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1.
J Exp Med ; 217(3)2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31914175

RESUMO

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31775019

RESUMO

CAPSULE SUMMARY: We characterise the immunopathogenesis of autoinflammation, HLH, and early onset intestinal inflammation caused by homozygous mutation in DNASE2, and provide the first description of favourable therapeutic response to JAK1/JAK2 blockade in this disease.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31501268

RESUMO

The lipid and protein phosphatase and tensin homolog (PTEN) controls the differentiation and activation of multiple immune cells. PTEN acts downstream from T- and B-cell receptors, costimulatory molecules, cytokine receptors, integrins, and also growth factor receptors. Loss of PTEN activity in human and mice is associated with cellular and humoral immune dysfunction, lymphoid hyperplasia, and autoimmunity. Although most patients with PTEN hamartoma tumor syndrome (PHTS) have no immunological symptoms, a subclinical immune dysfunction is present in many, and clinical immunodeficiency in few. Comparison of the immune phenotype caused by PTEN haploinsufficiency in PHTS, phosphoinositide 3-kinase (PI3K) gain-of-function in activated PI3K syndrome, and mice with conditional biallelic Pten deletion suggests a threshold model in which coordinated activity of several phosphatases control the PI3K signaling in a cell-type-specific manner. Emerging evidence highlights the role of PTEN in polygenic autoimmune disorders, infection, and the immunological response to cancer. Targeting the PI3K axis is an emerging therapeutic avenue.

4.
J Crohns Colitis ; 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31157858

RESUMO

Mendelian disorders in glucose-6-phosphate metabolism can present with inflammatory bowel disease (IBD). Using whole genome sequencing we identified a homozygous variant in the glucose-6-phosphatase G6PC3 (c.911dupC; p.Q305fs*82) in an adult patient with congenital neutropenia, lymphopenia and childhood-onset, therapy-refractory Crohn's disease. Since G6PC3 is expressed in several haematopoietic and non-haematopoietic cells it was unclear whether allogeneic stem cell transplantation (HSCT) would benefit this patient with intestinal inflammation. We show that HSCT resolves G6PC3-associated immunodeficiency and the Crohn's disease phenotype. It illustrates how even in adulthood, next generation sequencing can have a significant impact on clinical practice and healthcare utilization in patients with immunodeficiency and monogenic IBD.

6.
Immunity ; 50(2): 432-445.e7, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30683619

RESUMO

Host microbial cross-talk is essential to maintain intestinal homeostasis. However, maladaptation of this response through microbial dysbiosis or defective host defense toward invasive intestinal bacteria can result in chronic inflammation. We have shown that macrophages differentiated in the presence of the bacterial metabolite butyrate display enhanced antimicrobial activity. Butyrate-induced antimicrobial activity was associated with a shift in macrophage metabolism, a reduction in mTOR kinase activity, increased LC3-associated host defense and anti-microbial peptide production in the absence of an increased inflammatory cytokine response. Butyrate drove this monocyte to macrophage differentiation program through histone deacetylase 3 (HDAC3) inhibition. Administration of butyrate induced antimicrobial activity in intestinal macrophages in vivo and increased resistance to enteropathogens. Our data suggest that (1) increased intestinal butyrate might represent a strategy to bolster host defense without tissue damaging inflammation and (2) that pharmacological HDAC3 inhibition might drive selective macrophage functions toward antimicrobial host defense.


Assuntos
Anti-Infecciosos/farmacologia , Butiratos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Animais , Diferenciação Celular/genética , Células Cultivadas , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/microbiologia , Citocinas/genética , Citocinas/metabolismo , Disbiose/microbiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Microbiota/fisiologia , Monócitos/metabolismo , Monócitos/microbiologia
7.
Haematologica ; 104(3): 609-621, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30309848

RESUMO

Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as PN404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as PP498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4+ T cells (including T-helper 17-enriched subsets) and non-conventional CD8+T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (PP498L) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets.

8.
Proc Natl Acad Sci U S A ; 115(40): 10118-10123, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30217896

RESUMO

Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22-induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22-pretreated cells. The antimicrobial phenotype was absent in hIPSCs derived from a patient harboring a homozygous mutation in the IL10RB gene that inactivates the IL-22 receptor but was restored by genetically complementing the IL10RB deficiency. This study highlights a mechanism through which the IL-22 pathway facilitates the human intestinal epithelium to control microbial infection.


Assuntos
Células Epiteliais/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Fagossomos/imunologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/microbiologia , Células-Tronco Pluripotentes Induzidas/patologia , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-21/genética , Subunidade alfa de Receptor de Interleucina-21/imunologia , Interleucinas/genética , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Fagossomos/genética , Fagossomos/microbiologia , Fagossomos/patologia , Infecções por Salmonella/genética , Infecções por Salmonella/patologia , Salmonella typhimurium/genética
11.
Annu Rev Immunol ; 36: 755-781, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29677472

RESUMO

Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder-associated IBD increasingly directs treatment strategies as part of personalized medicine.


Assuntos
Suscetibilidade a Doenças/imunologia , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/terapia , Animais , Biomarcadores , Doença Crônica , Gerenciamento Clínico , Modelos Animais de Doenças , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Disbiose , Microbioma Gastrointestinal , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/prevenção & controle , Terapia de Alvo Molecular , Pesquisa Médica Translacional
12.
Clin Gastroenterol Hepatol ; 16(9): 1442-1449.e5, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29654912

RESUMO

BACKGROUND & AIMS: Celiac disease can be identified by a serologic test for IgA against tissue transglutaminase (IgA-TTG) in a large proportion of children. However, the increased concentrations of antibody rarely normalize within the months after children are placed on a gluten-free diet (GFD). Early serologic predictors of sufficient adherence to GFD are required for optimal treatment. METHODS: In a prospective study, we observed the response to a GFD in 345 pediatric patients (67% girls; mean age, 8.4 y) who underwent duodenal biopsy to confirm or refute celiac disease from October 2012 through December 2015. Baseline serum samples were tested centrally for IgA-TTG and IgG against deamidated gliadin. Follow-up serologic analyses of children on a GFD were performed about 3 months later. RESULTS: The geometric mean concentration of IgA-TTG decreased from 72.4-fold to 5.2-fold the upper limit of normal (ULN), or by a factor of 14.0 (95% CI, 12.0-16.4). A substantial response (defined as a larger change than the typical variation in patients not on a GFD) was observed in 80.6% of the children. Only 28.1% of patients had a substantial response in the concentration of IgG against deamidated gliadin. Concentration of IgA-TTG remained above 1-fold the ULN in 83.8% of patients, and above 10-fold the ULN in 26.6% of patients with a substantial response. CONCLUSIONS: Serum concentration of IgA-TTG decreases substantially in most children with celiac disease within 3 months after they are placed on a GFD, but does not normalize in most. This information on changes in antibody concentrations can be used to assess patient response to the diet at short-term follow-up evaluations. Patients with a substantial response to a GFD often still have high antibody levels after 3 months. German Clinical Trials Registry no. DRKS00003854.


Assuntos
Autoanticorpos/sangue , Doença Celíaca/patologia , Doença Celíaca/terapia , Dieta Livre de Glúten , Adolescente , Análise Química do Sangue , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Imunoglobulina A/sangue , Lactente , Masculino , Estudos Prospectivos , Fatores de Tempo
16.
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
17.
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
18.
Gastroenterology ; 153(5): 1320-1337.e16, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28782508

RESUMO

BACKGROUND & AIMS: Interactions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4+ T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation. METHODS: We collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13-30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn's disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4+ T cells. We sequenced T-cell receptor Vß genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4+ T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction. RESULTS: Circulating and gut-resident CD4+ T cells from controls responded to bacteria at frequencies of 40-4000 per million for each bacterial species tested. Microbiota-reactive CD4+ T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vß repertoire. These cells were functionally heterogeneous, produced barrier-protective cytokines, and stimulated intestinal stromal and epithelial cells via interleukin 17A, interferon gamma, and tumor necrosis factor. In patients with inflammatory bowel diseases, microbiota-reactive CD4+ T cells were reduced in the blood compared with intestine; T-cell responses that we detected had an increased frequency of interleukin 17A production compared with responses of T cells from blood or intestinal tissues of controls. CONCLUSIONS: In an analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls, we found that reactivity to intestinal bacteria is a normal property of the human CD4+ T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota. T-cell responses to commensals might support intestinal homeostasis, by producing barrier-protective cytokines and providing a large pool of T cells that react to pathogens.


Assuntos
Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Microbioma Gastrointestinal/imunologia , Intestinos/imunologia , Bactérias/classificação , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/microbiologia , Estudos de Casos e Controles , Linhagem Celular , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Interações Hospedeiro-Patógeno , Humanos , Imunidade nas Mucosas , Memória Imunológica , Interleucina-17/imunologia , Intestinos/microbiologia , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Células Th17/imunologia , Células Th17/microbiologia
19.
Trends Genet ; 33(9): 629-641, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28755896

RESUMO

Genomic technologies inform the complex genetic basis of polygenic inflammatory bowel disease (IBD) as well as Mendelian disease-associated IBD. Aiming to diagnose patients that present with extreme phenotypes due to monogenic forms of IBD, genomics has progressed from 'orphan disease' research towards an integrated standard of clinical care. Advances in diagnostic clinical genomics are increasingly complemented by pathway-specific therapies that aim to correct the consequences of genetic defects. This highlights the exceptional potential for personalized precision medicine. IBD is nevertheless a challenging example for genomic medicine because the overall fraction of patients with Mendelian defects is low, the number of potential candidate genes is high, and interventional evidence is still emerging. We discuss requirements and prospects of explanatory and predictive clinical genomics in IBD.


Assuntos
Genoma Humano , Doenças Inflamatórias Intestinais/genética , Humanos
20.
J Exp Med ; 214(9): 2547-2562, 2017 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-28747427

RESUMO

Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.


Assuntos
Craniossinostoses/genética , Receptor gp130 de Citocina/genética , Síndromes de Imunodeficiência/genética , Mutação de Sentido Incorreto/genética , Pré-Escolar , Receptor gp130 de Citocina/fisiologia , Exoma/genética , Feminino , Humanos , Interleucina-11/deficiência , Interleucina-6/deficiência , Interleucinas/deficiência
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