A Decreased Response to Resistin in Mononuclear Leukocytes Contributes to Oxidative Stress in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. AIMS: To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. METHODS: We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. RESULTS: Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. CONCLUSIONS: Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis.

Obesity is associated with metabolic perturbations including liver and adipose tissue inflammation, insulin resistance, and type 2 diabetes. Omega-6 fatty acids (ω6) promote and omega-3 fatty acids (ω3) reduce inflammation as they can be metabolized to pro- and anti-inflammatory eicosanoids, respectively. 12/15-lipoxygenase (12/15-LO) enzymatically produces some of these metabolites and is induced by high fat (HF) diet. We investigated the effects of altering dietary ω6/ω3 ratio and 12/15-LO deficiency on HF diet-induced tissue inflammation and insulin resistance. We examined how these conditions affect circulating concentrations of oxidized metabolites of ω6 arachidonic and linoleic acids and innate and adaptive immune system activity in the liver. For 15 weeks, wild-type (WT) mice were fed either a soybean oil-enriched HF diet with high dietary ω6/ω3 ratio (11∶1, HFH), similar to Western-style diet, or a fat Kcal-matched, fish oil-enriched HF diet with a low dietary ω6/ω3 ratio of 2.7∶1 (HFL). Importantly, the total saturated, monounsaturated and polyunsaturated fat content was matched in the two HF diets, which is unlike most published fish oil studies in mice. Despite modestly increased food intake, WT mice fed HFL were protected from HFH-diet induced steatohepatitis, evidenced by decreased hepatic mRNA expression of pro-inflammatory genes and genes involved in lymphocyte homing, and reduced deposition of hepatic triglyceride. Furthermore, oxidized metabolites of ω6 arachidonic acid were decreased in the plasma of WT HFL compared to WT HFH-fed mice. 12/15-LO knockout (KO) mice were also protected from HFH-induced fatty liver and elevated mRNA markers of inflammation and lymphocyte homing. 12/15-LOKO mice were protected from HFH-induced insulin resistance but reducing dietary ω6/ω3 ratio in WT mice did not ameliorate insulin resistance or adipose tissue inflammation. In conclusion, lowering dietary ω6/ω3 ratio in HF diet significantly reduces steatohepatitis.

Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis natren life start strain super strain in active celiac disease.

BACKGROUND/AIMS: The aim of this exploratory trial was to establish if the probiotic Bifidobacterium natren life start (NLS) strain strain may affect the clinical course and pathophysiological features of patients with untreated celiac disease (CD). Positive findings would be helpful in directing future studies. METHODS: Twenty-two adult patients having 2 positives CD-specific tests were enrolled. Patients were randomized to receive 2 capsules before meals for 3 weeks of either Bifidobacterium infantis natren life start strain super strain (Lifestart 2) (2×10(9) colony-forming units per capsule) (n = 12) or placebo (n = 10), whereas they also consumed at least 12 g of gluten/day. A biopsy at the end of the trial confirmed CD in all cases. The primary outcome was intestinal permeability changes. Secondary endpoints were changes in symptoms and the Gastrointestinal Symptom Rating Scale, and in immunologic indicators of inflammation. RESULTS: The abnormal baseline intestinal permeability was not significantly affected by either treatment. In contrast to patients on placebo, those randomized to B. infantis experienced a significant improvement in Gastrointestinal Symptom Rating Scale (P = 0.0035 for indigestion; P = 0.0483 for constipation; P = 0.0586 for reflux). Final/baseline IgA tTG and IgA DGP antibody concentration ratios were lower in the B. infantis arm (P = 0.055 for IgA tTG and P = 0.181 for IgA DGP). Final serum macrophage inflammatory protein-1ß increased significantly (P < 0.04) only in patients receiving B. infantis. The administration of B. infantis was safe. CONCLUSIONS: The study suggests that B. infantis may alleviate symptoms in untreated CD. The probiotic produced some immunologic changes but did not modify abnormal intestinal permeability. Further studies are necessary to confirm and/or expand these observations.

The role of innate cells is coupled to a Th1-polarized immune response in pediatric nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory liver disease influenced by risk factors for the metabolic syndrome. In adult patients, NASH is associated with an altered phenotype and functionality of peripheral immune cells, the recruitment of leukocytes and intrahepatic activation, and an exacerbated production of reactive oxygen species (ROS) and cytokines. It remains unclear if the previously described differences between pediatric and adult nonalcoholic fatty liver diseases also reflect differences in their pathogenesis. AIMS: We aimed to investigate the phenotype and functionality of circulating immune cells and the potential contribution of liver infiltrating leukocytes to the immunological imbalance in pediatric NASH. RESULTS: By a real-time PCR-based analysis of cytokines and immunohistochemical staining of liver biopsies, we demonstrated that the hepatic microenvironment is dominated by interferon-gamma (IFN-γ) but not interleukin-4 and is infiltrated by a higher number of CD8(+) cells in pediatric NASH. The number of infiltrating neutrophils positively correlated with ROS generation by peripheral polymorphonuclear cells. By a flow cytometric analysis of peripheral blood lymphocytes, a distinctive increase in CD8(+) CD45RO and CD8(+) CD45RA subpopulations and an increased production of IFN-γ by CD4(+) and CD8(+) cells were shown. The production of ROS following PMA stimulation was augmented in circulating neutrophils but not in monocytes. CONCLUSION: In sum, the distinctive phenotype and functionality of infiltrating and circulating cells suggest that the role of innate cells is coupled to a Th1-polarized immune response in pediatric NASH.

The simultaneous high expression of Vα24, IFN-γ and FoxP3 characterizes the liver of children with type I autoimmune hepatitis.

The immunopathogenesis of type I autoimmune hepatitis (AIH-I) might involve the deregulation of different cellular processes. Here, we investigated the liver expression of selected cytokines and genes of regulatory cell populations in children both at diagnosis and during biochemical remission following immunosuppressive treatment (AIH-Ir). We found a higher Vα24, IFN-γ, FoxP3, IL-27p28, IL-12p40 and IL-21 expression at diagnosis as well as a positive correlation between IL-21 and transaminase levels. Interestingly, only IFN-γ and FoxP3 were decreased in AIH-Ir. An "AIH-I phenotype" (high Vα24, IFN-γ and FoxP3 expression at diagnosis) was observed in only 5 out of 22 AIH-Ir patients but not in controls. These results indicate a local deregulation of the innate and adaptive immune responses with an increased transcriptional activity of immunoregulatory cells at diagnosis. In addition, IL-21 is highlighted as a mediator of liver injury. AIH-Ir is characterized by a partial reversal of the deregulated response.

Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases.

OBJECTIVES: Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations. METHODS: To replicate this association in non-European populations, we evaluated case-control association between rs763361 and coeliac disease (CED) samples from Argentina; SLE, RA, type-1 diabetes (T1D) and primary SS (pSS) from Colombia; and SLE samples from China and Japan. We genotyped rs763361 and evaluated its genetic association with multiple ADs, using chi(2)-test. For each association, odds ratio (OR) and 95% CI were calculated. RESULTS: We show that rs763361 is significantly associated with Argentinean CED (P = 0.0009, OR = 1.60). We also observed a trend of possible association with Chinese SLE (P = 0.01, OR = 1.19), RA (P = 0.047, OR = 1.25), SLE (P = 0.0899, OR = 1.24) and pSS (P = 0.09, OR = 1.33) in Colombians. Meta-analyses for SLE (using our three populations) and T1D (our population and three published populations) yielded significant association with rs763361, P = 0.009 (OR = 1.16) and P = 1.1.46 x 10(-9) (OR = 1.14), respectively. CONCLUSIONS: Our results demonstrate that the coding variant rs763361 in CD226 gene is associated with multiple ADs in non-European populations.

Confirmation of an association between rs6822844 at the Il2-Il21 region and multiple autoimmune diseases: evidence of a general susceptibility locus.

OBJECTIVE: Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2-IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in non-European populations, and to perform disease-specific and overall meta-analyses using data from previously published studies. METHODS: We evaluated case-control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçet's disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies. RESULTS: We detected significant associations of rs6822844 with SLE (P = 0.008), type 1 DM (P = 0.014), RA (P = 0.019), and primary SS (P = 0.033) but not with BD (P = 0.34) or CD (P = 0.98). We identified little evidence of population differentiation (F(ST) = 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (P(meta) = 3.61 x 10(-6)), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) (P(meta) = 3.48 x 10(-12)), type 1 DM (P(meta) = 5.33 x 10(-5)), and CD (P(meta) = 5.30 x 10(-3)). Overall meta-analysis across all autoimmune diseases reinforced association with rs6822844 (23 data sets; P(meta) = 2.61 x 10(-25), odds ratio 0.73 [95% confidence interval 0.69-0.78]). CONCLUSION: Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.

Clinical characteristics and long-term outcome of patients with refractory sprue diagnosed at a single institution.

BACKGROUND: Refractory sprue (RS) is a rare and severe celiac-like enteropathy not responding to a strict gluten-free diet. Although prognosis is generally poor, little is known about the long-term outcome of patients. AIM: to report baseline characteristics and long-term outcome of a series of patients diagnosed and treated in a single institution. MATERIALS: We report a retrospective cohort of 25 consecutive patients (15 females; mean age 46 yr; range 28-71) diagnosed with RS based on the presence of a non-responsive celiac-like enteropathy. All patients were intensively treated with a gluten-free diet, steroids, nutritional support and immunosupression. RESULTS: Clinical and biological characteristics of patients suggest that, at least, 24 patients had clear evidences of celiac disease. HLA DQ2/DQ8 genes were present in all the 24 patients typed and autoimmune enteropathy was excluded in all. According to the genotyping, 12 patients had a polyclonal lymphocyte population (RS type I) and 13 exhibited monoclonal TCR-gamma gene rearrangements (RS type II). Sixteen patients had evidence of ulcerative jejunitis (UJ) (7 in RS type I and 9 in type II). Overall median follow-up time after diagnosis of RS was 29 mo/patient (range 7 to 204) (45 mo for type I and 24 mo for type II). Overall mortality was 48% (12 patients), 6 in each type. Eight patients with UJ (50%), 3 with lymphoma (two T-cell and one B-cell type) and 4 (44%) without ulcers died during follow-up. The causes of death were sepsis in the context of a progressive deterioration but without overt malignancies (n=5), vascular causes (n=3) and severe malnutrition (n=1). Three- and 5-yr survival rate after diagnosis of RS for the overall population was 60% and 56%. There was no differences between type I (67%, 58%) and type II RS patients (54% for both periods). Patients with UJ had lower but non-significant 3- and 5-yr survival rates (56% and 50%, respectively) compared with patients without ulcers (78% and 66%). Survivors had a favorable outcome. While 11 patients persists asymptomatic, two other cases still have mild diarrhea and one low body weight. CONCLUSIONS: We confirm that RS is a severe celiac disease-related disorder with very high mortality. Diagnosis of overt lymphoma (12%) in our long-term follow-up was not as frequent as was reported by other groups. A proportion of patients persist in good health for a long time irrespective of the nature of the IEL infiltration or the presence of UJ.

Clinical characteristics and long-term outcome of patients with refractory sprue diagnosed at a single institution

BACKGROUND: Refractory sprue (RS) is a rare and severe celiac-like enteropathy not responding to a strict gluten-free diet. Although prognosis is generally poor, little is known about the long-term outcome of patients. AIM: to report baseline characteristics and long-term outcome of a series of patients diagnosed and treated in a single institution. MATERIALS: We report a retrospective cohort of 25 consecutive patients (15 females; mean age 46 yr; range 28-71) diagnosed with RS based on the presence of a non-responsive celiac-like enteropathy. All patients were intensively treated with a gluten-free diet, steroids, nutritional support and immunosupression. RESULTS: Clinical and biological characteristics of patients suggest that, at least, 24 patients had clear evidences of celiac disease. HLA DQ2/DQ8 genes were present in all the 24 patients typed and autoimmune enteropathy was excluded in all. According to the genotyping, 12 patients had a polyclonal lymphocyte population (RS type I) and 13 exhibited monoclonal TCR-gamma gene rearrangements (RS type II). Sixteen patients had evidence of ulcerative jejunitis (UJ) (7 in RS type I and 9 in type II). Overall median follow-up time after diagnosis of RS was 29 mo/patient (range 7 to 204) (45 mo for type I and 24 mo for type II). Overall mortality was 48% (12 patients), 6 in each type. Eight patients with UJ (50%), 3 with lymphoma (two T-cell and one B-cell type) and 4 (44%) without ulcers died during follow-up. The causes of death were sepsis in the context of a progressive deterioration but without overt malignancies (n=5), vascular causes (n=3) and severe malnutrition (n=1). Three- and 5-yr survival rate after diagnosis of RS for the overall population was 60% and 56%. There was no differences between type I (67%, 58%) and type II RS patients (54% for both periods). Patients with UJ had lower but non-significant 3- and 5-yr survival rates (56% and 50%, respectively) compared with patients without ulcers... (AU)

Introducción: El sprue refractario (SR) es una rara y severa entidad consistente en una enteropatía tipo celíaca que no responde a una estricta dieta libre degluten. Aún cuando el pronóstico es generalmente pobre, poco es conocido acerca de la evolución de lospacientes a largo plazo. Objetivo: reportar las característicasclínicas y la evolución a largo plazo de una serie de pacientes diagnosticados y tratados en una solainstitución. Materiales: Reportamos una cohorteretrospectiva de 25 pacientes consecutivos (15 mujeres; edad media 46 años; rango 28-71) diagnosticadoscomo SR sobre la base de una enteropatía tipo celíaca que no respondió a la dieta libre de gluten. Todos los pacientes recibieron un tratamiento intensivo consistenteen dieta libre de gluten, alimentación enteral o parenteral, corticosteroides e inmunosupresión. Resultados: Los elementos clínicos y biológicos sugierenque 24 pacientes exhibían claras evidencias de enfermedadcelíaca. Los genes HLA DQ2/DQ8 estuvieron presentes en los 24 pacientes estudiados y se excluyó laenteropatía autoinmune en todos los casos. De acuerdo al genotipo, 12 pacientes presentaron una poblaciónlinfocitaria intraepitelial policlonal (SR tipo I) y 13 exhibieron un rearreglo genético monoclonal del TCR-γ (SR tipo II). Dieciséis pacientes presentaron evidencias de yeyunitis ulcerativa (YU) (7 en SR tipo I y 9 enel tipo II). El tiempo promedio de seguimiento luego del diagnóstico de SR fue 29 meses/paciente (rango 7 -204) (45 y 24 meses para tipo I y tipo II, respectivamente). La mortalidad global fue del 48% (12 pacientes),6 en cada tipo de SR. Ocho pacientes con YU (50%) murieron durante el seguimiento, 3 con linfoma(dos de células T y uno de células B) y cuatro(44%) individuos sin úlceras también fallecieron. Lascausas de muerte fueron vasculares (n=3), sepsis en elmarco de deterioro progresivo sin desarrollo de malignidad(n=5) y desnutrición progresiva (n=1)...(AU)

Clinical characteristics and long-term outcome of patients with refractory sprue diagnosed at a single institution

BACKGROUND: Refractory sprue (RS) is a rare and severe celiac-like enteropathy not responding to a strict gluten-free diet. Although prognosis is generally poor, little is known about the long-term outcome of patients. AIM: to report baseline characteristics and long-term outcome of a series of patients diagnosed and treated in a single institution. MATERIALS: We report a retrospective cohort of 25 consecutive patients (15 females; mean age 46 yr; range 28-71) diagnosed with RS based on the presence of a non-responsive celiac-like enteropathy. All patients were intensively treated with a gluten-free diet, steroids, nutritional support and immunosupression. RESULTS: Clinical and biological characteristics of patients suggest that, at least, 24 patients had clear evidences of celiac disease. HLA DQ2/DQ8 genes were present in all the 24 patients typed and autoimmune enteropathy was excluded in all. According to the genotyping, 12 patients had a polyclonal lymphocyte population (RS type I) and 13 exhibited monoclonal TCR-gamma gene rearrangements (RS type II). Sixteen patients had evidence of ulcerative jejunitis (UJ) (7 in RS type I and 9 in type II). Overall median follow-up time after diagnosis of RS was 29 mo/patient (range 7 to 204) (45 mo for type I and 24 mo for type II). Overall mortality was 48% (12 patients), 6 in each type. Eight patients with UJ (50%), 3 with lymphoma (two T-cell and one B-cell type) and 4 (44%) without ulcers died during follow-up. The causes of death were sepsis in the context of a progressive deterioration but without overt malignancies (n=5), vascular causes (n=3) and severe malnutrition (n=1). Three- and 5-yr survival rate after diagnosis of RS for the overall population was 60% and 56%. There was no differences between type I (67%, 58%) and type II RS patients (54% for both periods). Patients with UJ had lower but non-significant 3- and 5-yr survival rates (56% and 50%, respectively) compared with patients without ulcers... (AU)

Introducción: El sprue refractario (SR) es una rara y severa entidad consistente en una enteropatía tipo celíaca que no responde a una estricta dieta libre degluten. Aún cuando el pronóstico es generalmente pobre, poco es conocido acerca de la evolución de lospacientes a largo plazo. Objetivo: reportar las característicasclínicas y la evolución a largo plazo de una serie de pacientes diagnosticados y tratados en una solainstitución. Materiales: Reportamos una cohorteretrospectiva de 25 pacientes consecutivos (15 mujeres; edad media 46 años; rango 28-71) diagnosticadoscomo SR sobre la base de una enteropatía tipo celíaca que no respondió a la dieta libre de gluten. Todos los pacientes recibieron un tratamiento intensivo consistenteen dieta libre de gluten, alimentación enteral o parenteral, corticosteroides e inmunosupresión. Resultados: Los elementos clínicos y biológicos sugierenque 24 pacientes exhibían claras evidencias de enfermedadcelíaca. Los genes HLA DQ2/DQ8 estuvieron presentes en los 24 pacientes estudiados y se excluyó laenteropatía autoinmune en todos los casos. De acuerdo al genotipo, 12 pacientes presentaron una poblaciónlinfocitaria intraepitelial policlonal (SR tipo I) y 13 exhibieron un rearreglo genético monoclonal del TCR-γ (SR tipo II). Dieciséis pacientes presentaron evidencias de yeyunitis ulcerativa (YU) (7 en SR tipo I y 9 enel tipo II). El tiempo promedio de seguimiento luego del diagnóstico de SR fue 29 meses/paciente (rango 7 -204) (45 y 24 meses para tipo I y tipo II, respectivamente). La mortalidad global fue del 48% (12 pacientes),6 en cada tipo de SR. Ocho pacientes con YU (50%) murieron durante el seguimiento, 3 con linfoma(dos de células T y uno de células B) y cuatro(44%) individuos sin úlceras también fallecieron. Lascausas de muerte fueron vasculares (n=3), sepsis en elmarco de deterioro progresivo sin desarrollo de malignidad(n=5) y desnutrición progresiva (n=1)...(AU)

Clinical characteristics and long-term outcome of patients with refractory sprue diagnosed at a single institution / Características clínicas y evolución a largo plazo de una serie de pacientes con sprue refractario diagnosticados en una sola institución

BACKGROUND: Refractory sprue (RS) is a rare and severe celiac-like enteropathy not responding to a strict gluten-free diet. Although prognosis is generally poor, little is known about the long-term outcome of patients. AIM: to report baseline characteristics and long-term outcome of a series of patients diagnosed and treated in a single institution. MATERIALS: We report a retrospective cohort of 25 consecutive patients (15 females; mean age 46 yr; range 28-71) diagnosed with RS based on the presence of a non-responsive celiac-like enteropathy. All patients were intensively treated with a gluten-free diet, steroids, nutritional support and immunosupression. RESULTS: Clinical and biological characteristics of patients suggest that, at least, 24 patients had clear evidences of celiac disease. HLA DQ2/DQ8 genes were present in all the 24 patients typed and autoimmune enteropathy was excluded in all. According to the genotyping, 12 patients had a polyclonal lymphocyte population (RS type I) and 13 exhibited monoclonal TCR-gamma gene rearrangements (RS type II). Sixteen patients had evidence of ulcerative jejunitis (UJ) (7 in RS type I and 9 in type II). Overall median follow-up time after diagnosis of RS was 29 mo/patient (range 7 to 204) (45 mo for type I and 24 mo for type II). Overall mortality was 48% (12 patients), 6 in each type. Eight patients with UJ (50%), 3 with lymphoma (two T-cell and one B-cell type) and 4 (44%) without ulcers died during follow-up. The causes of death were sepsis in the context of a progressive deterioration but without overt malignancies (n=5), vascular causes (n=3) and severe malnutrition (n=1). Three- and 5-yr survival rate after diagnosis of RS for the overall population was 60% and 56%. There was no differences between type I (67%, 58%) and type II RS patients (54% for both periods). Patients with UJ had lower but non-significant 3- and 5-yr survival rates (56% and 50%, respectively) compared with patients without ulcers...

Introducción: El sprue refractario (SR) es una rara y severa entidad consistente en una enteropatía tipo celíaca que no responde a una estricta dieta libre degluten. Aún cuando el pronóstico es generalmente pobre, poco es conocido acerca de la evolución de lospacientes a largo plazo. Objetivo: reportar las característicasclínicas y la evolución a largo plazo de una serie de pacientes diagnosticados y tratados en una solainstitución. Materiales: Reportamos una cohorteretrospectiva de 25 pacientes consecutivos (15 mujeres; edad media 46 años; rango 28-71) diagnosticadoscomo SR sobre la base de una enteropatía tipo celíaca que no respondió a la dieta libre de gluten. Todos los pacientes recibieron un tratamiento intensivo consistenteen dieta libre de gluten, alimentación enteral o parenteral, corticosteroides e inmunosupresión. Resultados: Los elementos clínicos y biológicos sugierenque 24 pacientes exhibían claras evidencias de enfermedadcelíaca. Los genes HLA DQ2/DQ8 estuvieron presentes en los 24 pacientes estudiados y se excluyó laenteropatía autoinmune en todos los casos. De acuerdo al genotipo, 12 pacientes presentaron una poblaciónlinfocitaria intraepitelial policlonal (SR tipo I) y 13 exhibieron un rearreglo genético monoclonal del TCR-γ (SR tipo II). Dieciséis pacientes presentaron evidencias de yeyunitis ulcerativa (YU) (7 en SR tipo I y 9 enel tipo II). El tiempo promedio de seguimiento luego del diagnóstico de SR fue 29 meses/paciente (rango 7 -204) (45 y 24 meses para tipo I y tipo II, respectivamente). La mortalidad global fue del 48% (12 pacientes),6 en cada tipo de SR. Ocho pacientes con YU (50%) murieron durante el seguimiento, 3 con linfoma(dos de células T y uno de células B) y cuatro(44%) individuos sin úlceras también fallecieron. Lascausas de muerte fueron vasculares (n=3), sepsis en elmarco de deterioro progresivo sin desarrollo de malignidad(n=5) y desnutrición progresiva (n=1)...

Coeliac disease.

Coeliac disease is a gluten-sensitive enteropathy characterized by villous atrophy, hyperplastic crypts and increased numbers of intraepithelial lymphocytes which are reversed by gluten withdrawal. Diverse autoimmune disorders are frequently associated with the disease, and patients also carry an increased risk of gastrointestinal malignancy. This review is aimed at outlining the current knowledge on the contribution of the innate immunity to the whole progress of coeliac disease, catalogued as the prototype of an immune-mediated response dominated by the activation of the adaptive immune system. The accumulated data suggest a model in which the gliadin moiety triggers the upregulation of costimulatory molecules on antigen presenting cells in the lamina propria, and the generation of specialized functions on intraepithelial lymphocytes. In the lamina propria, gliadin effects are essential for the generation of a robust T cell response while in the epithelial compartment, gliadin effects confer both innate-like and TCR-mediated cytotoxicity strongly contributing to tissue injury.

Clinical characteristics and long-term outcome of patients with refractory sprue diagnosed at a single institution.

BACKGROUND: Refractory sprue (RS) is a rare and severe celiac-like enteropathy not responding to a strict gluten-free diet. Although prognosis is generally poor, little is known about the long-term outcome of patients. AIM: to report baseline characteristics and long-term outcome of a series of patients diagnosed and treated in a single institution. MATERIALS: We report a retrospective cohort of 25 consecutive patients (15 females; mean age 46 yr; range 28-71) diagnosed with RS based on the presence of a non-responsive celiac-like enteropathy. All patients were intensively treated with a gluten-free diet, steroids, nutritional support and immunosupression. RESULTS: Clinical and biological characteristics of patients suggest that, at least, 24 patients had clear evidences of celiac disease. HLA DQ2/DQ8 genes were present in all the 24 patients typed and autoimmune enteropathy was excluded in all. According to the genotyping, 12 patients had a polyclonal lymphocyte population (RS type I) and 13 exhibited monoclonal TCR-gamma gene rearrangements (RS type II). Sixteen patients had evidence of ulcerative jejunitis (UJ) (7 in RS type I and 9 in type II). Overall median follow-up time after diagnosis of RS was 29 mo/patient (range 7 to 204) (45 mo for type I and 24 mo for type II). Overall mortality was 48

(12 patients), 6 in each type. Eight patients with UJ (50

), 3 with lymphoma (two T-cell and one B-cell type) and 4 (44

) without ulcers died during follow-up. The causes of death were sepsis in the context of a progressive deterioration but without overt malignancies (n=5), vascular causes (n=3) and severe malnutrition (n=1). Three- and 5-yr survival rate after diagnosis of RS for the overall population was 60

and 56

. There was no differences between type I (67

, 58

) and type II RS patients (54

for both periods). Patients with UJ had lower but non-significant 3- and 5-yr survival rates (56

and 50

, respectively) compared with patients without ulcers (78

and 66

). Survivors had a favorable outcome. While 11 patients persists asymptomatic, two other cases still have mild diarrhea and one low body weight. CONCLUSIONS: We confirm that RS is a severe celiac disease-related disorder with very high mortality. Diagnosis of overt lymphoma (12

) in our long-term follow-up was not as frequent as was reported by other groups. A proportion of patients persist in good health for a long time irrespective of the nature of the IEL infiltration or the presence of UJ.

Evidences of the involvement of Bak, a member of the Bcl-2 family of proteins, in active coeliac disease.

Apoptosis of enterocytes is a feature that characterises the development of lesions in coeliac disease (CD). However, the intracellular pathways that lead to apoptosis of enterocytes have not been completely clarified. Bak is a member of the Bcl-2 family of proteins that acts as an endogenous promoter of apoptosis in normal enterocytes. However, its role in coeliac lesions has not been explored. We used small intestinal mucosa from patients with CD to evaluate the differential expression of members of the Bcl-2 family of proteins. Gene expression of Bak was analysed by RT-PCR of biopsies from 14 patients with untreated CD and from 19 controls without CD. In these samples, we also investigated the localisation of the Bak protein by immunohistochemistry and its apoptotic activity. In patients with untreated CD there was a 2.3-fold higher expression of Bak mRNA (p = 0.026), without significant differences in the expression of related genes bax or bcl-2. The higher expression of interferon gamma (IFN-gamma) (p = 0.036) and the higher number of apoptotic cells identified by the TUNEL method (p = 0.032) confirmed the proapoptotic status in the intestinal mucosa of CD patients. We found a significant positive correlation (p < 0.0001) between the expression of IFN-gamma and Bak mRNA in patients with untreated CD. The expression of Bak protein was higher in patients with CD, and the immunoreactivity was almost restricted to the epithelium. We found that Bak mRNA and its protein were overexpressed in the intestinal lesions of CD patients and that IFNgamma confers increased susceptibility for enterocytes to undergo apoptosis via upregulation of Bak.