Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients’ biopsies, and ALPI activity was undetectable in ALPI-deficient patient\u27s stool. Our findings highlight the crucial role of ALPI in regulating host–microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders

Is alfa-interferon still current in the management of Kasabach-Merritt syndrome?

International audienceKasabach-Merritt syndrome (KMS), characterized by thrombocytopenia, may complicate vascular tumors such as kaposiform hemangioendothelioma and tufted angioma. We report on two infants, respectively 2 months and 15 days old at the onset of symptoms, the first of whom presented with a left cervico-occipito-scapular hemangioma with parotid extension, and the second with a vascular tumor located on the left shoulder with fast extension on the left inferior hemithorax and the left arm. Thrombocytopenia (\textless 20 G/L) was associated in both cases. Treatment comprised first high-dose corticosteroids (2mg/kg) in association with vincristine (1mg/m(2)/week). Interferon was introduced as third-line treatment at 3 MIU/m(2)/day. In the first patient, interferon was effective both on thrombocytopenia and tumor in 2 months. In the second patient, the first interferon treatment was not effective despite 6 months of therapy. However, a second treatment 8 years later was successful. After 10 and 3 years follow-up, respectively, there were no side effects and most particularly no neurologic complications. These two observations open the discussion of the role of interferon (3 MIU/m(2)/day) as well as new therapies in the control of angiogenesis in case of failure of first-line treatment of complicated KMS vascular tumors

Selective Autophagy Receptors in Antiviral Defense

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Regulation of anti-microbial autophagy by factors of the complement system

International audienceThe complement system is a major component of innate immunity that participates in the defense of the host against a myriad of pathogenic microorganisms. Activation of complement allows for both local inflammatory response and physical elimination of microbes through phagocytosis or lysis. The system is highly efficient and is therefore finely regulated. In addition to these well-established properties, recent works have revealed that components of the complement system can be involved in a variety of other functions including in autophagy, the conserved mechanism that allows for the targeting and degradation of cytosolic materials by the lysosomal pathway after confining them into specialized organelles called autophagosomes. Besides impacting cell death, development or metabolism, the complement factors-autophagy connection can greatly modulate the cell autonomous, antimicrobial activity of autophagy: xenophagy. Both surface receptorligand interactions and intracellular interactions are involved in the modulation of the autophagic response to intracellular microbes by complement factors. Here, we review works that relate to the recently discovered connections between factors of the complement system and the functioning of autophagy in the context of host-pathogen relationship

Pediatric combined liver-kidney transplantation: a single-center experience of 18 cases

Background Experience in combined liver-kidney transplantation (CLKT) in children is limited. Methods We conducted a retrospective study of all pediatric CLKTs performed at our medical institution between 1992 and 2013.L'expérience de fond dans la transplantation combinée de reins de foie (CLKT) dans des enfants est limitée. Les méthodes nous ont conduit vers une étude rétrospective de tout le CLKTS pédiatrique réalisé dans notre institution médicale entre 1992 et 2013

Carotenoids in familial hypobetalipoproteinemia disorders: Malabsorption in Caco2 cell models and severe deficiency in patients

International audienceBACKGROUND: Familial hypobetalipoproteinemias (FHBL) are rare genetic diseases characterized by lipid malabsorption. We focused on abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3), caused by mutations in microsomal triglyceride transfer protein (MTTP) and SAR1B genes, respectively. Treatments include a low-fat diet and high -dose fat-soluble vitamin supplementations. However, patients are not supplemented in carotenoids, a group of lipid-soluble pigments essential for eye health. OBJECTIVE: Our aim was to evaluate carotenoid absorption and status in the context of hypobetalipoproteinemia. METHODS: We first used knock-out Caco-2/TC7 cell models of FHBL-SD1 and FHBL-SD3 to evaluate carotenoid absorption. We then characterized FHBL-SD1 and FHBL-SD3 patient status in the main dietary carotenoids and compared it to that of control subjects. RESULTS: In vitro results showed a significant decrease in basolateral secretion of alpha - and beta -carotene, lutein, and zeaxanthin (-88.8 + 2.2 % to -95.3 + 5.8 %, -79.2 + 4.4 % to -96.1 + 2.6 %, -91.0 + 4.5 % to -96.7 + 0.3 % and -65.4 + 3.6 % to -96.6 + 1.9 %, respectively). Carotenoids plasma levels in patients confirmed significant deficiencies, with decreases ranging from -89 % for zeaxanthin to -98 % for acarotene, compared to control subjects. CONCLUSION: Given the continuous loss in visual function despite fat-soluble vitamin treatment in some patients, carotenoid supplementation may be of clinical utility. Future studies should assess the correlation between carotenoid status and visual function in aging patients and investigate whether carotenoid supplementation could prevent their visual impairment. (c) 2023 National Lipid Association

Unexpected Actors in Inflammatory Bowel Disease Revealed by Machine Learning from Whole-Blood Transcriptomic Data

Although big data from transcriptomic analyses have helped transform our understanding of inflammatory bowel disease (IBD), they remain underexploited. We hypothesized that the application of machine learning using lasso regression to transcriptomic data from IBD patients and controls can help identify previously overlooked genes. Transcriptomic data provided by Ostrowski et al. (ENA PRJEB28822) were subjected to a two-stage process of feature selection to discriminate between IBD and controls. First, a principal component analysis was used for dimensionality reduction. Second, the least absolute shrinkage and selection operator (lasso) regression was employed to identify genes potentially involved in the pathobiology of IBD. The study included data from 294 participants: 100 with ulcerative colitis (48 adults and 52 children), 99 with Crohn’s disease (45 adults and 54 children), and 95 controls (46 adults and 49 children). IBD patients presented a wide range of disease severity. Lasso regression preceded by principal component analysis successfully selected interesting features in the IBD transcriptomic data and yielded 12 models. The models achieved high discriminatory value (range of the area under the receiver operating characteristic curve 0.61–0.95) and identified over 100 genes as potentially associated with IBD. PURA, GALNT14, and FCGR1A were the most consistently selected, highlighting the role of the cell cycle, glycosylation, and immunoglobulin binding. Several known IBD-related genes were among the results. The results included genes involved in the TGF-beta pathway, expressed in NK cells, and they were enriched in ontology terms related to immunity. Future IBD research should emphasize the TGF-beta pathway, immunoglobulins, NK cells, and the role of glycosylation

Impaired reprogramming of the autophagy flux in maturing dendritic cells from crohn disease patients with core autophagy gene-related polymorphisms

International audienceCrohn disease (CD) is an inflammatory bowel disease whose pathogenesis involves inappropriate immune responses toward gut microbiota on genetically predisposed backgrounds. Notably, CD is associated with single-nucleotide polymorphisms affecting several genes involved in macroautophagy/ autophagy, the catabolic process that ensures the degradation and recycling of cytosolic components and microorganisms. In a clinical translation perspective, monitoring the autophagic activity of CD patients will require some knowledge on the intrinsic functional status of autophagy. Here, we focused on monocyte-derived dendritic cells (DCs) to characterize the intrinsic quantitative features of the autophagy flux. Starting with DCs from healthy donors, we documented a reprogramming of the steady state flux during the transition from the immature to mature status: both the autophagosome pool size and the flux were diminished at the mature stage while the autophagosome turnover remained stable. At the cohort level, DCs from CD patients were comparable to control in term of autophagy flux reprogramming capacity. However, the homozygous presence of ATG16L1 rs2241880 A&gt;G (T300A) and ULK1 rs12303764 (G/T) polymorphisms abolished the capacity of CD patient DCs to reprogram their autophagy flux during maturation. This effect was not seen in the case of CD patients heterozygous for these polymorphisms, revealing a gene dose dependency effect. In contrast, the NOD2 rs2066844 c.2104C&gt;T (R702W) polymorphism did not alter the flux reprogramming capacity of DCs. The data, opening new clinical translation perspectives, indicate that polymorphisms affecting autophagy-related genes can differentially influence the capacity of DCs to reprogram their steady state autophagy flux when exposed to proinflammatory challenges.</div

Salivary cholesterol level does not reflect cholesterolemia in children with heterozygous familial hypercholesterolemia

International audienceObjectivesHeterozygous familial hypercholesterolemia is a common genetic disease responsible for premature atherosclerosis. Therefore, early diagnosis and treatment are recommended to reduce cardiovascular risk. Usually, the screening is based on high plasma LDL-cholesterol. In children, blood testing is often an obstacle for screening. This study aims to evaluate the relevance of a salivary non-invasive LDL dosage in heterozygous familial hypercholesterolemia in a pediatric population.Materials and methodsProspective, case control, monocentric study comparaing the salivary cholesterol of 30 heterozygous familial hypercholesterolemia pediatric patients and 30 healthy age-matched controls with two different enzymatic kits (Amplite™ kit - AAT Bioquest® and Total Cholesterol Assay kit - CELL BIOLABS®, Inc).ResultsWhile the median serum total-cholesterol was significantly different in control and heterozygous familial hypercholesterolemia patients as expected, the median salivary cholesterol concentration was similar between the two groups and 1000 times lower than in serum. No correlation was found between salivary and serum cholesterol concentrations.ConclusionAlthough cholesterol is detectable in saliva, our study suggests that the low salivary cholesterol concentrations result mostly from variable gingival bleeding, precluding any reliable use for Heterozygous Familial Hypercholesterolemia screening in children.But/ObjectifL’hypercholestérolémie familiale est une maladie génétique fréquente responsable de lésion d’athérosclérose précoce. Ainsi, le diagnostic et le traitement précoce sont recommandés pour réduire le risque cardiovasculaire. Le dépistage actuellement recommandé est réalisé par le dosage sanguin de LDL-cholestérol. Chez l’enfant, le caractère invasif des prises de sang peut être un obstacle à la réalisation du dépistage. Cette étude a pour but d’évaluer la pertinence du dosage salivaire non invasif du LDL-cholestérol chez les enfants atteints d’hypercholestérolémie familiale.Matériels et méthodesÉtude prospective, cas-contrôle, monocentrique comparant le cholestérol salivaire chez 30 enfant témoins et chez 30 enfants hypercholestérolémiques apparié en age dosé par deux kits enzymatiques (Amplite™ kit - AAT Bioquest® et Total Cholesterol Assay kit - CELL BIOLABS®, Inc)RésultatsLe cholestérol total sérique médian est significativement différent entre les deux groupes comme attendu, néanmoins les taux médians de cholestérol salivaire sont similaires entre les deux groupes et 1000 fois inférieures au sérum. Aucune corrélation n’a été retrouvée entre la salive et le cholestérol total sérique.ConclusionLe cholestérol total est bien détectable dans la salive, notre étude suggère que le faible taux de cholestérol dans la salive résulte en majeur parti d’une contamination par micro-saignement gingival, ne permettant pas de l’envisager comme un outil fiable non invasif pour le dépistage de l’hypercholestérolémie familiale chez l’enfant

Comparison of Endoscopic Dilatation and Heller's Myotomy for Treating Esophageal Achalasia in Children: A Multicenter Study

International audienceObjective: To compare the efficacy of, and complications from, the 2 main treatments for achalasia: endoscopic dilatation and surgical cardiomyotomy (Heller's myotomy).Study design: We retrospectively collected data on children treated for achalasia over an 11-year period from 8 tertiary pediatric centers. A line of treatment was defined as performing either Heller's myotomy or 1-3 sessions of endoscopy dilatation over 3 months. Treatment success was a priori defined as clinical improvement and no need for new treatment.Results: Ninety-seven children (median age, 12 years; 57% boys) were included. The median time to diagnosis was 10.5 months, and the median follow-up period was 27 months. Thirty-seven children were treated by Heller's myotomy and 60 by endoscopy dilatation as the first-line treatment. After adjustment for potentially confounding factors, Heller's myotomy was significantly more successful than endoscopy dilatation (hazard ratio, 3.93 [1.74; 8.88]; P = .001), with a median survival without failure of 49 and 7 months, respectively, and with no significant difference in the occurrence of complications (35.2% for Heller's myotomy, 29.7% for endoscopy dilatation, P = .56). Hydrostatic dilatation was as successful as pneumatic dilatation (hazard ratio, 1.35 [0.56; 3.23]; P = .50).Conclusions: Heller's myotomy is more successful than endoscopy dilatation, with no significant difference in the occurrence of serious complications. This raises the potential role of peroral endoscopic myotomy as an alternative treatment to Heller's myotomy