune activation status of gut mucosa. Among these factors is recognized the intestinal parasitosis. Post-infection IBS (PI-IBS) is recognised as a subgroup of functional disorders whose symptoms onset appear after a symptomatic intestinal infection caused by microbial agents. There are few studies regarding of relationship between IBS and intestinal parasitosis in Chile. However, is has been well described a positive association between IBS and Blastocystis hominis infections, one of prevalent parasites in Chile. In other countries, is also described a relationship between IBS and amebiasis and giardiasis. Both, characterized by a common mode of transmission through water as well as contaminated food. Because the high prevalence of parasitosis in our country it is necessary to expand the association studies to clarify the strength of the parasites ethiology in IBS.

Copper oxide nanoparticles recruit macrophages and modulate nitric oxide, proinflammatory cytokines and PGE2 production through arginase activation.

AIM: In the present study, we examine the effects of copper oxide nanoparticles (CuNP) on macrophage immune response and the signaling pathways involved. MATERIALS & METHODS: A peritonitis model was used to determine in vivo immune cells recruitment, while primary macrophages were used as an in vitro model for the cellular and molecular analysis. RESULTS: In vivo, CuNP induce significant macrophages recruitment to the site of injection. In vitro, in LPS-stimulated primary macrophages, the co-treatment with CuNP inhibited the production of NO in a dose-dependent manner. The mechanism underlying NO and proinflammatory cytokines inhibition was associated with an increased arginase activity. Macrophage stimulation with CuNP did not provoke any cytokine secretion; however, arginase inhibition promoted TNFα and MIP-1ß production. In addition, CuNP induced the expression of COX-2 and the production of PGE2 through arginase activation. CONCLUSION: Our results demonstrate that CuNP activate arginase and suppress macrophage innate immune response.

Differential nanotoxicological and neuroinflammatory liabilities of non-viral vectors for RNA interference in the central nervous system.

Progression of RNA interference-based gene silencing technologies for the treatment of disorders of the central nervous system (CNS) depends on the availability of efficient non-toxic nanocarriers. Despite advances in the field of nanotechnology undesired and non-specific interactions with different brain-cell types occur and are poorly investigated. To this end, we studied the cytotoxic and neuroinflammatory effects of widely-used transfection reagents and modified amphiphilic ß-cyclodextrins (CDs). All non-viral vectors formed positively charged nanoparticles with distinctive physicochemical properties. Differential and significant cytotoxic effects were observed among commercially available cationic vectors, whereas CDs induced limited disruptions of cellular membrane integrity and mitochondrial dehydrogenase activity. Interestingly, murine derived BV2 microglia cells and a rat striatal in vitro model of Huntington's disease (ST14A-HTT120Q) were more susceptible to toxicity than human U87 astroglioma cells. BV2 microglia presented significant increases in cytokine, toll-like receptor 2 and cyclooxygenase-2 gene expression after transfection with selected commercial vectors but not with CD.siRNA nanoparticles. Non-viral siRNA nanoparticles formulated with G6 polyamidoamine (PAMAM) also significantly increased cytokine gene expression in the brain following injections into the mouse striatum. Together our data identify modified CDs as nanosystems that enable siRNA delivery to the brain with low levels of cytotoxicity and immunological activation.

Increased production of soluble TLR2 by lamina propria mononuclear cells from ulcerative colitis patients.

Toll-like receptor 2 (TLR2) is a type I pattern recognition receptor that has been shown to participate in intestinal homeostasis. Its increased expression in the lamina propria has been associated with the pathogenesis in inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). Recently, soluble TLR2 (sTLR2) variants have been shown to counteract inflammatory responses driven by the cognate receptor. Despite the evident roles of TLR2 in intestinal immunity, no study has elucidated the production and cellular source of sTLR2 in IBD. Furthermore, an increase in the population of activated macrophages expressing TLR2 that infiltrates the intestine in IBD has been reported. We aimed first to assess the production of the sTLR2 by UC and CD organ culture biopsies and lamina propria mononuclear cells (LPMCs) as well as the levels of sTLR2 in serum, and then characterize the cell population from lamina propria producing the soluble protein. Mucosa explants, LPMCs and serum were obtained from UC, CD patients and control subjects. The level of sTLR2 was higher in conditioned media from organ culture biopsies and LPMCs from UC patients in comparison to CD and controls. Moreover, an inverse correlation between the content of intestinal and serum sTLR2 levels was observed in UC patients. Additionally, when characterizing the cellular source of the increased sTLR2 by LPMCs from UC patients, an increase in TLR2(+)/CD33(+) cell population was found. Also, these cells expressed CX3CR1, which was related to the increased levels of intestinal FKN in UC patients, suggesting that a higher proportion of TLR2(+) mononuclear cells infiltrate the lamina propria. The increased production of sTLR2 suggests that a differential regulating factor of the innate immune system is present in the intestinal mucosa of UC patients.

Soluble ST2: a new and promising activity marker in ulcerative colitis.

AIM: To correlate circulating soluble ST2 (sST2) levels with the severity of ulcerative colitis (UC) and serum levels of pro-inflammatory cytokines, and to demonstrate the predictive power of sST2 levels for differentiation between active and inactive UC. METHODS: We recruited 153 patients: 82 with UC, 26 with Crohn's disease (CD) and 43 disease controls [non-inflammatory bowel disease (IBD)]. Subjects were excluded if they had diagnosis of asthma, autoimmune diseases or hypertension. The serum levels of sST2 and pro-inflammatory cytokines [pg/mL; median (25th-75th)] as well as clinical features, endoscopic and histological features, were subjected to analyses. The sST2 performance for discrimination between active and inactive UC, non-IBD and healthy controls (HC) was determined with regard to sensitivity and specificity, and Spearman's rank correlation coefficient (r). To validate the method, the area under the curve (AUC) of receiver-operator characteristic (ROC) was determined (AUC, 95% CI) and the total ST2 content of the colonic mucosa in UC patients was correlated with circulating levels of sST2. RESULTS: The serum sST2 value was significantly higher in patients with active [235.80 (90.65-367.90) pg/mL] rather than inactive UC [33.19 (20.04-65.32) pg/mL], based on clinical, endoscopic and histopathological characteristics, as well as compared with non-IBD and HC (P < 0.001). The median level of sST2 in CD patients was 54.17 (35.02-122.0) pg/mL, significantly higher than that of the HC group only (P < 0.01). The cutoff was set at 74.87 pg/mL to compare active with inactive UC in a multicenter cohort of patients. Values of sensitivity, specificity, and ability to correctly classify UC, according to activity, were 83.33%, 83.33% and 83.33%, respectively. The AUC of the ROC curve to assess the ability of this molecule to discriminate between active vs inactive UC was 0.92 (0.86-0.97, P < 0.0001). The serum levels of sST2 in patients with UC significantly correlated with endoscopic and histopathological scores (r = 0.76 and r = 0.67, P < 0.0001, respectively), and with the pro-inflammatory cytokine, tumor necrosis factor-α (r = 0.69 and r = 0.61, respectively, P < 0.0001). Interestingly, we found a direct correlation between total intestinal ST2 content and serum levels of sST2, adjusted to endoscopic activity score in patients with mild (r = 0.44, P = 0.004), moderate (r = 0.59, P = 0.002) and severe disease (r = 0.82, P = 0.002). Only patients with inactive UC showed no significant correlation (r = 0.45, P = 0.267). CONCLUSION: sST2 levels correlated with disease severity and inflammatory cytokines, are able to differentiate active from inactive UC and might have a role as a biomarker.

Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease.

BACKGROUND: ST2 has been proposed to be a regulator of inflammation and Th1/Th2 balance. ST2L is the IL-33 membrane receptor and belongs to the IL-1R family. The soluble variant, ST2s, is identical to the extracellular region of ST2L and competes for IL-33 binding, inhibiting receptor signaling. Although ST2s has been associated with inflammatory processes in patients with sepsis, trauma, asthma, and autoimmunity, until now there are no reported studies showing the role of ST2/IL-33 in inflammatory bowel disease (IBD). METHODS: Expression of ST2 and IL-33 was determined in serum and colonic biopsies from IBD patients. ST2 transcript and protein was determined by reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA)/immunoblot, respectively, and IL-33 protein by ELISA. Intestinal mucosa localization of ST2 and IL-33 was conducted by immunofluorescence. RESULTS: ST2s transcript in the colonic mucosa was mainly expressed in UC patients rather than Crohn's disease or control; however, ST2L mRNA remained constant in all samples. Total ST2 protein was significantly higher in mucosa samples from patients with active UC, with a predominant induction of ST2s that strongly correlates with serum ST2 levels. Mucosa IL-33 levels were higher in UC patients and serum levels were barely detected in all patient groups. ST2 and IL-33 are both abundantly expressed in the cytoplasm of epithelial cells of control subjects; however, in ulcerative colitis patients ST2 decreases and IL-33 showed cytoplasm-nuclear redistribution. CONCLUSIONS: The novel association between the ST2/IL-33 system and IBD seems to identify that variations in this axis might regulate the inflammatory process in these diseases.

Peripheral cytokine profile in Chilean patients with Crohn's disease and ulcerative colitis.

Crohn's disease (CD) and ulcerative colitis (UC) belong to the group of inflammatory bowel diseases (IBD), with complex ethiopathogenic factors that include an unbalanced immune and inflammatory response to commensal and food antigens. The differential diagnosis between CD and UC is performed using clinical, endoscopic, histopathological, serological and radiological methods; however between 10-15% of IBD patients are diagnosed as "unclassified colitis". Further research into IBD is necessary in order to develop additional diagnostic tools. The aim of this work was to see if the Th1, Th17 or Th2 immune pattern, represented by CD4+ lymphocytes producing IFN-gamma, IL-17 and IL-5 or IL-13, respectively (CD4/IFN-gamma+, CD4/IL-17+,CD4/IL-5+ or, CD4/IL13+), are useful peripheral markers which can be used to differentiate between UC and CD. Peripheral blood samples were taken from IBD patients from the Clinic Hospital of the University of Chile. The percentage of IFN-gamma-, IL-17-, IL-5- or IL-13-expressing CD4+ cells was determined by flow cytometry in phorbol ester- (PMA) and calcymycin-activated blood samples. The percentages of the CD4+ cell populations producing each cytokine were compared between UC and CD. IFN-gamma production by CD4+ lymphocytes was significantly higher in CD compared to UC and the control. The percentage of IL-17-expressing cells was significantly higher in CD patients compared to to the control; however, there were no differences between UC and CD; or between UC and healthy individuals. No significant differences were observed between the different groups as regards the representative Th2 cytokines. This study suggests that, under pathogenic conditions, several immune profiles may be operating, in the development of IBD. Although peripheral IFN-gamma and IL-17 expression, as indicators of the immune pattern, may help in the diagnosis of IBD, other cytokines and adaptive immune markers should be analyzed to allow better differentiation between the two entities.

IL-23R Arg381Gln polymorphism in Chilean patients with inflammatory bowel disease.

UNLABELLED: Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with a genetic background. Recent results have shown that a non-synonymous, single nucleotide polymorphism (rs11209026, c.1142G>A, p.Arg381Gln) located in the IL-23R gene is associated with inflammatory bowel disease (IBD). The prevalence of IBD is rapidly rising in Chile and there is no information about the frequency of this polymorphism in the Chilean population. AIM: To assess the distribution of DNA variants in the IL-23R gene in Chilean patients with IBD. METHODS: We studied 100 IBD patients (38 CD and 62 UC) and 59 healthy controls. IL-23R Arg381Gln (G1142A) was genotyped by the polymerase chain reaction and restriction fragment length polymorphism assay. Clinical and demographic features were characterized. RESULTS: The IL-23R genetic variant did not have an association with IBD in Chilean patients. This polymorphism was present in 5.2% of the control group and 5% of IBD patients (7.9% for CD and 3.2% for UC) (p > 0.05). CONCLUSIONS: These results suggest that the IL-23R Arg381Gln seems not to be involved in the genetic predisposition to IBD in a Chilean population, and confirms that there are ethnic differences in the genetic background of IBD. Replication studies by independent groups are necessary to elucidate the contribution of susceptibility genes to IBD in different ethnic populations.

[Inflammatory bowel diseases: an immunological approach]. / Enfermedad inflamatoria intestinal: Una mirada inmunológica.

Inflammatory bowel diseases (IBD) are inflammatory diseases with a multifactorial component that involve the intestinal tract. The two relevant IBD syndromes are Crohn's disease (CD) and ulcerative colitis (UC). One factor involved in IBD development is a genetic predisposition, associated to NOD2/CARD15 and Toll-like receptor 4 (TLR4) polymorphisms that might favor infectious enterocolitis that is possibly associated to the development of IBD. The identification of specific immunologic alterations in IBD and their relationship to the etiology of the disease is a relevant research topic. The role of intra and extracellular molecules, such as transcription factors and cytokines that are involved in the inflammatory response, needs to be understood. The relevance of immunologic molecules that might drive the immune response to a T helper (Th) 1, Th 2 or the recently described Th 17 phenotype, has been demonstrated in animal models and clinical studies with IBD patients. CD and UC predominantly behave with a Th 1 and Th 2 immune phenotype, respectively. Recently, an association between CD and Th 17 has been reported. The knowledge acquired from immunologic and molecular research will help to develop accurate diagnostic methods and efficient therapies.

Enfermedad inflamatoria intestinal: Una mirada inmunológica: [revisión] / Inflammatory bowel diseases: An immunological approach: [review]

Inflammatory bowel diseases (IBD) are inflammatory diseases with a multifactorial component that involve the intestinal tract. The two relevant IBD syndromes are Crohn's disease (CD) and ulcerative colitis (UC). One factor involved in IBD development is a genetic predisposition, associated to NOD2/CARD15 and Toll-like receptor 4 (TLR4) polymorphisms that might favor infectious enterocolitis that is possibly associated to the development of IBD. The identification of specific immunologic alterations in IBD and their relationship to the etiology of the disease is a relevant research topic. The role of intra and extracellular molecules, such as transcription factors and cytokines that are involved in the inflammatory response, needs to be understood. The relevance of immunologic molecules that might drive the immune response to a T helper (Th) 1, Th 2 or the recently described Th 17 phenotype, has been demonstrated in animal models and clinical studies with IBD patients. CD and UC predominantly behave with a Th 1 and Th 2 immune phenotype, respectively. Recently, an association between CD and Th 17 has been reported. The knowledge acquired from immunologic and molecular research will help to develop accurate diagnostic methods and efficient therapies.

Toll-like receptors are key participants in innate immune responses.

During an infection, one of the principal challenges for the host is to detect the pathogen and activate a rapid defensive response. The Toll-like family of receptors (TLRs), among other pattern recognition receptors (PRR), performs this detection process in vertebrate and invertebrate organisms. These type I transmembrane receptors identify microbial conserved structures or pathogen-associated molecular patterns (PAMPs). Recognition of microbial components by TLRs initiates signaling transduction pathways that induce gene expression. These gene products regulate innate immune responses and further develop an antigen-specific acquired immunity. TLR signaling pathways are regulated by intracellular adaptor molecules, such as MyD88, TIRAP/Mal, between others that provide specificity of individual TLR- mediated signaling pathways. TLR-mediated activation of innate immunity is involved not only in host defense against pathogens but also in immune disorders. The involvement of TLR-mediated pathways in auto-immune and inflammatory diseases is described in this review article.