Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Pediatr Gastroenterol Nutr ; 70(3): 389-403, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32079889

RESUMO

The rate of pediatric inflammatory bowel disease (IBD) has been increasing over the last decade and this increase has occurred most rapidly in the youngest children diagnosed <6 years, known as very early-onset inflammatory bowel disease (VEO-IBD). These children can present with more extensive and severe disease than older children and adults. The contribution of host genetics in this population is underscored by the young age of onset and the distinct, aggressive phenotype. In fact, monogenic defects, often involving primary immunodeficiency genes, have been identified in children with VEO-IBD and have led to targeted and life-saving therapy. This position paper will discuss the phenotype of VEO-IBD and outline the approach and evaluation for these children and what factors should trigger concern for an underlying immunodeficiency. We will then review the immunological assays and genetic studies that can facilitate the identification of the underlying diagnosis in patients with VEO-IBD and how this evaluation may lead to directed therapies. The position paper will also aid the pediatric gastroenterologist in recognizing when a patient should be referred to a center specializing in the care of these patients. These guidelines are intended for pediatricians, allied health professionals caring for children, pediatric gastroenterologists, pediatric pathologists, and immunologists.

3.
Clin Gastroenterol Hepatol ; 18(3): 612-619.e1, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31009795

RESUMO

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is commonly used to treat Clostridium difficile infection (CDI). CDI is an increasing cause of diarrheal illness in pediatric patients, but the effects of FMT have not been well studied in children. We performed a multi-center retrospective cohort study of pediatric and young adult patients to evaluate the efficacy, safety, and factors associated with a successful FMT for the treatment of CDI. METHODS: We performed a retrospective study of 372 patients, 11 months to 23 years old, who underwent FMT at 18 pediatric centers, from February 1, 2004, to February 28, 2017; 2-month outcome data were available from 335 patients. Successful FMT was defined as no recurrence of CDI in the 2 months following FMT. We performed stepwise logistic regression to identify factors associated with successful FMT. RESULTS: Of 335 patients who underwent FMT and were followed for 2 months or more, 271 (81%) had a successful outcome following a single FMT and 86.6% had a successful outcome following a first or repeated FMT. Patients who received FMT with fresh donor stool (odds ratio [OR], 2.66; 95% CI, 1.39-5.08), underwent FMT via colonoscopy (OR, 2.41; 95% CI, 1.26-4.61), did not have a feeding tube (OR, 2.08; 95% CI, 1.05-4.11), or had 1 less episode of CDI before FMT (OR, 1.20; 95% CI, 1.04-1.39) had increased odds for successful FMT. Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations. CONCLUSIONS: Based on the findings from a large multi-center retrospective cohort, FMT is effective and safe for the treatment of CDI in children and young adults. Further studies are required to optimize the timing and method of FMT for pediatric patients-factors associated with success differ from those of adult patients.

4.
Inflamm Bowel Dis ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31560377

RESUMO

BACKGROUND: Insight into the pathogenesis of very early onset-inflammatory bowel disease (VEO-IBD) has expanded through the identification of causative monogenic defects detected in a subset of patients. However, the clinical course of this population remains uncertain. The study objective is to determine whether VEO-IBD is associated with more severe disease, defined as increased surgical intervention and growth failure, than older pediatric IBD. Secondary outcomes included therapeutic response and hospitalizations. METHODS: Subjects with IBD diagnosed younger than 6 years old (VEO-IBD) were compared with children diagnosed 6 to 10 (intermediate-onset) and older than 10 years of age (older-onset IBD). Metadata obtained from the medical record included age of onset, disease phenotype and location, surgeries, medical therapy, and comorbid conditions. Length of follow-up was at least 1 year from diagnosis. RESULTS: There were 229, 221, and 521 subjects with VEO, intermediate-onset, and older-onset IBD, respectively. Very early onset-inflammatory bowel disease subjects underwent more diverting ileostomies (P < 0.001) and colectomies (P < 0.001) than the older children. There was less improvement in weight- and height-for-age Z scores during the follow-up period in subjects with VEO-IBD. Additionally, subjects with VEO-IBD had higher rates of medication failure at 1 year and were more frequently readmitted to the hospital. Targeted therapy was successfully used almost exclusively in VEO-IBD. CONCLUSION: Patients with VEO-IBD can have a more severe disease course with increased surgical interventions and poor growth as compared with older-onset IBD patients. Further, VEO-IBD patients are more likely to be refractory to conventional therapies. Strategies using targeted therapy in these children can improve outcome and, in some cases, be curative.

5.
J Pediatr Gastroenterol Nutr ; 69(1): e13-e18, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31232887

RESUMO

Very early onset inflammatory bowel disease (VEO-IBD) represents a diagnostic and treatment challenge. Here we present a case of VEO-IBD secondary to a mutation in BIRC4 gene, which encodes X-linked inhibitor of apoptosis protein (XIAP), in a 17-month-old boy with severe failure to thrive, intractable diarrhea, and hepatosplenomegaly. Endoscopy and histology identified only mild duodenitis and ileitis, but severe pancolitis with crypt abscesses and epithelium apoptosis. Minimal improvement in symptoms was achieved with total parenteral nutrition (TPN), intravenous (IV) corticosteroids, and tacrolimus, whereas induction and maintenance therapy with adalimumab led to complete remission. After 6 months, the patient developed hemophagocytic lymphohistiocytosis and eventually died due to multisystem organ failure. A review of the literature revealed that some patients with VEO-IBD secondary to XIAP deficiency develop symptoms that are refractory to medical and surgical management, while initial reports suggest that allogeneic hematopoietic stem cell transplantation (HSCT), with reduced intensity conditioning, can successfully induce long-lasting remission and may even be curative. We propose that in patients with XIAP deficiency a constellation of symptoms including colitis at an early age, severe failure to thrive, and splenomegaly/hepatosplenomegaly can identify a subgroup of patients at high risk of experiencing medically refractory IBD phenotype and increased mortality. Hematopoietic stem cell transplant should be considered early in these high-risk patients, as it may resolve both their intestinal inflammation and a risk of developing life threatening hemophagocytic lymphohistiocytosis .

7.
J Exp Med ; 216(6): 1255-1267, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31040184

RESUMO

The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rß, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rß, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rß surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rß-/- animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rß expression and signaling in T and NK cells.

8.
Nature ; 568(7752): 405-409, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30944470

RESUMO

Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract1-4. The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (Treg) cells4-8, and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease9. However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we show, in a mouse model, that IL-2 is acutely required to maintain Treg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce Treg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group-3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL-2, which is induced selectively by IL-1ß. Macrophages in the small intestine produce IL-1ß, and activation of this pathway involves MYD88- and NOD2-dependent sensing of the microbiota. Our loss-of-function studies show that ILC3-derived IL-2 is essential for maintaining Treg cells, immunological homeostasis and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL-2 by ILC3s was significantly reduced in the small intestine of patients with Crohn's disease, and this correlated with lower frequencies of Treg cells. Our results reveal a previously unappreciated pathway in which a microbiota- and IL-1ß-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine.


Assuntos
Imunidade Inata/imunologia , Interleucina-2/imunologia , Intestinos/citologia , Intestinos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos/administração & dosagem , Antígenos/imunologia , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Feminino , Microbioma Gastrointestinal/imunologia , Homeostase/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-2/deficiência , Interleucina-2/metabolismo , Intestino Delgado/citologia , Intestino Delgado/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Linfócitos T Reguladores/classificação , Linfócitos T Reguladores/metabolismo
9.
Dev Cell ; 49(1): 10-29, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30930166

RESUMO

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.


Assuntos
Desenvolvimento Embrionário/genética , Redes Reguladoras de Genes/genética , Pediatria/tendências , Análise de Célula Única/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Distribuição Tecidual/genética
10.
Pediatr Dev Pathol ; 22(3): 183-193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30841788

RESUMO

PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic intestinal microbes, resulting in chronic intestinal inflammation. However, a subset of patients with IBD diagnosed <6 years of age, known as very early-onset (VEO)-IBD, can be phenotypically and genetically distinct from older onset IBD. We aim to review the clinical presentation of children with VEO-IBD and recent discoveries that point to the underlying genomic and immunologic drivers of disease, and the significant impact on our therapeutic decisions. RECENT FINDINGS: VEO-IBD is increasing in incidence and is associated with more severe disease, aggressive progression, and poor response to most conventional therapies. This article will review some of the genetic findings in this population and the subsequent impact on therapy, with targeted approaches. SUMMARY: Children with VEO-IBD may present with a different phenotype and more severe disease than older children and adults. An integrated approach combining genetics, immunology, and traditional IBD evaluations can lead to the identification of causal defects that directly impact management. These strategies can also be employed in older onset refractory IBD.


Assuntos
Genômica , Doenças Inflamatórias Intestinais/genética , Idade de Início , Pré-Escolar , Predisposição Genética para Doença , Humanos , Lactente , Doenças Inflamatórias Intestinais/classificação , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/terapia , Mutação , Fenótipo
11.
Inflamm Bowel Dis ; 25(9): 1586-1593, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30715364

RESUMO

BACKGROUND: Recent studies have shown that oral combination antibiotics may improve disease course in refractory inflammatory bowel disease (IBD). Here, we describe the use of combination oral antibiotics as salvage therapy in refractory ulcerative colitis (UC), Crohn's colitis, and IBD-unclassified (IBD-U) at a large pediatric IBD center. METHODS: Clinical response, disease activity indices, adverse events, and clinical outcomes were measured up to 1 year after antibiotic treatment in this retrospective cohort study of children with medically refractory IBD colitis. RESULTS: Sixty-three patients with refractory UC, Crohn's colitis, and IBD-U (median age [interquartile range {IQR}], 15.3 [11.2-16.5] years; median disease duration [IQR], 1.2 [0.41-4.6] years) received a combination of 3 or 4 oral antibiotics (most commonly amoxicillin, metronidazole, and either doxycycline or ciprofloxacin) for a median (IQR) of 29 (21-58) days. Thirty-four patients (54%) were deemed corticosteroid-refractory or -dependent, with the majority (62/63) having a previous or present loss of response or primary nonresponse to anti-tumor necrosis factor alpha (anti-TNFα) therapy. Use of combination antibiotics led to a significant decrease in median Pediatric Ulcerative Colitis Activity Index (PUCAI) score (IQR) from 55 (40-65) to 10 (0-40; P < 0.0001) over 3 ± 1 weeks, with 25/63 (39.7%) patients achieving clinical remission (PUCAI <10 points). The clinical benefits of oral antibiotics were independent of anti-TNFα therapy optimization. Among children entering clinical remission (n = 25), only 1 patient required surgery at 1-year follow-up, vs 10 patients in the nonresponder group. Negative predictors of response to combination antibiotics were exposure to doxycycline (odds ratio [OR], 0.25; 95% CI, 0.08-0.76) and PUCAI ≥65 at baseline (OR, 0.2; 95% CI, 0.05-0.74). CONCLUSIONS: Oral combination antibiotics appears to be an effective rescue and steroid-sparing therapy to induce remission in the short term in patients failing a biologic.

12.
Immunol Allergy Clin North Am ; 39(1): 63-79, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30466773

RESUMO

The epidemiology of inflammatory bowel disease has changed over the past 4 decades. The incidence is rising dramatically and the age of onset has become younger. This changing landscape of inflammatory bowel disease reflects the new recognition that the youngest children with inflammatory bowel disease are enriched in cases with underlying primary immunodeficiency and monogenic causes. The management of these cases can be quite different, with specific genetic etiologies supporting unique interventions and some requiring hematopoietic cell transplantation for effective treatment.


Assuntos
Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/epidemiologia , Idade de Início , Autoimunidade , Diagnóstico Diferencial , Suscetibilidade a Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/etiologia , Fenótipo
13.
J Crohns Colitis ; 13(5): 615-625, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-30551128

RESUMO

BACKGROUND AND AIMS: Children with very early onset inflammatory bowel disease [VEO-IBD] represent a unique cohort, often with a severe phenotype that is refractory to conventional medications, and some cases have underlying primary immunodeficiencies. Previous work has identified distinct histopathological patterns in the gastrointestinal tract in patients with primary immunodeficiencies. The aim of this study is to characterise the diagnostic histological findings in patients with VEO-IBD as compared with older onset paediatric IBD, and determine if there are unique pathological changes that can shed light on the driving forces of the disease, particularly immunodeficiencies. METHODS: Clinical retrospective chart review, including disease characteristics and endoscopic findings, was performed on all included subjects. Two paediatric pathologists reviewed biopsies from diagnostic upper endoscopies and colonoscopies of subjects with very early onset inflammatory bowel disease and older onset inflammatory bowel disease, to evaluate for the presence of 11 histological features previously associated with inflammatory bowel disease and primary immunodeficiencies. RESULTS: The diagnostic gastrointestinal biopsies of subjects with very early onset inflammatory bowel disease differed from those in older onset paediatric IBD, demonstrated by increased frequency of apoptosis, severe chronic architectural changes, small intestine villous blunting, and eosinophils in the crypts, lamina propria, and surface epithelium. CONCLUSIONS: The diagnostic biopsies of children with very early onset inflammatory bowel disease can identify characteristic features that may be important in guiding the diagnostic work-up in this population.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Adolescente , Idade de Início , Biópsia , Criança , Pré-Escolar , Colonoscopia , Feminino , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Intestinos/patologia , Masculino , Estudos Retrospectivos
14.
Artigo em Inglês | MEDLINE | ID: mdl-31899730

RESUMO

The rate of pediatric inflammatory bowel disease (IBD) has been increasing over the last decade and this increase has occurred most rapidly in the youngest children diagnosed <6 year, known as very early-onset inflammatory bowel disease (VEO-IBD). 1-5 These children can present with more extensive and severe disease than older children and adults. The contribution of host genetics in this population is underscored by the young age of onset and the distinct, aggressive phenotype. In fact, monogenic defects, often involving primary immunodeficiency genes, have been identified in children with VEO-IBD and have led to targeted and life-saving therapy. 4,6-10 This position paper will discuss the phenotype of VEO-IBD and outline the approach and evaluation for these children and what factors should trigger concern for an underlying immunodeficiency. We will then review the immunological assays and genetic studies that can facilitate the identification of the underlying diagnosis in patients with VEO-IBD and how this evaluation may lead to directed therapies. The position paper will also aid the pediatric gastroenterologist in recognizing when a patient should be referred to a center specializing in the care of these patients. These guidelines are intended for pediatricians, allied health professionals caring for children, pediatric gastroenterologists, pediatric pathologists and immunologists.

15.
Curr Opin Allergy Clin Immunol ; 18(6): 459-469, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30299395

RESUMO

PURPOSE OF REVIEW: Immune dysregulation disorders are among the most rapidly growing set of inborn errors of immunity. One particular subset is the category where early-onset inflammatory bowel disease (IBD) is the most common manifestation. These disorders are being increasingly appreciated although there has been minimal effort to articulate a unified approach to their diagnosis and management. This review will cover current thinking and strategies related to diagnosis and management of very early-onset IBD. RECENT FINDINGS: There is an expanding set of monogenic causes of early-onset IBD. In many cases, the precise genetic cause dictates management. Lessons learned from the management of these monogenic conditions can sometimes be extrapolated to other refractory cases of IBD. SUMMARY: An integrated approach to diagnosis, risk analysis, and management can include diagnostic approaches not often utilized for traditional IBD such as whole exome sequencing. Management can also include nontraditional approaches such as targeted biologics or hematopoietic cell transplantation.


Assuntos
Predisposição Genética para Doença , Doenças Inflamatórias Intestinais , Sequenciamento Completo do Exoma , Idade de Início , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/terapia
16.
Genome Med ; 10(1): 70, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30261899

RESUMO

BACKGROUND: Mutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction. METHODS: Here we interrogate T cell reconstitution using four forms of high throughput analysis. (1) Estimation of the numbers of transduced progenitor cells by monitoring unique positions of integration of the therapeutic gene transfer vector. (2) Estimation of T cell population structure by sequencing of the recombined T cell receptor (TCR) beta locus. (3) Metagenomic analysis of microbial populations in oropharyngeal, nasopharyngeal, and gut samples. (4) Metagenomic analysis of viral populations in gut samples. RESULTS: Comparison of progenitor and mature T cell populations allowed estimation of a minimum number of cell divisions needed to generate the observed populations. Analysis of microbial populations showed the effects of immune reconstitution, including normalization of gut microbiota and clearance of viral infections. Metagenomic analysis revealed enrichment of genes for antibiotic resistance in gene-corrected subjects relative to healthy controls, likely a result of higher healthcare exposure. CONCLUSIONS: This multi-omic approach enables the characterization of multiple effects of SCID-X1 gene therapy, including T cell repertoire reconstitution, estimation of numbers of cell divisions between progenitors and daughter T cells, normalization of the microbiome, clearance of microbial pathogens, and modulations in antibiotic resistance gene levels. Together, these results quantify several aspects of the long-term efficacy of gene therapy for SCID-X1. This study includes data from ClinicalTrials.gov numbers NCT01410019, NCT01175239, and NCT01129544.


Assuntos
Terapia Genética , Microbiota , Linfócitos T/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Divisão Celular , Pré-Escolar , Regiões Determinantes de Complementaridade/genética , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/microbiologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/virologia
17.
Am J Hum Genet ; 103(1): 131-137, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29909964

RESUMO

Homozygous nonsense mutations in WNT2B were identified in three individuals from two unrelated families with severe, neonatal-onset osmotic diarrhea after whole-exome sequencing was performed on trios from the two families. Intestinal biopsy samples from affected individuals were used for histology and immunofluorescence and to generate enteroids ex vivo. Histopathologic evaluation demonstrated chronic inflammatory changes in the stomach, duodenum, and colon. Immunofluorescence demonstrated diminished staining for OLFM4, a marker for intestinal stem cells (ISCs). The enteroids generated from WNT2B-deficient intestinal epithelium could not be expanded and did not survive passage. Addition of CHIR-99021 (a GSK3A and GSK3B inhibitor and activator of canonical WNT/ß-CATENIN signaling) could not rescue WNT2B-deficient enteroids. Addition of supplemental recombinant murine WNT2B was able to perpetuate small enteroids for multiple passages but failed to expand their number. Enteroids showed a 10-fold increase in the expression of LEF1 mRNA and a 100-fold reduction in TLR4 expression, compared with controls by quantitative RT-PCR, indicating alterations in canonical WNT and microbial pattern-recognition signaling. In summary, individuals with homozygous nonsense mutations in WNT2B demonstrate severe intestinal dysregulation associated with decreased ISC number and function, likely explaining their diarrheal phenotype. WNT2B deficiency should be considered for individuals with neonatal-onset diarrhea.


Assuntos
Códon sem Sentido/genética , Diarreia/genética , Glicoproteínas/genética , Proteínas Wnt/genética , Criança , Pré-Escolar , Feminino , Homozigoto , Humanos , Lactente , Intestinos/patologia , Masculino , RNA Mensageiro/genética , Transdução de Sinais/genética , Células-Tronco/patologia
19.
J Clin Invest ; 128(5): 1793-1806, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29408806

RESUMO

In these studies, we evaluated the contribution of the NLRP3 inflammasome to Crohn's disease (CD) in a kindred containing individuals having a missense mutation in CARD8, a protein known to inhibit this inflammasome. Whole exome sequencing and PCR studies identified the affected individuals as having a V44I mutation in a single allele of the T60 isoform of CARD8. The serum levels of IL-1ß in the affected individuals were increased compared with those in healthy controls, and their peripheral monocytes produced increased amounts of IL-1ß when stimulated by NLRP3 activators. Immunoblot studies probing the basis of these findings showed that mutated T60 CARD8 failed to downregulate the NLRP3 inflammasome because it did not bind to NLRP3 and inhibit its oligomerization. In addition, these studies showed that mutated T60 CARD8 exerted a dominant-negative effect by its capacity to bind to and form oligomers with unmutated T60 or T48 CARD8 that impeded their binding to NLRP3. Finally, inflammasome activation studies revealed that intact but not mutated CARD8 prevented NLRP3 deubiquitination and serine dephosphorylation. CD due to a CARD8 mutation was not effectively treated by anti-TNF-α, but did respond to IL-1ß inhibitors. Thus, patients with anti-TNF-α-resistant CD may respond to this treatment option.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Doença de Crohn/imunologia , Inflamassomos/imunologia , Mutação com Perda de Função , Monócitos/imunologia , Mutação de Sentido Incorreto , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteínas de Neoplasias/imunologia , Substituição de Aminoácidos , Proteínas Adaptadoras de Sinalização CARD/genética , Doença de Crohn/genética , Doença de Crohn/patologia , Feminino , Células HEK293 , Humanos , Inflamassomos/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Monócitos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Neoplasias/genética , Fosforilação/genética , Fosforilação/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Ubiquitinação/genética , Ubiquitinação/imunologia , Sequenciamento Completo do Genoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA