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1.
Am J Hum Genet ; 108(6): 1126-1137, 2021 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-34010604

RESUMEN

Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.


Asunto(s)
Enfermedades Óseas/etiología , Enfermedades Cardiovasculares/etiología , Enfermedades del Tejido Conjuntivo/etiología , Inmunidad Celular/inmunología , Mutación con Pérdida de Función , Pérdida de Heterocigocidad , beta Carioferinas/genética , Adolescente , Adulto , Animales , Enfermedades Óseas/patología , Enfermedades Cardiovasculares/patología , Niño , Enfermedades del Tejido Conjuntivo/patología , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven , Pez Cebra , beta Carioferinas/metabolismo
2.
J Pediatr Gastroenterol Nutr ; 78(5): 1116-1125, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38314896

RESUMEN

BACKGROUND: Infliximab (IFX) and adalimumab (ADA) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD). ADA is now often used in first line due to its efficacy and tolerability, but a loss of response (LOR) can occur over time. The aim was to assess the efficacy of IFX as second line therapy after LOR or intolerance to ADA in pediatric CD patients at 1 year. METHODS: We conducted a retrospective and multicenter study in France among the "GETAID pédiatrique" centers between April 2019 and April 2022. CD patients under 18 years old and treated with IFX after ADA failure or intolerance were included. We collected anthropometric, clinical, and biological data at baseline (start of IFX), at 6 and 12 months. Clinical remission was defined by a Weighted Pediatric CD Activity Index (wPCDAI) score less than 12.5 points. RESULTS: Of the 32 patients included in our study, 27 (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At M12, 22 patients were in corticosteroid free clinical remission (68.7%). Under IFX, the wPCDAI decreased over time (47.5 ± 24.1, 16.6 ± 21.2 and 9.7 ± 19.0 at M0, M6 and M12 respectively). The only factor associated with clinical remission at 12 months was absence of perianal disease at the end of the IFX induction. CONCLUSIONS: IFX is effective in maintaining remission at 1 year in pediatric CD patients experiencing a LOR or intolerance with ADA, and IFX could be an interesting therapeutic choice instead of other biologics in this situation.


Asunto(s)
Adalimumab , Enfermedad de Crohn , Fármacos Gastrointestinales , Infliximab , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Adalimumab/uso terapéutico , Estudios Retrospectivos , Infliximab/uso terapéutico , Masculino , Femenino , Niño , Adolescente , Fármacos Gastrointestinales/uso terapéutico , Francia , Resultado del Tratamiento , Inducción de Remisión/métodos , Insuficiencia del Tratamiento
3.
J Pediatr Gastroenterol Nutr ; 78(6): 1261-1272, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38651614

RESUMEN

OBJECTIVES: Previous studies have shown rates of surgical resection of up to 41% in stricturing pediatric Crohn's disease (CD). In this retrospective multicenter study, our aims were to identify clinical risk factors and magnetic resonance enterography (MRE) features of small bowel strictures associated with surgery. METHODS: Pediatric patients with symptomatic stricturing small bowel CD (defined as obstructive symptoms or proximal dilatation on MRE) confirmed by MRE between 2010 and 2020 were recruited from 12 French tertiary hospitals. Patient characteristics were compared by surgical outcome multivariable Cox regression. RESULTS: Fifty-six patients (61% boys) aged 12.2 ± 2.7 years at diagnosis of CD were included. Median duration of CD before diagnosis of stricture was 11.7 months (interquartile range [IQR]: 25-75: 1.2-29.9). Nineteen (34%) patients had stricturing phenotype (B2) at baseline. Treatments received  before stricture diagnosis included MODULEN-IBD (n = 31), corticosteroids (n = 35), antibiotics (n = 10), anti-TNF (n = 27), immunosuppressants (n = 28). Thirty-six patients (64%) required surgery, within 4.8 months (IQR: 25-75: 1.8-17.3) after stricture diagnosis. Parameters associated with surgical resection were antibiotic exposure before stricture diagnosis (adjusted odds ratio [aOR]: 15.62 [3.35-72.73], p = 0.0005), Crohn's disease obstructive symptoms score (CDOS) > 4 (aOR: 3.04 [1.15-8.03], p = 0.02) and dilation proximal to stricture >28 mm (aOR: 3.62 [1.17-11.20], p = 0.03). CONCLUSION: In this study, antibiotic treatment before stricture diagnosis, intensity of obstructive symptoms, and diameter of dilation proximal to small bowel stricture on MRE were associated with risk for surgical resection.


Asunto(s)
Enfermedad de Crohn , Intestino Delgado , Humanos , Enfermedad de Crohn/cirugía , Enfermedad de Crohn/complicaciones , Masculino , Estudios Retrospectivos , Femenino , Factores de Riesgo , Niño , Intestino Delgado/cirugía , Intestino Delgado/patología , Adolescente , Constricción Patológica/etiología , Francia , Imagen por Resonancia Magnética , Obstrucción Intestinal/etiología , Obstrucción Intestinal/cirugía
4.
J Pediatr Gastroenterol Nutr ; 76(6): 763-770, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36893481

RESUMEN

OBJECTIVES: Ustekinumab is known to be efficient in adult patients suffering from moderate to severe Crohn disease (CD) and ulcerative colitis (UC) resistant to anti-tumor necrosis factor-alpha (TNF-α). Here, we described the clinical course of treatment with ustekinumab in French pediatric inflammatory bowel disease (IBD) patients treated with ustekinumab. METHODS: This study includes all pediatric patients treated by ustekinumab injection for IBD (CD and UC), between January 2016 and December 2019. RESULTS: Fifty-three patients were enrolled, 15 males and 38 females. Forty-eight patients (90%) had a diagnosis of CD and 5 (9.4%) had UC. Sixty-five percent of CD patients presented an ileocolitis. Perineal disease was observed in 20 out of 48 CD patients (41.7%), among them 9 were treated surgically. All patients included were resistant to anti-TNF-α treatment. Fifty-one percent had presented side effects linked to anti-TNF-α, including psoriasis and anaphylactic reaction. The average Pediatric Crohn Disease Activity Index (PCDAI) at induction was 28.7 (5-85), 18.7 (0-75) at 3 months of treatment and 10 (0-35) at the last follow-up. The average Pediatric Ulcerative Colitis Activity Index at induction was 47 (25-65), 25 (15-40) at 3 months of treatment and 18.3 (0-35) at the last follow-up. No severe side effects were observed. CONCLUSION: In this retrospective, multicentral study, ustekinumab proved to be efficient in pediatric patients resistant to anti-TNF-α. PCDAI has been significantly improved in patients with severe disease, treated with ustekinumab.


Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Enfermedades Inflamatorias del Intestino , Masculino , Adulto , Femenino , Humanos , Niño , Ustekinumab/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Estudios Retrospectivos , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Colitis Ulcerosa/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/uso terapéutico , Resultado del Tratamiento
5.
J Pediatr ; 251: 134-139.e2, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35853483

RESUMEN

OBJECTIVE: 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.


Asunto(s)
Acalasia del Esófago , Miotomía de Heller , Niño , Masculino , Humanos , Femenino , Acalasia del Esófago/cirugía , Dilatación , Estudios Retrospectivos , Endoscopía
6.
Scand J Immunol ; 93(5): e13025, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33528856

RESUMEN

BACKGROUND: Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signalling pathways are modulated by a number of transcription factors, one of which is runt-related transcription factor 3 (RUNX3). OBJECTIVE: To systematically review the immune roles of RUNX3 in immune regulation, with a focus on the context of IBD. METHODS: Relevant articles and reviews were identified through a Scopus search in April 2020. Information was categorized by immune cell types, analysed and synthesized. IBD transcriptome data sets and FANTOM5 regulatory networks were processed in order to complement the literature review. RESULTS: The available evidence on the immune roles of RUNX3 allowed for its description in twelve cell types: intraepithelial lymphocyte, Th1, Th2, Th17, Treg, double-positive T, cytotoxic T, B, dendritic, innate lymphoid, natural killer and macrophages. In the gut, the activity of RUNX3 is multifaceted and context-dependent: it may promote homeostasis or exacerbated reactions via cytokine signalling and regulation of receptor expression. RUNX3 is mostly engaged in pathways involving ThPOK, T-bet, IFN-γ, TGF-ß/IL-2Rß, GATA/CBF-ß, SMAD/p300 and a number of miRNAs. RUNX3 targets relevant to IBD may include RAG1, OSM and IL-17B. Moreover, in IBD RUNX3 expression correlates positively with GZMM, and negatively with IFNAR1, whereas in controls, it strongly associates with TGFBR3. CONCLUSIONS: Dysregulation of RUNX3, mostly in the form of deficiency, likely contributes to IBD pathogenesis. More clinical research is needed to examine RUNX3 in IBD.


Asunto(s)
Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Linfocitos B/inmunología , Células Dendríticas/inmunología , Humanos , Mucosa Intestinal/inmunología , Linfocitos Intraepiteliales/inmunología , Linfocitos T/inmunología
7.
J Pediatr Gastroenterol Nutr ; 73(3): 333-337, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34117192

RESUMEN

OBJECTIVES: Digestive perianastomotic ulcerations (DPAU) resembling Crohn disease lesions are long-term complications of intestinal resections, occurring in children and young adults. They are known to be uncommon, severe and difficult to treat. METHODS: In the absence of recommendations, we performed a large European survey among the members of the ESPGHAN working group on inflammatory bowel disease (IBD) in order to collect the experience of expert pediatric gastroenterologists on DPAU. RESULTS: Fifty-one patients (29 boys and 22 girls) were identified from 19 centers in 8 countries. Most patients were followed after necrotizing enterocolitis (n = 20) or Hirschsprung disease (n = 11). The anastomosis was performed at a median age (interquartile range) of 6 [1-23] months, and first symptoms occurred 39 [22-106] months after surgery. Anemia was the most prevalent symptom followed by diarrhea, abdominal pain, bloating, and failure to thrive. Hypoalbuminemia, elevated CRP, and fecal calprotectin were common. Deep ulcerations were found in 59% of patients usually proximally to the anastomosis (68%). During a median follow-up of 40 [19-67] months, treatments reported to be the most effective included exclusive enteral nutrition (31/35, 88%), redo anastomosis (18/22, 82%), and alternate antibiotic treatment (37/64, 58%). CONCLUSIONS: Unfortunately, persistence of symptoms, failure to thrive, and abnormal laboratory tests at last follow-up in most of patients show the burden of DPAU lacking optimal therapy and incomplete understanding of the pathophysiology.


Asunto(s)
Enfermedad de Crohn , Procedimientos Quirúrgicos del Sistema Digestivo , Enfermedad de Hirschsprung , Anastomosis Quirúrgica , Niño , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/terapia , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Úlcera/diagnóstico , Úlcera/etiología , Adulto Joven
8.
Dig Dis Sci ; 66(12): 4429-4435, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-33387123

RESUMEN

BACKGROUND/AIMS: In Crohn's disease (CD) few data are available on the usefulness of monitoring fecal calprotectin (FC) in the early postoperative setting. We assessed prospectively the accuracy of FC measured 3 months after surgery to predict the risk of endoscopic postoperative recurrence (POR) within 1 year after resection. METHODS: In 55 consecutive CD patients who had undergone ileocolonic resection samples were collected 3 months after surgery for measuring serum CRP and FC. Endoscopic POR was assessed by ileocolonoscopy within 6-12 months (median 7 months). Receiver operating characteristic (ROC) curves were generated to assess accuracy of the markers, to determine the best threshold and to calculate sensitivity, specificity, positive and negative predictive values. RESULTS: In contrast with median CRP levels, median FC concentrations measured 3 months after surgery were significantly higher in patients who later experienced endoscopic POR (Rutgeerts ≥ i2) compared with those who stayed in endoscopic remission within the following 6-12 months (205 µg/g IQR [106-721] vs. 103 µg/g IQR [60-219], p = 0.008). Area under the ROC curve for FC was 0.71. The best cutoff value of FC to identify patients in subsequent endoscopic remission 3 months after surgery was 65 µg/g (96% sensitivity, 31% specificity, 50% positive and 91% negative predictive values). In multivariate analysis, FC < 65 µg/g at 3 months was the only factor associated with subsequent endoscopic remission. CONCLUSION: FC measured 3 months after surgery below 65 µg/g is an accurate marker to identify CD patients who will later stay in endoscopic remission within 1 year after resection.


Asunto(s)
Enfermedad de Crohn/metabolismo , Complejo de Antígeno L1 de Leucocito/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores/análisis , Biomarcadores/metabolismo , Colectomía , Enfermedad de Crohn/cirugía , Heces/química , Femenino , Estudios de Seguimiento , Humanos , Complejo de Antígeno L1 de Leucocito/análisis , Masculino , Persona de Mediana Edad , Inducción de Remisión , Adulto Joven
9.
Clin Gastroenterol Hepatol ; 17(12): 2610-2612, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30851477

RESUMEN

Ustekinumab is approved for treatment of Crohn's disease (CD).1,2 Few data are available to assess the usefulness of monitoring inflammatory biomarkers and therapeutic drug monitoring to predict response to ustekinumab. We conducted a prospective study to assess the relationships between these parameters and the clinical outcome at week 16 in active CD patients receiving ustekinumab.


Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Inducción de Remisión , Ustekinumab/sangre , Ustekinumab/uso terapéutico , Biomarcadores/análisis , Proteína C-Reactiva/análisis , Heces/química , Fármacos Gastrointestinales/sangre , Fármacos Gastrointestinales/uso terapéutico , Humanos , Complejo de Antígeno L1 de Leucocito/análisis , Valor Predictivo de las Pruebas , Estudios Prospectivos , Sensibilidad y Especificidad
10.
Pediatr Nephrol ; 31(9): 1517-29, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27060059

RESUMEN

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. RESULTS: We identified 18 pediatric patients (9 girls) who had undergone CLKT at our institution during the study period. The median age [range] and body weight [range] of this patient group was 3.6 [1.0-18.6] years and 13 [10-40] kg, respectively; 11 patients weighed <15 kg at the time of CLKT. Indications for CLKT were primary hyperoxaluria (PH1; n = 14), association of hepatic fibrosis and end-stage renal disease (n = 3) and methylmalonic acidemia (n = 1). In the early postoperative period, eight patients required dialysis. Median stay in the pediatric intensive care unit was 10 [6-29] days. One patient died from cardiovascular disease 10 years after CLKT. There were no liver graft losses despite six acute liver rejection episodes, whereas four kidney grafts were lost. At last follow-up (6 [0.5-21] years) for patients with a functioning renal graft, the glomerular filtration rate was 71 [26-146] mL/min/1.73 m(2). In PH1 patients, urine oxalate normalized in six patients within 3 years after CLKT, but three patients still presented with elevated oxaluria at 1, 2 and 3 years after CLKT. CONCLUSIONS: Pediatric CLKT provides encouraging results in the long term, even in the youngest patients.


Asunto(s)
Trasplante de Riñón , Trasplante de Hígado , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Hígado , Masculino , Diálisis Renal , Estudios Retrospectivos , Resultado del Tratamiento
11.
J Clin Lipidol ; 18(1): e105-e115, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37989694

RESUMEN

BACKGROUND: 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 α- and ß-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 α-carotene, 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.


Asunto(s)
Hipobetalipoproteinemias , Proteínas de Unión al GTP Monoméricas , Sindactilia , Humanos , Células CACO-2 , Zeaxantinas/metabolismo , Hipobetalipoproteinemias/genética , Carotenoides/metabolismo , Vitaminas , Lípidos , Proteínas de Unión al GTP Monoméricas/genética
12.
Autophagy ; 20(8): 1837-1853, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38615686

RESUMEN

Crohn 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>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>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.Abbreviation: BAFA1: bafilomycin A1, CD: Crohn disease; DC: dendritic cells; HD: healthy donor; iDCs: immature DCs; IL: interleukin; J: autophagosome flux; LPS: lipopolysaccharide; MHC: major histocompatibility complex; nA: autophagosome pool size; SNPs: single-nucleotide polymorphisms; PCA: principal component analysis; TLR: toll like receptor; τ: transition time; TNF: tumor necrosis factor.


Asunto(s)
Proteínas Relacionadas con la Autofagia , Autofagia , Enfermedad de Crohn , Células Dendríticas , Polimorfismo de Nucleótido Simple , Enfermedad de Crohn/genética , Enfermedad de Crohn/patología , Enfermedad de Crohn/metabolismo , Humanos , Autofagia/genética , Células Dendríticas/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Polimorfismo de Nucleótido Simple/genética , Reprogramación Celular/genética , Adulto , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Masculino , Femenino , Autofagosomas/metabolismo , Proteína Adaptadora de Señalización NOD2/genética , Proteína Adaptadora de Señalización NOD2/metabolismo , Péptidos y Proteínas de Señalización Intracelular
13.
Autophagy ; 19(3): 858-872, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-35900944

RESUMEN

Although it is admitted that secondary infection can complicate viral diseases, the consequences of viral infection on cell susceptibility to other infections remain underexplored at the cellular level. We though to examine whether the sustained macroautophagy/autophagy associated with measles virus (MeV) infection could help cells oppose invasion by Salmonella Typhimurium, a bacterium sensitive to autophagic restriction. We report here the unexpected finding that Salmonella markedly replicated in MeV-infected cultures due to selective growth within multinucleated cells. Hyper-replicating Salmonella localized outside of LAMP1-positive compartments to an extent that equaled that of the predominantly cytosolic sifA mutant Salmonella. Bacteria were subjected to effective ubiquitination but failed to be targeted by LC3 despite an ongoing productive autophagy. Such a phenotype could not be further aggravated upon silencing of the selective autophagy regulator TBK1 or core autophagy factors ATG5 or ATG7. MeV infection also conditioned primary human epithelial cells for augmented Salmonella replication. The analysis of selective autophagy receptors able to target Salmonella revealed that a lowered expression level of SQSTM1/p62 and TAX1BP1/T6BP autophagy receptors prevented effective anti-Salmonella autophagy in MeV-induced syncytia. Conversely, as SQSTM1/p62 is promoting the cytosolic growth of Shigella flexneri, MeV infection led to reduced Shigella replication. The results indicate that the rarefaction of dedicated autophagy receptors associated with MeV infection differentially affects the outcome of bacterial coinfection depending on the nature of the functional relationship between bacteria and such receptors. Thus, virus-imposed reconfiguration of the autophagy machinery can be instrumental in determining the fate of bacterial coinfection.Abbreviations: ACTB/ß-ACTIN: actin beta; ATG: autophagy related; BAFA1: bafilomycin A1; CFU: colony-forming units; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; FIP: fusion inhibitory peptide; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LIR: MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MeV: measles virus; MOI: multiplicity of infection; OPTN: optineurin; PHH: primary human hepatocyte; SCV: Salmonella-containing vacuoles; SQSTM1/p62: sequestosome 1; S. flexneri: Shigella flexneri; S. Typhimurium: Salmonella enterica serovar Typhimurium; TAX1BP1/T6BP: Tax1 binding protein 1; TBK1: TANK binding kinase 1.


Asunto(s)
Autofagia , Coinfección , Humanos , Autofagia/genética , Proteína Sequestosoma-1/metabolismo , Virus del Sarampión/metabolismo , Salmonella typhimurium , Proteínas Portadoras
14.
J Clin Invest ; 133(12)2023 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-36976641

RESUMEN

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.


Asunto(s)
COVID-19 , Encefalitis por Herpes Simple , Gripe Humana , Neumonía , Virosis , Humanos , Preescolar , Virosis/genética , Alelos , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT2/genética
15.
JPGN Rep ; 3(1): e139, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37168749

RESUMEN

Heterozygous TGFBR2 loss-of-function mutation is an extremely rare cause of very-early onset inflammatory bowel disease (VEOIBD) as, so far, only three cases have been reported in the literature. VEOIBD therapeutic management remains a real challenge for clinicians. Here, we described an interesting new case of Loeys-Dietz syndrome presenting severe, very early intestinal inflammation associated with dysmorphic features, aortic arch tortuosity joint hyper laxity and severe scoliosis. TGFBR2 Sanger sequencing revealed a missense mutation c.1583G>A (p.Arg528His). As endoscopy confirmed a severe colitis, we chose a classical IBD therapeutic approach. We finally obtained remission under Ustekinumab (90 mg/6 weeks).

16.
Genes (Basel) ; 13(9)2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36140740

RESUMEN

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.


Asunto(s)
Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Adulto , Niño , Colitis Ulcerosa/genética , Humanos , Enfermedades Inflamatorias del Intestino/genética , Aprendizaje Automático , Transcriptoma/genética , Factor de Crecimiento Transformador beta/genética
17.
Clin Nutr ; 41(9): 1961-1968, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35947897

RESUMEN

BACKGROUND AND AIMS: Central line-associated bloodstream infections (CLABSIs) are the main complication in children with home parenteral nutrition (HPN) and some patients develop recurrent CLABSIs (REC-CLABSIs), defined as two or more infections within six months. Our aims were to assess the incidence and to characterize the risk factors of REC-CLABSIs in children with HPN. METHODS: We characterized 79 HPN children from 2014 to 2019 and calculated the incidence of CLABSIs. To minimize the risk of bias related to the exposure time of the septic risk, we paired the patients according to their central venous catheter (CVC) dwell time. After analyzing the whole cohort, a univariate and multivariate unconditional logistic regression was performed on the paired cohort. RESULTS: We included 75 (94.9%) children with a mean age of 7.11 years. The rate of septicemia was 1.55/1000 CVC days, mainly with Staphyloccocus sp. The patients with recurrent CLABSIs (REC group) represented 25% of the cohort, with an incidence of 2.99/1000 CVC days. In the whole cohort, a higher risk of recurrent infections was significantly associated with a longer CVC dwell time (OR = 1.04, IC 95% [1.01-1.06], p = 0.004), and with care located in rehabilitation care facilities (RCF) compared to home (OR = 6, IC 95% [1.5-26.6], p = 0.012). When children were paired according to their CVC dwell time, only in univariate analysis did the care in RCF remain significant (OR = 6.27, IC 95% [1.21-32.5], p = 0.03). CONCLUSIONS: Recurrent CLABSIs incidence was 2.99/1000 CVC days. Our study suggests that preventive measures should be implemented especially in RCFs to reduce the proportion of children with recurrent infections. A multicenter study is needed to confirm our results in a larger cohort with several RCFs.


Asunto(s)
Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Catéteres Venosos Centrales , Nutrición Parenteral en el Domicilio , Sepsis , Infecciones Relacionadas con Catéteres/prevención & control , Cateterismo Venoso Central/efectos adversos , Catéteres Venosos Centrales/efectos adversos , Niño , Humanos , Incidencia , Nutrición Parenteral en el Domicilio/efectos adversos , Nutrición Parenteral en el Domicilio/métodos , Reinfección , Estudios Retrospectivos , Sepsis/complicaciones
18.
Front Immunol ; 13: 864353, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36405740

RESUMEN

Background and aims: We aimed to analyze circulating CD4+ T cell subsets and cytokines during the course of Crohn's disease (CD). Methods and results: CD4+ T cell subsets, ultrasensitive C-reactive protein (usCRP), and various serum cytokines (IL-6, IL-8, IL-10, IL-13, IL-17A, IL-23, TNFα, IFNγ, and TGFß) were prospectively monitored every 3 months for 1 year, using multicolor flow cytometry and an ultrasensitive Erenna method in CD patients in remission at inclusion. Relapse occurred in 35 out of the 113 consecutive patients (31%). For patients in remission within 4 months prior to relapse and at the time of relapse, there was no significant difference in Th1, Th17, Treg, and double-positive CD4+ T cell subsets co-expressing either IFNγ and FOXP3, IL-17A and FOXP3, or IFNγ and IL-17A. On the contrary, in patients who remained in remission, the mean frequency and number of double-positive IL-17A+FOXP3+ CD4+ T cells and the level of usCRP were significantly higher (p ≤ 0.01) 1 to 4 months prior to relapse. At the time of relapse, only the IL-6 and usCRP levels were significantly higher (p ≤ 0.001) compared with those patients in remission. On multivariate analysis, a high number of double-positive IL-17A+FOXP3+ CD4+ T cells (≥1.4 cells/mm3) and elevated serum usCRP (≥3.44 mg/L) were two independent factors associated with risk of relapse. Conclusions: Detection of circulating double-positive FOXP3+IL-17A+ CD4+ T cell subsets supports that T cell plasticity may reflect the inflammatory context of Crohn's disease. Whether this subset contributes to the pathogenesis of CD relapse needs further studies.


Asunto(s)
Enfermedad de Crohn , Interleucina-17 , Humanos , Interleucina-17/metabolismo , Enfermedad de Crohn/patología , Citocinas/metabolismo , Interleucina-6/metabolismo , Subgrupos de Linfocitos T/metabolismo , Células Th17/metabolismo , Factores de Transcripción Forkhead/metabolismo , Recurrencia
19.
J Clin Invest ; 132(10)2022 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-35575086

RESUMEN

Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.


Asunto(s)
Diarrea Infantil , Síndromes de Malabsorción , Mucolipidosis , Miosina Tipo V , Animales , Células CACO-2 , Diarrea Infantil/metabolismo , Diarrea Infantil/patología , Facies , Retardo del Crecimiento Fetal , Enfermedades del Cabello , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Síndromes de Malabsorción/metabolismo , Microvellosidades/genética , Microvellosidades/patología , Mucolipidosis/genética , Mucolipidosis/metabolismo , Mucolipidosis/patología , Miosina Tipo V/genética , Miosina Tipo V/metabolismo , Fenotipo , Pez Cebra/genética , Pez Cebra/metabolismo
20.
Trends Microbiol ; 29(9): 798-810, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33678557

RESUMEN

Autophagy ensures the degradation of cytosolic substrates by the lysosomal pathway. Cargoes destined to be eliminated are confined within double-membrane vesicles called autophagosomes, prior to fusion with endolysosomal vacuoles. Autophagy receptors selectively interact with cargoes and route them to elongating autophagic membranes, a process referred to as selective autophagy. Besides contributing to cell homeostasis, selective autophagy constitutes an important cell-autonomous defense mechanism against viruses. We review observations related to selective autophagy receptor engagement during host cell responses to virus infection. We examine the distinct roles of autophagy receptors in antiviral autophagy, consider the strategies viruses have evolved to escape or oppose such restrictions, and delineate the contributions of selective autophagy to the tailoring of antiviral innate responses. Finally, we mention some open and emerging questions in the field.


Asunto(s)
Autofagia , Receptores Virales/inmunología , Virosis/fisiopatología , Animales , Humanos , Receptores Virales/genética , Virosis/inmunología , Virosis/virología , Fenómenos Fisiológicos de los Virus , Replicación Viral , Virus/genética , Virus/inmunología
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