Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
1.
Nature ; 598(7880): 327-331, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34588693

RESUMO

Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception1,2, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).


Assuntos
Células da Medula Óssea/citologia , Medula Óssea , Síndrome de Down/sangue , Síndrome de Down/imunologia , Feto/citologia , Hematopoese , Sistema Imunitário/citologia , Linfócitos B/citologia , Células Dendríticas/citologia , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Células Endoteliais/patologia , Eosinófilos/citologia , Células Eritroides/citologia , Granulócitos/citologia , Humanos , Imunidade , Células Mieloides/citologia , Células Estromais/citologia
2.
Nature ; 574(7778): 365-371, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597962

RESUMO

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.


Assuntos
Feto/citologia , Hematopoese , Fígado/citologia , Fígado/embriologia , Células Sanguíneas/citologia , Microambiente Celular , Feminino , Feto/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Fígado/metabolismo , Tecido Linfoide/citologia , Análise de Célula Única , Células-Tronco/metabolismo
3.
J Immunol ; 207(9): 2245-2254, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34561227

RESUMO

Targeting interactions between α4ß7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEß7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. ß1 and ß7 integrin expression on circulating lymphocytes was similar across groups. TGF-ß1 treatment induced expression of αE on both ß7+ and ß7- T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4ß7 can become αEß7+ ITGAE gene polymorphisms did not alter protein induction following TGF-ß1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-ß, and increased TGF-ß-responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline ß7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE+ and αE- T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4ß7-, and α4ß7+ T cells may upregulate αEß7 in response to TGF-ß once within the gut mucosa.


Assuntos
Antígenos CD/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Cadeias alfa de Integrinas/metabolismo , Cadeias beta de Integrinas/metabolismo , Mucosa Intestinal/imunologia , Receptores de Retorno de Linfócitos/metabolismo , Linfócitos T/imunologia , Adulto , Idoso , Movimento Celular , Feminino , Humanos , Cadeias beta de Integrinas/genética , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
4.
Blood ; 136(9): 1055-1066, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32518946

RESUMO

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.


Assuntos
Proteínas de Ligação a DNA/deficiência , Mutação em Linhagem Germinativa , Mutação com Perda de Função , Transtornos Linfoproliferativos/genética , Proteínas Proto-Oncogênicas/deficiência , Imunodeficiência Combinada Severa/genética , Aloenxertos , Apoptose , Subpopulações de Linfócitos B/patologia , Técnicas de Reprogramação Celular , Códon sem Sentido , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Dioxigenases , Evolução Fatal , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Recém-Nascido , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Masculino , Mutação de Sentido Incorreto , Neoplasias Primárias Múltiplas/genética , Linhagem , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Imunodeficiência Combinada Severa/patologia , Subpopulações de Linfócitos T/patologia , Sequenciamento do Exoma
7.
Science ; 381(6659): eadd7564, 2023 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-37590359

RESUMO

The extraembryonic yolk sac (YS) ensures delivery of nutritional support and oxygen to the developing embryo but remains ill-defined in humans. We therefore assembled a comprehensive multiomic reference of the human YS from 3 to 8 postconception weeks by integrating single-cell protein and gene expression data. Beyond its recognized role as a site of hematopoiesis, we highlight roles in metabolism, coagulation, vascular development, and hematopoietic regulation. We reconstructed the emergence and decline of YS hematopoietic stem and progenitor cells from hemogenic endothelium and revealed a YS-specific accelerated route to macrophage production that seeds developing organs. The multiorgan functions of the YS are superseded as intraembryonic organs develop, effecting a multifaceted relay of vital functions as pregnancy proceeds.


Assuntos
Desenvolvimento Embrionário , Saco Vitelino , Feminino , Humanos , Gravidez , Coagulação Sanguínea/genética , Macrófagos , Saco Vitelino/citologia , Saco Vitelino/metabolismo , Desenvolvimento Embrionário/genética , Atlas como Assunto , Expressão Gênica , Perfilação da Expressão Gênica , Hematopoese/genética , Fígado/embriologia
8.
J Exp Med ; 216(6): 1311-1327, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31040185

RESUMO

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) ß chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rß and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rß expression and function. IL-2Rß loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rß also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.


Assuntos
Tolerância Imunológica/genética , Imunidade/genética , Subunidade beta de Receptor de Interleucina-2/genética , Mutação/genética , Alelos , Autoimunidade/genética , Genótipo , Células HEK293 , Humanos , Síndromes de Imunodeficiência/genética , Células Matadoras Naturais/metabolismo , Lentivirus/metabolismo , Mutação de Sentido Incorreto/genética , Fenótipo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo
9.
Sci Immunol ; 4(42)2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836668

RESUMO

Excessive type I interferon (IFNα/ß) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/ß, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/ß signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/ß signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/ß activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.


Assuntos
Doenças do Sistema Imunitário/genética , Interferon Tipo I/imunologia , Fator de Transcrição STAT2/genética , Mutação em Linhagem Germinativa , Humanos , Doenças do Sistema Imunitário/imunologia , Lactente , Masculino , Transdução de Sinais
10.
Med Hypotheses ; 82(1): 1-5, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24139052

RESUMO

Fatal non-accidental head injury (NAHI) in infancy is characterised by severe bilateral retinal haemorrhage (sbRH), thin film diffuse bilateral subdural haemorrhage (dbSDH) and severe fatal hypoxic ischaemic encephalopathy (sfHIE). The Geddes hypothesis is that sfHIE is the direct cause of sbRH and dbSDH. The conventional hypothesis (post-Geddes) is that trauma precipitates hypoxia to cause sfHIE and independently tears veins to cause sbRH and dbSDH. These hypotheses are assessed using Bradford Hill criteria of causation. The triad (sbRH, dbSDH and sfHIE) is a strong, specific and consistent association which suggests a causative link. Furthermore sbRH and dbSDH are positively correlated with severity of HIE but negatively correlated with objective evidence of trauma. The conventional hypothesis (post-Geddes) fails the test of biological plausibility because trauma causes asymmetrical and focal bleeding not diffuse bilateral capillary and venular oozing. The conventional hypothesis lacks coherence since it was shown that the encephalopathy of the triad is not traumatic. Arguments by analogy also support the Geddes hypothesis. There is a paucity of experimental evidence for either hypothesis but this is likely to be rectified as molecular methods (genomics and proteomics) are used in the infant autopsy.


Assuntos
Maus-Tratos Infantis , Traumatismos Craniocerebrais/epidemiologia , Traumatismos Craniocerebrais/fisiopatologia , Hematoma Subdural/fisiopatologia , Hemorragia Retiniana/fisiopatologia , Fenômenos Biomecânicos , Causalidade , Humanos , Incidência , Lactente , Modelos Biológicos , Reino Unido/epidemiologia , Estados Unidos/epidemiologia
11.
Med Hypotheses ; 78(6): 772-5, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22465467

RESUMO

The hypothesis proposed is that anorexia nervosa (AN) is an autoimmune disease caused by delayed exposure to common micro-organisms in which auto-antibodies to regulatory peptides and hypothalamic neurons, which cross react with microbial antigens, disturb appetite and lead to decreased intake of food. IgG, IgA and IgM auto-antibodies to a range of regulatory peptides concerned with appetite and mood are found in patients with AN. The regulatory peptides show sequence homology with common micro-organisms of the microbial flora. Auto-antibodies to α melanocyte stimulating hormone (αMSH) are positively correlated with AN psychopathology. But patients with bulimia nervosa (BN) and normal healthy controls also have a similar range of auto-antibodies at comparable levels. The incidence of AN is rising in developed countries, the disease is more common in females than in males, the peak incidence is in the teenage years, there is seasonal variation in the month of birth and the disease is more common in higher socio-economic groups. These are all features which are consistent with the hygiene hypothesis. But there is no evidence that the disease is more common in first born than in later born children. There is a paucity of data on early life events such as attendance at nursery and exposure to pets. Genetic factors are important but the data on major histocompatibility complex (MHC) gene polymorphisms are contradictory. The epidemiological and serological data are consistent with the hypothesis under investigation but key questions in relation to the hygiene hypothesis have not been posed. A large case control study of AN epidemiology is indicated. MHC gene polymorphisms should be assessed. There is, however, sufficient evidence to justify a trial of pooled immunoglobulin therapy in patients with life threatening AN.


Assuntos
Anorexia Nervosa/epidemiologia , Anorexia Nervosa/etiologia , Autoanticorpos/imunologia , Autoimunidade/imunologia , Hipótese da Higiene , Modelos Biológicos , Adolescente , Anorexia Nervosa/imunologia , Autoanticorpos/sangue , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA