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1.
Inflamm Bowel Dis ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32064493

RESUMO

BACKGROUND: Genetic defects of pediatric-onset inflammatory bowel disease (IBD) provide critical insights into molecular factors controlling intestinal homeostasis. NOX1 has been recently recognized as a major source of reactive oxygen species (ROS) in human colonic epithelial cells. Here we assessed the functional consequences of human NOX1 deficiency with respect to wound healing and epithelial migration by studying pediatric IBD patients presenting with a stop-gain mutation in NOX1. METHODS: Functional characterization of the NOX1 variant included ROS generation, wound healing, 2-dimensional collective chemotactic migration, single-cell planktonic migration in heterologous cell lines, and RNA scope and immunohistochemistry of paraffin-embedded patient tissue samples. RESULTS: Using exome sequencing, we identified a stop-gain mutation in NOX1 (c.160C>T, p.54R>*) in patients with pediatric-onset IBD. Our studies confirmed that loss-of-function of NOX1 causes abrogated ROS activity, but they also provided novel mechanistic insights into human NOX1 deficiency. Cells that were NOX1-mutant showed impaired wound healing and attenuated 2-dimensional collective chemotactic migration. High-resolution microscopy of the migrating cell edge revealed a reduced density of filopodial protrusions with altered focal adhesions in NOX1-deficient cells, accompanied by reduced phosphorylation of p190A. Assessment of single-cell planktonic migration toward an epidermal growth factor gradient showed that NOX1 deficiency is associated with altered migration dynamics with loss of directionality and altered cell-cell interactions. CONCLUSIONS: Our studies on pediatric-onset IBD patients with a rare sequence variant in NOX1 highlight that human NOX1 is involved in regulating wound healing by altering epithelial cytoskeletal dynamics at the leading edge and directing cell migration.

2.
Gastroenterology ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32084423

RESUMO

BACKGROUND & AIMS: A proportion of infants and young children with inflammatory bowel diseases (IBD) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD. METHODS: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, 0-18 y old (median age at diagnosis, 11.96 y) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses. RESULTS: We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 y and 2.3% of children 6-18 y old. Of the 17 patients with monogenic Crohn's disease, 35% had abdominal pain, 24% had non-bloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 y (odds ratio [OR], 6.30; P=.020), family history of autoimmune disease (OR, 5.12; P=.002), extra-intestinal manifestations (OR, 15.36; P<.0001), and surgery (OR, 3.42; P=.042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare but should be considered in analysis of all patients with pediatric onset of IBD.

3.
J Clin Tuberc Other Mycobact Dis ; 17: 100123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788565

RESUMO

Background: The interleukin-12 receptor ß1 (IL-12Rß1) deficiency is a primary immunodeficiency (PID), affecting the immunological pathway of interleukin 12/interferon- γ (IL12/IFN-γ) axis and interleukin 23 receptor (IL23R). Defect in this pathway is mainly affecting the cellular immunity-related disorders. IL-12Rß1 is a receptor chain of both the IL-12 and the IL-23 receptors and thus, deficiency of IL-12Rß1 abolishes both IL-12 and IL-23 signaling. Material and methods: In this study, we performed whole exon sequencing and confirmatory Sanger sequencing in IL-12Rß1. Evaluation of the IL12/IFN-γ axis was performed by assessment of patients' whole blood cell to IL12/IFN-γ responding. Total and surface IL-12Rß1expression was evaluated, in peripheral blood mononuclear cells (PBMCs) and T cell- derived PBMCs, and Th17 count was assessed. Results: In the present study, we described a c.1791 + 2T > G mutation at a splicing site position in IL-12Rß1, using whole exome sequencing, and confirmed with targeted Sanger sequencing in a 26- year-old patient with Mendelian susceptibility to mycobacterial disease (MSMD) and Crohn's disease (CD). Complete lack of IL-12Rß1 protein expression was detected in patient's PBMCs, compared to the healthy control. Furthermore, no IL-12Rß1 protein was expressed on the cell surface. Interestingly, IL-12Rß1-mutant cells showed an impaired response to IL12, and Bacillus Calmette-Guérin stimulation, confirming that the mutation is causative in this patient. Conclusion: A 3'splicing site mutation in IL12Rß1, can be corresponding to the abolished expression of IL12Rß1 in patients' cells, and associated with an impaired IL12-mediated signaling, which may lead not only to MSMD, but also to inflammatory bowel disease (IBD).

4.
Inflamm Bowel Dis ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31833544

RESUMO

Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31843991

RESUMO

Inflammation is a fundamental biological process mediating host defense and wound healing during infections and tissue injury. Perpetuated and excessive inflammation may cause autoinflammation, autoimmunity, degenerative disorders, allergies, and malignancies. Multimodal signaling by tumor necrosis factor receptor 1 (TNFR1) plays a crucial role in determining the transition between inflammation, cell survival, and programmed cell death. Targeting TNF signaling has been proven as an effective therapeutic in several immune-related disorders. Mouse studies have provided critical mechanistic insights into TNFR1 signaling and its potential role in a broad spectrum of diseases. The characterization of patients with monogenic primary immunodeficiencies (PIDs) has highlighted the importance of TNFR1 signaling in human disease. In particular, patients with PIDs have revealed paradoxical connections between immunodeficiency, chronic inflammation, and dysregulated cell death. Importantly, studies on PIDs may help to predict beneficial effects and side-effects of therapeutic targeting of TNFR1 signaling.

6.
Gastroenterology ; 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31743734

RESUMO

BACKGROUND & AIMS: Mutations in the tetratricopeptide repeat domain 7A gene (TTC7A) cause intestinal epithelial and immune defects. Patients can become immune deficient and develop apoptotic enterocolitis, multiple intestinal atresia, and recurrent intestinal stenosis. The intestinal disease in patients with TTC7A deficiency is severe, untreatable, and recurs despite resection or allogeneic hematopoietic stem cell transplant. We screened drugs for those that prevent apoptosis of in cells with TTC7A deficiency and tested their effects in an animal model of the disease. METHODS: We developed a high-throughput screen to identify compounds approved by the Food and Drug Administration that reduce activity of caspases 3 and 7 in TTC7A-knockout HAP1 (human haploid) cells and reduce the susceptibility to apoptosis. We validated the effects of identified agents in HeLa cells that stably express TTC7A with point mutations found in patients. Signaling pathways in cells were analyzed by immunoblots. We tested the effects of identified agents in zebrafish with disruption of ttc7a, which develop intestinal defects, and colonoids derived from biopsies of patients with and without mutations in TTC7A. We performed real-time imaging of intestinal peristalsis in zebrafish and histologic analyses of intestinal tissues from patients and zebrafish. Colonoids were analyzed by immunofluorescence and for ion transport. RESULTS: TTC7A-knockout HAP1 cells have abnormal morphology and undergo apoptosis, due to increased levels of active caspases 3 and 7. We identified drugs that increased cell viability; leflunomide (used to treat patients with inflammatory conditions) reduced caspase 3 and 7 activity in cells by 96%. TTC7A-knockout cells contained cleaved caspase 3 and had reduced levels of phosphorylated AKT and XIAP; incubation of these cells with leflunomide increased levels of phosphorylated AKT and XIAP and reduced levels of cleaved caspase 3. Administration of leflunomide to ttc7a-/- zebrafish increased gut motility, reduced intestinal tract narrowing, increased intestinal cell survival, increased sizes of intestinal luminal spaces, and restored villi and goblet cell morphology. Exposure of patient-derived colonoids to leflunomide increased cell survival, polarity, and transport function. CONCLUSIONS: In a drug screen, we identified leflunomide as an agent that reduces apoptosis and levels of caspase 3 and activates AKT signaling and in TTC7A-knockout cells. In zebrafish with disruption of ttc7a, leflunomide restores gut motility, reduces intestinal tract narrowing, and increases intestinal cell survival. This drug might be repurposed for treatment of TTC7A deficiency.

8.
Inflamm Bowel Dis ; 25(11): 1788-1795, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31115454

RESUMO

BACKGROUND: Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. METHODS: To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. RESULTS: Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. CONCLUSION: Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

9.
Front Immunol ; 10: 497, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936881

RESUMO

B-cell development and function depend on stage-specific signaling through the B-cell antigen receptor (BCR). Signaling and intracellular trafficking of the BCR are connected, but the molecular mechanisms of this link are incompletely understood. Here, we investigated the role of the endosomal adaptor protein and member of the LAMTOR/Ragulator complex LAMTOR2 (p14) in B-cell development. Efficient conditional deletion of LAMTOR2 at the pre-B1 stage using mb1-Cre mice resulted in complete developmental arrest. Deletion of LAMTOR2 using Cd19-Cre mice permitted analysis of residual B cells at later developmental stages, revealing that LAMTOR2 was critical for the generation and activation of mature B lymphocytes. Loss of LAMTOR2 resulted in aberrant BCR signaling due to delayed receptor internalization and endosomal trafficking. In conclusion, we identify LAMTOR2 as critical regulator of BCR trafficking and signaling that is essential for early B-cell development in mice.

10.
J Clin Immunol ; 39(2): 207-215, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30903457

RESUMO

Inborn errors in interleukin 2 receptor, gamma (IL2RG) perturb signaling of the common gamma chain family cytokines and cause severe combined immunodeficiency (SCID). Here, we report two brothers suffering from chronic cryptosporidiosis, severe diarrhea, and cholangitis. Pan T, B, and NK cell numbers were normal, but immunophenotyping revealed defective B cell differentiation. Using whole exome sequencing, we identified a base pair deletion in the first exon of IL2RG predicted to cause a frameshift and premature stop. However, flow cytometry revealed normal surface expression of the IL-2Rγ chain. While IL-2, IL-7, and IL-15 signaling showed only mild defects of STAT5 phosphorylation in response to the respective cytokines, IL-4- and IL-21-induced phosphorylation of STAT3 and STAT6 was markedly reduced. Examination of RNA isoforms detected alternative splicing downstream of IL2RG exon 1 in both patients resulting in resolution of the predicted frameshift and 16 mutated amino acids. In silico modeling suggested that the IL-2Rγ mutation reduces the stabilization of IL-4 and IL-21 cytokine binding by affecting the N-terminal domain of the IL-2Rγ. Thus, our study shows that IL2RG deficiency can be associated with differential signaling defects. Confounding effects of alternative splicing may partially rescue genetic defects and should be considered in patients with inborn errors of immunity.

12.
Proc Natl Acad Sci U S A ; 116(3): 970-975, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30591564

RESUMO

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.


Assuntos
Diferenciação Celular , Imunidade nas Mucosas/genética , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Proteína Serina-Treonina Quinases de Interação com Receptores , Imunodeficiência Combinada Severa , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Células HCT116 , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mutação , NF-kappa B/genética , NF-kappa B/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
13.
J Clin Immunol ; 38(7): 787-793, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30255293

RESUMO

PURPOSE: Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM). METHODS: In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran, with disseminated BCG disease. We evaluated the patients' whole blood cell response to IL-12 and IFN-γ, IL-12Rß1 expression on T cell blasts, and sequenced candidate genes. RESULTS: We report four patients from Isfahan, Iran, ranging from 3 months to 26 years old, with impaired IL-12 signaling. All patients suffered from BCG disease. One of them presented mycobacterial osteomyelitis. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rß1 was completely abolished in the four patients with IL12RB1 mutations. CONCLUSIONS: IL-12Rß1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321* mutant IL-12Rß1 protein. Mycobacterial osteomyelitis is another type of location of BCG infection in an IL-12Rß1-deficient patient, notified for the first time in this study.


Assuntos
Suscetibilidade a Doenças , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Infecções por Mycobacterium/etiologia , Infecções por Mycobacterium/metabolismo , Receptores de Interleucina-12/deficiência , Adolescente , Adulto , Alelos , Vacina BCG/imunologia , Biomarcadores , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imunofenotipagem , Lactente , Irã (Geográfico)/epidemiologia , Masculino , Mutação , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/prevenção & controle , Prognóstico , Adulto Jovem
15.
J Clin Immunol ; 38(6): 699-710, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30030704

RESUMO

PURPOSE: RAS guanyl-releasing protein 1 (RASGRP1) deficiency has recently been shown to cause a primary immunodeficiency (PID) characterized by CD4+ T cell lymphopenia and Epstein-Barr virus (EBV)-associated B cell lymphoma. Our report of three novel patients widens the scope of RASGRP1 deficiency by providing new clinical and immunological insights on autoimmunity, immune cell development, and predisposition to lymphoproliferative disease. METHODS: One patient of Turkish origin (P1) and two Palestinian patients (P2, P3) were evaluated for immunodeficiency. To decipher the molecular cause of disease, whole exome sequencing was conducted. Identified mutations were validated by immunological and biochemical assays. RESULTS: We report three patients presenting with similar clinical characteristics of immunodeficiency and EBV-associated lymphoproliferative disease. In addition, P2 and P3 exhibited overt autoimmune manifestations. Genetic screening identified two novel loss-of-function mutations in RASGRP1. Immunoblotting and active Ras pull-down assays confirmed perturbed ERK1/2 signaling and reduced Ras-GTPase activity in heterologous Jurkat cells with ectopic expression of RASGRP1 mutants. All three patients had CD4+ T cell lymphopenia. P2 and P3 showed decreased mitogen-induced lymphocyte proliferation, reduced T cell receptor excision circles, abnormal T cell receptor (TCR) Vß repertoires, and increased frequencies of TCRγδ cells. TCR gamma repertoire diversity was significantly reduced with a remarkable clonal expansion. CONCLUSIONS: RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies. Early diagnosis is critical and hematopoietic stem cell transplantation might be considered as curative treatment.


Assuntos
Proteínas de Ligação a DNA/genética , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/complicações , Fatores de Troca do Nucleotídeo Guanina/genética , Síndromes de Imunodeficiência/etiologia , Imunomodulação/genética , Linfoma/etiologia , Mutação , Alelos , Autoimunidade , Biomarcadores , Sistemas CRISPR-Cas , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Pré-Escolar , Análise Mutacional de DNA , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Genótipo , Humanos , Síndromes de Imunodeficiência/metabolismo , Lactente , Recém-Nascido , Linfoma/metabolismo , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/metabolismo , Masculino , Linhagem , Sequenciamento Completo do Exoma
16.
17.
Nat Genet ; 50(3): 344-348, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29483653

RESUMO

Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.


Assuntos
Encefalopatias/complicações , Encefalopatias/genética , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Fator de Crescimento Transformador beta1/genética , Análise Mutacional de DNA , Feminino , Humanos , Doenças Inflamatórias Intestinais/patologia , Masculino , Linhagem , Índice de Gravidade de Doença
18.
Inflamm Bowel Dis ; 23(11): 1950-1961, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29023267

RESUMO

BACKGROUND: IL10 receptor (IL10R) deficiency causes severe infantile-onset inflammatory bowel disease. Intact IL10R-dependent signals have been shown to be important for innate and adaptive immune cell functions in mice. We have previously reported a key role of IL10 in the generation and function of human anti-inflammatory macrophages. Independent of innate immune cell defects, the aim of the current study was to determine the role of IL10R signaling in regulating human CD4 T-cell function. METHODS: Peripheral blood mononuclear cells and intestinal biopsies cells were collected from IL10/IL10R-deficient patients and controls. Frequencies of CD4 T-cell subsets, naive T-cell proliferation, regulatory T cell (Treg)-mediated suppression, and Treg and TH17 generation were determined by flow cytometry. Transcriptional profiling was performed by NanoString and quantitative real-time polymerase chain reaction. RNA in situ hybridization was used to determine the quantities of various transcripts in intestinal mucosa. RESULTS: Analysis of 16 IL10- and IL10R-deficient patients demonstrated similar frequencies of peripheral blood and intestinal Tregs, compared with control subjects. In addition, in vitro Treg suppression of CD4 T-cell proliferation and generation of Treg were not dependent on IL10R signaling. However, IL10R-deficient T naive cells exhibited higher proliferative capacity, a strong TH17 signature, and an increase in polarization toward TH17 cells, compared with controls. Moreover, the frequency of TH17 cells was increased in the colon and ileum of IL10R-deficient patients. Finally, we show that stimulation of IL10R-deficient Tregs in the presence of IL1ß leads to enhanced production of IL17A. CONCLUSIONS: IL10R signaling regulates TH17 polarization and T-cell proliferation in humans but is not required for the generation and in vitro suppression of Tregs. Therapies targeting the TH17 axis might be beneficial for IL10- and IL10R-deficient patients as a bridge to allogeneic hematopoietic stem cell transplantation.


Assuntos
Doenças Inflamatórias Intestinais/genética , Interleucina-10/genética , Receptores de Interleucina-10/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adolescente , Adulto , Estudos de Casos e Controles , Proliferação de Células , Criança , Pré-Escolar , Colo/patologia , Feminino , Humanos , Lactente , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Transdução de Sinais/genética , Adulto Jovem
19.
Inflamm Bowel Dis ; 23(12): 2109-2120, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28930861

RESUMO

BACKGROUND: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. METHODS: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. RESULTS: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. CONCLUSIONS: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.


Assuntos
Diarreia/etiologia , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Idade de Início , Criança , Pré-Escolar , Doença Crônica , Feminino , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Sequenciamento Completo do Exoma
20.
World J Gastrointest Pathophysiol ; 8(2): 87-92, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28573071

RESUMO

Chronic granulomatous disease (CGD) is a primary immune deficiency that is commonly diagnosed under the age of 5 years (95%) and is rarely seen in adulthood. CGD may manifest as inflammatory bowel disease (IBD) in childhood. Without proper diagnosis, these patients may be monitored for years as IBD; some may even be regarded as steroid-resistant ulcerative colitis (UC) and end up having a colectomy. In this case report, we described a patient who had been followed-up for years as UC and subsequently underwent colectomy, but was finally diagnosed in adulthood as primary immune deficiency.

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