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Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.
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Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Sialiltransferasas/genética , Animales , Homeostasis , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Ratones , Moco/metabolismo , Sialiltransferasas/metabolismo , SimbiosisRESUMEN
BACKGROUND & AIMS: Advances in genomic technologies have led to increasing reports of monogenic inflammatory bowel disease (IBD). Here, we systematically review the literature to determine the clinical features, genetic profile, and previously used treatment strategies in monogenic IBD. METHODS: A systematic review of MEDLINE articles published between January 2000 and December 2020 was conducted. A total of 750 individual monogenic IBD cases were identified from 303 eligible articles. RESULTS: The most frequently reported monogenic IBD genes were IL10RA/B, XIAP, CYBB, LRBA, and TTC7A. In total, 63.4% of patients developed IBD before 6 years of age, 17.4% developed IBD between ages 10 and 17.9 years, and 10.9% developed IBD after age 18. There was a substantial difference between these age groups and the underlying monogenic disorders. Only 31.7% had any history of extraintestinal comorbidity (EIC) before IBD onset, but 76.0% developed at least 1 EIC during their clinical course. The most common EICs were atypical infection (44.7%), dermatologic abnormality (38.4%), and autoimmunity (21.9%). Bowel surgery, biologic therapy, and hematopoietic stem cell transplantation were performed in 27.1%, 32.9%, and 23.1% of patients, respectively. CONCLUSIONS: Monogenic IBD cases, although rare, have varied extraintestinal comorbidities and limited treatment options including surgery and transplant. Early identification and improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is important for effective management.
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Colitis , Enfermedades Inflamatorias del Intestino , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Edad de Inicio , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/terapia , ProteínasRESUMEN
BACKGROUND AND AIMS: The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms of intestinal dysmotility disorders. we aimed to describe the diverse phenotype of this newly reported and rare disease. METHODS: Report of 4 new patients, and a systematic review of ACTG2-related disorders. we analyzed the population frequency and used in silico gene damaging predictions. Genotype-phenotype correlations were explored. RESULTS: One hundred three patients (52% girls), from 14 publications, were included. Twenty-eight unique variants were analyzed, all exceedingly rare, and 27 predicted to be highly damaging. The median Combined Annotation Dependent Depletion (CADD) score was 29.2 (Interquartile range 26.3-29.4). Most patients underwent abdominal surgery (66%), about half required intermittent bladder catheterization (48.5%), and more than half were parenteral nutrition (PN)-dependent (53%). One-quarter of the patients died (25.7%), and 6 required transplant (5.8%). Girls had a higher rate of microcolon (Pâ =â0.009), PN dependency (Pâ=â0.003), and death/transplant (Pâ=â0.029) compared with boys, and early disease onset (<2âyears of age) was associated with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) features. There was no statistical association between disease characteristics and CADD scores. CONCLUSIONS: Damaging ACTG2 variants are rare, often associated with MMIHS phenotype, and overall have a wide phenotypic variation. Symptoms usually present in the perinatal period but can also appear at a later age. The course of the disease is marked by frequent need for surgical interventions, PN support, and mortality. Poor outcomes are more common among girls with ACTG2 variants.
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Anomalías Múltiples , Seudoobstrucción Intestinal , Anomalías Múltiples/diagnóstico , Actinas/genética , Colon/anomalías , Femenino , Humanos , Seudoobstrucción Intestinal/diagnóstico , Seudoobstrucción Intestinal/genética , Masculino , Fenotipo , Embarazo , Vejiga Urinaria/anomalíasRESUMEN
In 2021 and 2022, there were noted to be clusters of pediatric acute hepatitis of unknown origin (AHUO) occurring across the globe. While there was not necessarily a global increase in cases, understanding the pattern of liver injury in AHUO is crucial to properly identify cases of this unexplained phenomenon, especially since it occurred simultaneously with a global resurgence of COVID-19. The objective of this study was to contrast the patterns in liver-relevant biochemical data from COVID-19 patients and AHUO. Studies reporting liver chemistries for cases of AHUO and COVID-19 were identified by a systematic review and search of the literature. For each case, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin, and international normalized ratio (INR) levels were extracted as available. These were normalized to multiples of the upper limit of normal by patient age. There were statistically significant greater elevations of ALT and AST in patients with AHUO than in those with COVID-19. Only a subset of patients with COVID-19 had an AST or ALT greater than the normal range. INR elevation could be substantial for both conditions but was also statistically higher in the AHUO group. Liver chemistry changes were not statistically correlated with age. The pattern of liver chemistry changes between AHUO and COVID-19 have some distinctions, which suggests that AHUO is not a phenomenon driven primarily by SARS-CoV-2 infection alone. Differentiating AHUO and COVID-19 would be challenging based on patterns of liver chemistry changes alone.
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OBJECTIVES: We aimed to use the high fidelity urgent care patient data to model the factors that have led to the increased demand at our local pediatric urgent care centre. METHODS: The dataset for this retrospective cohort study was obtained from our local healthcare centre's national reporting data for pediatric urgent care visits from 2006 to 2022. Variables analyzed included: basic patient demographics, chief complaint, triage urgency, date and time of registration/discharge, discharge diagnosis, and discharge destination. Statistical analysis of non-linear trends was summarized by locally estimated scatterplot smoothing splines. For machine learning, we used the tidymodels R package. Models were validated in training using k-fold cross validation with k = 5. We used univariate linear regression as a baseline model. After the data was standardized, correlation and homoscedasticity were evaluated between all parameter permutations. RESULTS: This dataset consisted of 164,660 unique visits to our academic centre's pediatric urgent care. Over the study period, there was an overall substantial increase in the number of urgent care visits per day, with a rapid increase beyond previous levels in 2021 and further in 2022. The increased length of stay trend was consistent across presenting complaint categories. The proportion of patients without primary care in 2022 was 2.5 times higher than in 2013. A random forest machine learning model revealed the relative importance of features to predicting a visit in 2022 were: longer stay, later registration in the day, diagnosis of an infectious illness, and younger age. CONCLUSIONS: This study identified a combination of declining primary care access, circulating viral infections, and shifting chief complaints as factors driving the recent increase in frequency and duration of visits to our urgent care service.
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INTRODUCTION: Previous national registry studies have reported an increased risk of eating disorders in immune-mediated conditions (inflammatory bowel disease and celiac disease). Our objective was to examine the association between immune-mediated gastrointestinal (GI) diseases and incident eating disorders in Ontario. METHODS: This was a retrospective matched cohort study of individuals <50 years of age with a diagnosis of an immune-mediated GI disease between 2002 and 2020 ("cases"). Those with a pre-existing eating disorder were excluded. Cases (n = 83,920) were matched with controls (n = 167,776) based on birth year, sex, and region of residence. Incidence rate ratio and hazard ratio were estimated using Poisson regression model and adjusted Cox proportional models, respectively. RESULTS: Over the follow-up period (up to January 31, 2022), 161 cases and 160 controls were identified with eating disorders. The overall incidence rate ratio (95% confidence interval, P -value) of eating disorders in immune-mediated GI disease was 1.99 (1.6-2.5, P < 0.001). The adjusted hazard ratio for eating disorder in cases with immune-mediated GI diseases was 1.98 (1.6-2.5, P < 0.001). In the pediatric group of incident cases (≤18 years of age), overall adjusted hazard ratio was 2.62 (1.9-3.7, P < 0.001) compared with 1.56 (1.02-2.4, P = 0.041) for adults (>18 years of age). The largest hazard ratio of 4.11 (1.6-10.3, P = 0.003) was observed for pediatric incident cases of ulcerative colitis. DISCUSSION: Inflammatory bowel disease and celiac disease are associated with the development of eating disorders. The magnitude of the association was stronger in the pediatric age group, underscoring the need for early screening and detection.
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Enfermedad Celíaca , Trastornos de Alimentación y de la Ingestión de Alimentos , Enfermedades Inflamatorias del Intestino , Humanos , Masculino , Femenino , Enfermedad Celíaca/epidemiología , Ontario/epidemiología , Estudios Retrospectivos , Adulto , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Incidencia , Adolescente , Adulto Joven , Niño , Persona de Mediana Edad , Enfermedades Inflamatorias del Intestino/epidemiología , Factores de Riesgo , Preescolar , Bases de Datos Factuales , Estudios de Casos y Controles , Modelos de Riesgos Proporcionales , LactanteAsunto(s)
Analgésicos/uso terapéutico , Ketamina/uso terapéutico , Metadona/uso terapéutico , Dolor Intratable/tratamiento farmacológico , Pancreatitis/tratamiento farmacológico , Adolescente , Humanos , Masculino , Uso Fuera de lo Indicado , Manejo del Dolor/métodos , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
BACKGROUND AND OBJECTIVES: Diagnosing eosinophilic esophagitis (EoE) depends on intraepithelial eosinophil count of ≥15 eosinophils per high-power field (HPF); however, differentiating EoE from gastroesophageal reflux disease (GERD) continues to be a challenge because no true "criterion standard" criteria exist. Identifying clinical and endoscopic characteristics that distinguish EoE could provide a more comprehensive diagnostic strategy than the present criteria. The aim of the study was to determine symptoms and signs that can be used to distinguish EoE from reflux esophagitis. METHODS: Adult and pediatric patients with EoE were identified by present diagnostic guidelines including an esophageal biopsy finding of ≥15 eosinophils/HPF. Patients with GERD were age-matched one to one with patients with EoE. Clinical, endoscopic, and histologic information at the time of diagnosis was obtained from the medical record and compared between pairs by McNemar test. A conditional logistic regression model was created using 6 distinguishing disease characteristics. This model was used to create a nomogram to differentiate EoE from reflux-induced esophagitis. RESULTS: Patients with EoE were 75% men and 68% had a history of atopy. Many aspects of EoE were statistically distinct from GERD when controlling for age. Male sex, dysphagia, history of food impaction, absence of pain/heartburn, linear furrowing, and white papules were the distinguishing variables used to create the logistic regression model and scoring system based on odds ratios. The area under the curve of the receiver-operator characteristic curve for this model was 0.858. CONCLUSIONS: EoE can be distinguished from GERD using a scoring system of clinical and endoscopic features. Prospective studies will be needed to validate this model.
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Esofagitis Eosinofílica/diagnóstico , Esofagitis Péptica/diagnóstico , Esófago/fisiopatología , Estudios de Casos y Controles , Estudios de Cohortes , Trastornos de Deglución/etiología , Diagnóstico Diferencial , Registros Electrónicos de Salud , Endoscopios Gastrointestinales , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/patología , Esofagitis Eosinofílica/fisiopatología , Esofagitis Péptica/inmunología , Esofagitis Péptica/patología , Esofagitis Péptica/fisiopatología , Esófago/inmunología , Esófago/patología , Femenino , Pirosis/etiología , Humanos , Modelos Logísticos , Masculino , Pigmentación , Guías de Práctica Clínica como Asunto , Curva ROC , Estudios Retrospectivos , Distribución por Sexo , Propiedades de SuperficieRESUMEN
In April 2022, the World Health Organization (WHO) declared a global outbreak of acute hepatitis of unknown etiology (AHUE) with a high risk of severe outcomes, for which various etiologies have been proposed by the literature. This study examines primary reports of pediatric AHUE cases and summarizes the proposed etiologies. This systematic review collected and evaluated published peer-reviewed articles, official data, and clinical reports of AHUE cases that met the WHO working case definition. 19 hypothesized etiologies for AHUE were identified from 36 sources, which fell into eight categories. While human adenovirus (HAdV) infection, viral infection, and immune-mediated responses were commonly suspected as causes of AHUE, no definitive etiology or epidemiological link has been established. However, recent evidence implicates adeno-associated virus-2 (AAV2) as a likely significant contributor. Conducting a comprehensive literature review following outbreaks is necessary for developing responsive strategies and protocols.
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Professional antigen-presenting cells (APCs) play a crucial role in initiating immune responses. Under pathological conditions, epithelial cells at mucosal surfaces act as nonprofessional APCs, thereby regulating immune responses at the site of exposure. Epithelial cells in the esophagus may contribute to the pathogenesis of eosinophilic esophagitis (EoE) by presenting antigens on the major histocompatibility complex (MHC) class II. Our goal was to demonstrate the ability of esophageal epithelial cells to process and present antigens on the MHC class II system and to investigate the contribution of epithelial cell antigen presentation to EoE. Immunohistochemistry detected HLA-DR, CD80, and CD86 expression and enzyme-linked immunosorbent assay detected interferon-γ (IFNγ) in esophageal biopsies. Antigen presentation was studied using the human esophageal epithelial cell line HET-1A by reverse transcriptase-PCR, flow cytometry, and confocal microscopy. T helper cell lymphocyte proliferation was assessed by flow cytometry and IL-2 secretion. IFNγ and MHC class II were increased in mucosa of patients with EoE. IFNγ increased mRNA of HLA-DP, HLA-DQ, HLA-DR, and CIITA in HET-1A cells. HET-1A engulfed cell debris and processed ovalbumin. HET-1A cells expressed HLA-DR after IFNγ treatment. HET-1A stimulated T helper cell activation. In this study, we demonstrated the ability of esophageal epithelial cells to act as nonprofessional APCs in the presence of IFNγ. Esophageal epithelial cell antigen presentation may contribute to the pathophysiology of eosinophilic esophagitis.
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Presentación de Antígeno/inmunología , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/patología , Células Epiteliales/inmunología , Esófago/inmunología , Esófago/patología , Antígenos de Histocompatibilidad Clase II/inmunología , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/genética , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Reactividad Cruzada/efectos de los fármacos , Esofagitis Eosinofílica/genética , Células Epiteliales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Inmunización , Interferón gamma/metabolismo , Interferón gamma/farmacología , Interleucina-4/farmacología , Activación de Linfocitos/efectos de los fármacos , Membrana Mucosa/inmunología , Membrana Mucosa/patología , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Toxina Tetánica/farmacologíaRESUMEN
AIMS: Eosinophilic oesophagitis (EoE) occurs in atopic individuals and features eosinophils and mast cells, but differences in the inflammatory cell density between the epithelium and lamina propria (LP) are not fully understood. The aim of this study was to determine if numbers of eosinophils, B lymphocytes and immunoglobulin E (IgE)-bearing mast cells are increased in the mucosa of EoE patients with and without concurrent atopy. METHODS AND RESULTS: Oesophageal biopsies containing ≥ 4 high-power fields (HPF) of epithelium and LP were identified for normal (n = 9), gastroesophageal reflux disease (GERD) (n = 5) and EoE (n = 25) patients. Patients were classified as atopic or not by clinical history. Immunohistochemistry identified mast cells, B lymphocytes and eosinophils. Eosinophil density was increased in the LP in EoE. Intraepithelial eosinophil density correlated with eosinophils/HPF, CD20(+) B lymphocyte density and tryptase(+) IgE(+) mast cell density. Increased intraepithelial IgE(+) cell density in EoE was associated with mast cells and not B lymphocytes. Intraepithelial IgE(+) mast cell densities were significantly higher in biopsies from the subgroup of EoE patients with atopy. CONCLUSIONS: EoE diagnosis using maximal eosinophil count/HPF correlates with average counts/mm(2), and intraepithelial eosinophil densities are higher in children than adults with EoE. In EoE, numbers of eosinophils and mast cells are increased in the LP. IgE-bearing mast cells are increased in atopic EoE patients but not in non-atopic EoE patients.
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Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/patología , Hipersensibilidad Inmediata/inmunología , Hipersensibilidad Inmediata/patología , Inmunoglobulina E/metabolismo , Mastocitos/inmunología , Mastocitos/patología , Adolescente , Adulto , Anciano , Linfocitos B/patología , Recuento de Células , Niño , Preescolar , Eosinófilos/patología , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Reflujo Gastroesofágico/inmunología , Reflujo Gastroesofágico/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Membrana Mucosa/inmunología , Membrana Mucosa/patologíaRESUMEN
BACKGROUND: The chronic disease eosinophilic esophagitis may be mediated by the innate immune system. Activation of toll-like receptors (TLRs) in other tissues is known to initiate eosinophil infiltration, thus TLRs may be a potential mediator of esophageal eosinophilia. Little is known about TLRs in the esophagus. AIMS: The purpose of this study was to identify the presence and activation of TLR2 and TLR3 on esophageal epithelial cell lines, primary epithelial cells and mucosal esophageal biopsies. METHODS: TLR2 and TLR3 were identified by immunocytochemistry and immunoblot. PCR assessed alterations to gene expression by activation of TLR2 and TLR3. Immunohistochemistry co-localized eosinophils and TLR2/TLR3 on esophageal biopsies. RESULTS: TLR2 and TLR3 were expressed on the esophageal adenocarcinoma cell lines TE-1 and TE-7, but only TLR3 was present on the esophageal epithelial cell line HET-1A. Thymic stromal lymphopoietin gene expression was altered in response to ligands zymosan and polyI:C, demonstrating activation. Primary esophageal epithelial cells did not express TLR2 or TLR3. In esophageal biopsies, TLR2 and TLR3 expression was limited to eosinophils and other immune cells during esophagitis. CONCLUSIONS: TLR2 and TLR3 expression on cultured esophageal epithelial cells differs from TLR2 and TLR3 expression in esophageal biopsies, which is limited to immune cells during esophagitis.
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Esofagitis Eosinofílica/inmunología , Eosinófilos/inmunología , Células Epiteliales/inmunología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 3/metabolismo , Adenocarcinoma/inmunología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Biopsia , Línea Celular Transformada , Citocinas/genética , Citocinas/inmunología , Esofagitis Eosinofílica/metabolismo , Esofagitis Eosinofílica/patología , Eosinófilos/citología , Eosinófilos/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Esófago/citología , Esófago/inmunología , Esófago/metabolismo , Expresión Génica/inmunología , Humanos , Cultivo Primario de Células , Linfopoyetina del Estroma TímicoRESUMEN
Background: Obesity is associated with chronic, low-grade inflammation, which is reflected in altered peripheral blood monocyte characteristics. The aim of this study was to analyze the monocyte subset composition (classical (CM), intermediate (IM) and non-classical monocytes (NCM)), and their inflammatory marker profile (CD14, CD16, CD36, CD45, CD64, CD300e, HLA-DR) in individuals with obesity during a 1.5 year combined lifestyle intervention (CLI), comprising healthy nutrition, increased exercise and behavioral changes. Methods: We analyzed monocyte subset counts and immunophenotypes in 73 individuals with obesity, and associated these to baseline body mass index (BMI) and waist circumference (WC). The measurements were repeated after 10 weeks and at the end of the intervention (1.5 years). Results: Generally, monocyte subset counts were not associated to BMI or WC at baseline, neither did monocyte counts change during the 1.5 year CLI. Immunophenotypically, higher baseline BMI and WC were associated to lower CD14 and higher CD300e expression by all subsets. During CLI there were remarkable changes in marker profiles: expression of CD14, CD36, CD45 and CD64 significantly decreased in CM and IM, as did CD16 (IM and NCM) (p<0.05). CD300e initially decreased after 10 weeks, but increased sharply at 1.5 years (all subsets). We observed no consistent associations between changes in monocyte characteristics and anthropometric changes. Conclusion: A 1.5 year CLI in individuals with obesity mediates persistent immunophenotypic adaptations related to cellular activation in blood monocytes, whereas changes in subset distribution are limited. Lifestyle-induced changes in the inflammatory profile of monocytes differ from the 'less-severe-obesity'-phenotype, suggesting a novel, 'post-weight-loss' monocyte setpoint.
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Monocitos , Obesidad , Humanos , Obesidad/terapia , Índice de Masa Corporal , Pérdida de Peso , Recuento de Leucocitos , Receptores de IgG , Antígenos CD36 , InflamaciónRESUMEN
Background and Aims: Diagnosis of monogenic disease is increasingly important for patient care and personalizing therapy. However, the current process is nonstandardized, expensive, and time consuming. There is currently no accepted strategy to help identify disease-causing variants in monogenic inflammatory bowel disease (IBD). The aim of the study is to develop a prioritization strategy for monogenic IBD variant discovery through detailed analysis of a whole-exome sequencing (WES) data set. Methods: All consenting pediatric patients with IBD presenting to our tertiary care hospital during the study period were enrolled and underwent WES (n = 1005). Available family members also underwent WES. Variants were analyzed en masse using the GEMINI framework and were further annotated using data from dbNSFP, Combined Annotation Dependent Depletion, and gnomAD. Known disease-causing variants (n = 36) were used as positive controls. Machine learning algorithms were optimized and then compared to assist with identifying monogenic IBD case characteristics. Results: Initial gene-level analysis identified 11 genes not previously linked to IBD that could potentially harbor IBD-causing variants. Machine learning algorithms identified 4 primary variant characteristics (Combined Annotation Dependent Depletion score, dbNSFP score, relationship with a known immunodeficiency gene, and alternate allele frequency), and optimal threshold values for each were determined to assist with identifying monogenic IBD variants. Based on these characteristics, an automated variant prioritization pipeline was then created that filters and prioritizes variants from >100,000 variants per patient down to a mean of 15. This pipeline is available online for all to use. Conclusion: Leveraging a large WES data set, we demonstrate a statistically rigorous strategy for prioritization of variants for monogenic IBD diagnosis.
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BACKGROUND: Biologic agents are a highly useful class of medications for treating inflammatory bowel disease (IBD). Limited evidence exists to guide initiation of biologic therapy, especially in pediatric patients. It is unclear if disease severity is connected to biologic response. We hypothesized that the clinical, biochemical and radiographic characteristics of pediatric IBD at diagnosis were associated with subsequent initiation of biologic therapy. METHODS: We performed a retrospective analysis of the charts of all pediatric patients diagnosed with IBD at our centre over 14 years. Kaplan-Meier curves evaluated patient characteristics at diagnosis with time to initiation of biologic therapy. A Cox proportional hazards model was used for multivariate characteristic analysis. RESULTS: A total of 198 patients were included, 57.6% had Crohn's disease, 27.8% had ulcerative colitis and 14.6% had IBD type unclassified. Mean follow-up time was 47.8 months. About 55.5% of the patients received a biologic medication, the mean time to biologic initiation was 21.5 months. Earlier initiation of biologic therapy was frequently associated with older age, higher disease activity index and lower serum albumin. CONCLUSIONS: Older pediatric patients with more severely active disease and lower serum albumin levels at the time of IBD diagnosis were more likely to initiate biologic therapy when considering biologic initiation, even many years after diagnosis. Identification of these characteristics may help inform decisions to initiate biologic therapy earlier in the IBD disease course.
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Immune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when they are elevated by genetic or environmental causes, they can lead to autoimmunity. Events that control ongoing signal transduction are, therefore, tightly regulated by submembrane cytoskeletal polymers like F-actin. The actin-binding proteins that underpin the process, however, are poorly described. By investigating patients with ARPC1B deficiency, we report that ARPC1B-containing ARP2/3 complexes are stimulated by Wiskott Aldrich Syndrome protein (WASP) to nucleate the branched actin networks that control tonic signaling from the B cell receptor (BCR). Despite an upregulation of ARPC1A, ARPC1B-deficient cells were not capable of WASP-mediated nucleation by ARP2/3, and this caused the loss of WASP-dependent structures, including podosomes in macrophages and lamellipodia in B cells. In the B cell compartment, ARPC1B deficiency also led to weakening of the cortical F-actin cytoskeleton that normally curtails the diffusion of BCRs and ultimately resulted in increased tonic lipid signaling, oscillatory calcium release from the endoplasmic reticulum (ER), and phosphorylated Akt. These events contributed to skewing the threshold for B cell activation in response to microbial-associated molecular patterns (MAMPs). Thus, ARPC1B is critical for ARP2/3 complexes to control steady-state signaling of immune cells.
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Complejo 2-3 Proteico Relacionado con la Actina/efectos adversos , Actinas/metabolismo , Linfocitos B/metabolismo , Proteína del Síndrome de Wiskott-Aldrich/metabolismo , Humanos , PolimerizacionRESUMEN
Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
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Artritis/genética , Colitis/genética , Dermatitis/genética , Linfoma de Células B Grandes Difuso/genética , Quinasa Syk/genética , Adulto , Animales , Artritis/inmunología , Artritis/patología , Artritis/terapia , Secuencia de Bases , Trasplante de Médula Ósea , Colitis/inmunología , Colitis/patología , Colitis/terapia , Dermatitis/inmunología , Dermatitis/patología , Dermatitis/terapia , Familia , Femenino , Expresión Génica , Técnicas de Sustitución del Gen , Humanos , Lactante , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Mutación , Linaje , Inhibidores de Proteínas Quinasas/farmacología , Quinasa Syk/antagonistas & inhibidores , Quinasa Syk/deficienciaRESUMEN
Celiac artery compression syndrome is a rare cause of abdominal pain and weight loss, likely caused by compression of the celiac artery or plexus by the median arcuate ligament. A case of celiac artery compression syndrome in a 17-year-old male patient with severe postprandial pain and weight loss is described. Imaging techniques such as computed tomography, angiography and Doppler ultrasound identified the abnormality, which was corrected by laparoscopic surgery.
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Dolor Abdominal/etiología , Arteria Celíaca , Pérdida de Peso , Adolescente , Aorta Abdominal/diagnóstico por imagen , Arteriopatías Oclusivas/complicaciones , Arteriopatías Oclusivas/diagnóstico , Arteria Celíaca/diagnóstico por imagen , Arteria Celíaca/patología , Constricción Patológica , Humanos , Masculino , Periodo Posprandial , Radiografía , Recurrencia , Síndrome , Ultrasonografía DopplerRESUMEN
INTRODUCTION: We hypothesized that variants within clinically relevant pharmacogenes could be identified using a whole exome sequencing data set derived from a cohort of more than 1,000 patients with inflammatory bowel disease (IBD). METHODS: Pediatric patients diagnosed with IBD underwent whole exome sequencing. We selected 18 genes with supporting literature where specific exonic variants would influence clinical care. RESULTS: We identified actionable pharmacogenomic variants in 63% of patients. Importantly, 5% of patients with IBD were at risk for serious adverse effects from anesthesia and 3% were at increased risk for thrombosis. DISCUSSION: We identified exonic variants in most of our patients with IBD that directly impact clinical care.