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1.
PLoS Pathog ; 16(9): e1008854, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956405

RESUMO

Aspergillus fumigatus is an opportunistic fungal pathogen of immunocompromised patient populations. Mortality is thought to be context-specific and occurs via both enhanced fungal growth and immunopathogenesis. NLRX1 is a negative regulator of immune signaling and metabolic pathways implicated in host responses to microbes, cancers, and autoimmune diseases. Our study indicates loss of Nlrx1 results in enhanced fungal burden, pulmonary inflammation, immune cell recruitment, and mortality across immuno-suppressed and immuno-competent models of IPA using two clinically derived isolates (AF293, CEA10). We observed that the heightened mortality is due to enhanced recruitment of CD103+ dendritic cells (DCs) that produce elevated amounts of IL-4 resulting in a detrimental Th2-mediated immune response. Adoptive transfer of Nlrx1-/- CD103+ DCs in neutropenic NRG mice results in enhanced mortality that can be ablated using IL-4 neutralizing antibodies. In vitro analysis of CD103+ DCs indicates loss of Nlrx1 results in enhanced IL-4 production via elevated activation of the JNK/JunB pathways. Interestingly, loss of Nlrx1 also results in enhanced recruitment of monocytes and neutrophils. Chimeras of irradiated Nlrx1-/- mice reconstituted with wild type bone marrow have enhanced neutrophil recruitment and survival during models of IPA. This enhanced immune cell recruitment in the absence of Nlrx1 is mediated by excessive production of CXCL8/IL-8 family of chemokines and IL-6 via early and enhanced activation of P38 in response to A. fumigatus conidia as shown in BEAS-2B airway epithelial cells. In summary, our results point strongly towards the cell-specific and contextual function of Nlrx1 during invasive pulmonary aspergillosis and may lead to novel therapeutics to reduce Th2 responses by CD103+ DCs or heightened recruitment of neutrophils.


Assuntos
Aspergillus fumigatus/imunologia , Células Dendríticas/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Proteínas Mitocondriais/imunologia , Aspergilose Pulmonar/imunologia , Células Th2/imunologia , Animais , Linhagem Celular , Citocinas/genética , Citocinas/imunologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/imunologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Neutrófilos/imunologia , Neutrófilos/patologia , Aspergilose Pulmonar/genética , Aspergilose Pulmonar/patologia , Células Th2/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
2.
Nat Commun ; 11(1): 4225, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839463

RESUMO

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Neoplasias da Vesícula Biliar/genética , Predisposição Genética para Doença/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Chile , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Humanos , Índia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , República da Coreia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
3.
Dermatol Online J ; 26(3)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32609448

RESUMO

Dermatomyositis is a clinically heterogenous inflammatory myopathy with unique cutaneous features. Myositis-specific antibodies can aid in diagnosis and anticipation of patient prognosis. Herein, we report a 22-year-old man who presented with multifocal erythematous plaques with violaceous papules on his bilateral elbows, neck, and face. He was diagnosed with biopsy-proven dermatomyositis and determined to be seropositive for nuclear matrix protein 2 antibody (NXP-2). He was treated with systemic corticosteroids, then intravenous methylprednisolone and azathioprine, and ultimately achieved greatest treatment response with intravenous immune globulin therapy.


Assuntos
Corticosteroides/uso terapêutico , Autoanticorpos/sangue , Proteínas de Ligação a DNA/imunologia , Dermatomiosite/imunologia , Dermatomiosite/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores de Transcrição/imunologia , Algoritmos , Biópsia , Dermatomiosite/diagnóstico , Dermatomiosite/patologia , Diagnóstico Diferencial , Humanos , Masculino , Adulto Jovem
4.
Mol Cell ; 79(1): 155-166.e9, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32454028

RESUMO

To understand gene function, the encoding DNA or mRNA transcript can be manipulated and the consequences observed. However, these approaches do not have a direct effect on the protein product of the gene, which is either permanently abrogated or depleted at a rate defined by the half-life of the protein. We therefore developed a single-component system that could induce the rapid degradation of the specific endogenous protein itself. A construct combining the RING domain of ubiquitin E3 ligase RNF4 with a protein-specific camelid nanobody mediates target destruction by the ubiquitin proteasome system, a process we describe as antibody RING-mediated destruction (ARMeD). The technique is highly specific because we observed no off-target protein destruction. Furthermore, bacterially produced nanobody-RING fusion proteins electroporated into cells induce degradation of target within minutes. With increasing availability of protein-specific nanobodies, this method will allow rapid and specific degradation of a wide range of endogenous proteins.


Assuntos
Endopeptidases/metabolismo , Proteína NEDD8/metabolismo , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Anticorpos de Domínio Único/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina/metabolismo , Endopeptidases/imunologia , Células HeLa , Humanos , Proteína NEDD8/imunologia , Proteínas Nucleares/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Proteólise , Anticorpos de Domínio Único/imunologia , Fatores de Transcrição/imunologia , Ubiquitinação
5.
Nat Neurosci ; 23(6): 730-740, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393896

RESUMO

Descending command neurons instruct spinal networks to execute basic locomotor functions, such as gait and speed. The command functions for gait and speed are symmetric, implying that a separate unknown system directs asymmetric movements, including the ability to move left or right. In the present study, we report that Chx10-lineage reticulospinal neurons act to control the direction of locomotor movements in mammals. Chx10 neurons exhibit mainly ipsilateral projection, and their selective unilateral activation causes ipsilateral turning movements in freely moving mice. Unilateral inhibition of Chx10 neurons causes contralateral turning movements. Paired left-right motor recordings identified distinct mechanisms for directional movements mediated via limb and axial spinal circuits. Finally, we identify sensorimotor brain regions that project on to Chx10 reticulospinal neurons, and demonstrate that their unilateral activation can impart left-right directional commands. Together these data identify the descending motor system that commands left-right locomotor asymmetries in mammals.


Assuntos
Tronco Encefálico/fisiologia , Vias Eferentes/fisiologia , Locomoção/fisiologia , Neurônios/fisiologia , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Proteínas de Homeodomínio/imunologia , Camundongos , Técnicas de Rastreamento Neuroanatômico , Neurônios/efeitos dos fármacos , Toxina Tetânica/farmacologia , Fatores de Transcrição/imunologia
6.
BMC Neurol ; 20(1): 208, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32450842

RESUMO

BACKGROUND: Cerebellar degeneration as a consequence of a malignancy is a rare condition most commonly related to the presence of anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. In recent years, several reports have indicated Zinc-finger protein 4 (Zic4) antibodies being associated with paraneoplastic cerebellar degeneration (PCD) in patients with small cell lung carcinoma. However, the prevalence and the significance of Zic4-antibodies may be underestimated due to their co-occurrence with more frequent antibodies such as anti-Hu. A literature review of isolated Zic4 mediated paraneoplastic syndromes yielded 14 cases reporting mainly benign clinical courses when treated early. CASE PRESENTATION: We present the case of a 67-year-old woman with progressive Zic4 antibody mediated PCD and rhombencephalitis. Immunomodulatory treatment, including intravenous methylprednisolone, plasmaphereses, and intravenous immunoglobulin (IVIG) was administered. Small cell lung cancer (SCLC) was detected, lobectomy performed and cyclophosphamide started. Despite this considerable therapeutic effort, rhombencephalitis led to defiant dysautonomia. CONCLUSION: Paraneoplastic syndromes related to isolated Zic4 antibodies are rare and typically show a benign clinical course. Here, we present the first case of a rapidly progressive isolated Zic4 associated PCD and rhombencephalitis. Despite considerable therapeutic efforts, the patient passed away on autonomic dysfunction, highlighting the significance of Zic4 associated disease.


Assuntos
Autoanticorpos/imunologia , Encefalite , Proteínas do Tecido Nervoso/imunologia , Degeneração Paraneoplásica Cerebelar , Rombencéfalo , Fatores de Transcrição/imunologia , Idoso , Encefalite/metabolismo , Encefalite/fisiopatologia , Feminino , Humanos , Neoplasias Pulmonares , Disautonomias Primárias , Rombencéfalo/metabolismo , Rombencéfalo/fisiopatologia , Carcinoma de Pequenas Células do Pulmão
7.
Mem Inst Oswaldo Cruz ; 115: e190396, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32321154

RESUMO

BACKGROUND: Nanoparticles (NPs) are viable candidates as carriers of exogenous materials into cells via transfection and can be used in the DNA vaccination strategy against leptospirosis. OBJECTIVES: We evaluated the efficiency of halloysite clay nanotubes (HNTs) and amine-functionalised multi-walled carbon nanotubes (NH2-MWCNTs) in facilitating recombinant LemA antigen (rLemA) expression and protecting Golden Syrian hamsters (Mesocricetus auratus) against Leptospira interrogans lethal infection. METHODS: An indirect immunofluorescent technique was used to investigate the potency of HNTs and NH2-MWCNTs in enhancing the transfection and expression efficiency of the DNA vaccine in Chinese hamster ovary (CHO) cells. Hamsters were immunised with two doses of vaccines HNT-pTARGET/lemA, NH2-MWCNTs-pTARGET/lemA, pTARGET/lemA, and empty pTARGET (control), and the efficacy was determined in terms of humoral immune response and protection against a lethal challenge. FINDINGS: rLemA DNA vaccines carried by NPs were able to transfect CHO cells effectively, inducing IgG immune response in hamsters (p < 0.05), and did not exhibit cytotoxic effects. Furthermore, 83.3% of the hamsters immunised with NH2-MWCNTs-pTARGET/lemA were protected against the lethal challenge (p < 0.01), and 66.7% of hamsters immunised with HNT-pTARGET/lemA survived (p < 0.05). MAIN CONCLUSIONS: NH2-MWCNTs and HNTs can act as antigen carriers for mammalian cells and are suitable for DNA nanovaccine delivery.


Assuntos
Antígenos de Bactérias/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Vacinas Bacterianas/administração & dosagem , Leptospirose/prevenção & controle , Fatores de Transcrição/administração & dosagem , Vacinas de DNA/administração & dosagem , Animais , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Cricetinae , Modelos Animais de Doenças , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Leptospira interrogans/imunologia , Leptospirose/imunologia , Nanopartículas , Fatores de Transcrição/imunologia , Vacinas de DNA/imunologia
8.
PLoS Pathog ; 16(4): e1008458, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32339205

RESUMO

The Immune Deficiency (IMD) pathway in Drosophila melanogaster is activated upon microbial challenge with Gram-negative bacteria to trigger the innate immune response. In order to decipher this nuclear factor κB (NF-κB) signaling pathway, we undertook an in vitro RNAi screen targeting E3 ubiquitin ligases specifically and identified the HECT-type E3 ubiquitin ligase Hyperplastic discs (Hyd) as a new actor in the IMD pathway. Hyd mediated Lys63 (K63)-linked polyubiquitination of the NF-κB cofactor Akirin was required for efficient binding of Akirin to the NF-κB transcription factor Relish. We showed that this Hyd-dependent interaction was required for the transcription of immunity-related genes that are activated by both Relish and Akirin but was dispensable for the transcription of genes that depend solely on Relish. Therefore Hyd is key in NF-κB transcriptional selectivity downstream of the IMD pathway. Drosophila depleted of Akirin or Hyd failed to express the full set of genes encoding immune-induced anti-microbial peptides and succumbed to immune challenges. We showed further that UBR5, the mammalian homolog of Hyd, was also required downstream of the NF-κB pathway for the activation of Interleukin 6 (IL6) transcription by LPS or IL-1ß in cultured human cells. Our findings link the action of an E3 ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases.


Assuntos
Proteínas de Drosophila/imunologia , Drosophila melanogaster/imunologia , Proteínas Nucleares/imunologia , Fatores de Transcrição/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Drosophila , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/microbiologia , Bactérias Gram-Negativas/fisiologia , Células HeLa , Humanos , Imunidade Inata , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
9.
Nat Commun ; 11(1): 1625, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242017

RESUMO

Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, forms large aggregate-like assemblies visualized as nuclear foci. Here we demonstrate that Aire utilizes its caspase activation recruitment domain (CARD) to form filamentous homo-multimers in vitro, and this assembly mediates foci formation and transcriptional activity. However, CARD-mediated multimerization also makes Aire susceptible to interaction with promyelocytic leukemia protein (PML) bodies, sites of many nuclear processes including protein quality control of nuclear aggregates. Several loss-of-function Aire mutants, including those causing autoimmune polyendocrine syndrome type-1, form foci with increased PML body association. Directing Aire to PML bodies impairs the transcriptional activity of Aire, while dispersing PML bodies with a viral antagonist restores this activity. Our study thus reveals a new regulatory role of PML bodies in Aire function, and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated protein quality control.


Assuntos
Poliendocrinopatias Autoimunes/imunologia , Linfócitos T/imunologia , Fatores de Transcrição/química , Fatores de Transcrição/genética , Animais , Núcleo Celular/genética , Núcleo Celular/imunologia , Regulação da Expressão Gênica , Humanos , Tolerância Imunológica , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/imunologia , Camundongos , Poliendocrinopatias Autoimunes/genética , Proteína da Leucemia Promielocítica/genética , Proteína da Leucemia Promielocítica/imunologia , Domínios Proteicos , Fatores de Transcrição/imunologia , Transcrição Genética
10.
BMJ Case Rep ; 13(4)2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32332045

RESUMO

An 80-year-old woman presented with a several-year history of progressive hair loss and scalp pruritus. No other rashes or muscle weakness were noted on examination. Scalp biopsy showed interface dermatitis, dense perivascular and periadnexal lymphocytic infiltrate, mucin and scarring alopecia. Laboratory analysis did not show evidence of myositis. The patient was started on hydroxychloroquine for possible cutaneous lupus erythematosus. On follow-up, she presented with a new violaceous rash on the superior eyelids and a well-defined oval patch on the mid-hard palate suspicious for dermatomyositis. Myositis-specific autoantibodies revealed presence of anti-transcriptional intermediary factor-1γ (anti-TIF1γ) in the serum. Anti-TIF1γ autoantibody-positive dermatomyositis is a newly recognised subtype of dermatomyositis that is highly associated with amyopathic disease and has an increased risk of malignancy, making prompt diagnosis crucial. This case highlights the utility of a thorough oral exam in patients suspected to have connective tissue disease as the distinctive ovoid palatal patch is nearly pathognomonic for anti-TIF1γ dermatomyositis.


Assuntos
Autoanticorpos/sangue , Dermatomiosite/diagnóstico , Eritema/patologia , Exantema/patologia , Palato Duro/patologia , Idoso de 80 Anos ou mais , Fármacos Dermatológicos/uso terapêutico , Dermatomiosite/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Humanos , Metotrexato/uso terapêutico , Fatores de Transcrição/imunologia
11.
Cell Prolif ; 53(4): e12791, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32162380

RESUMO

Hepatocellular carcinoma (HCC) is a primary liver malignancy with a high global prevalence and a dismal prognosis. Studies are urgently needed to examine the molecular pathogenesis and biological characteristics of HCC. Chromatin remodelling, an integral component of the DNA damage response, protects against DNA damage-induced genome instability and tumorigenesis by triggering the signalling events that activate the interconnected DNA repair pathways. The SWI/SNF complexes are one of the most extensively investigated adenosine triphosphate-dependent chromatin remodelling complexes, and mutations in genes encoding SWI/SNF subunits are frequently observed in various human cancers, including HCC. The mutated SWI/SNF complex subunits exert dual functions by accelerating or inhibiting HCC initiation and progression. Furthermore, the abnormal SWI/SNF complexes influence the transcription of interferon-stimulated genes, as well as the differentiation, activation and recruitment of several immune cell types. In addition, they exhibit synergistic effects with immune checkpoint inhibitors in the treatment of diverse tumour types. Therefore, understanding the mutations and deficiencies of the SMI/SNF complexes, together with the associated functional mechanisms, may provide a novel strategy to treat HCC through targeting the related genes or modulating the tumour microenvironment.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Carcinogênese/genética , Carcinogênese/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Montagem e Desmontagem da Cromatina , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Humanos , Imunidade , Imunoterapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Proteínas Nucleares/imunologia , Fatores de Transcrição/imunologia
12.
PLoS Pathog ; 16(3): e1008429, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32208449

RESUMO

Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.


Assuntos
Proteínas de Ciclo Celular/imunologia , Dano ao DNA/imunologia , Vírus de DNA/imunologia , Imunidade Inata , Proteínas Nucleares/imunologia , Vírus de RNA/imunologia , Fatores de Transcrição/imunologia , Células A549 , Animais , Chlorocebus aethiops , Infecções por Vírus de DNA/imunologia , Cães , Feminino , Células HEK293 , Células HeLa , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Células RAW 264.7 , Infecções por Vírus de RNA/imunologia , Suínos , Células Vero
13.
J Neuroimmunol ; 341: 577192, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32087460

RESUMO

Stiff person spectrum disorders (SPSD) are a broad group of immune-mediated disorders. Clinical presentations include classical stiff person syndrome (SPS), focal SPS, and progressive encephalomyelitis with rigidity and myoclonus (PERM). The most frequently associated antibodies are anti-GAD65, anti-GlyR, anti-amphiphysin, and anti-DPPX. Immunotherapy is the primary treatment modality. We present an illustrative case series of three patients: anti-GlyR antibody-mediated PERM presenting as rapidly progressive dementia; anti-amphiphysin antibody-mediated SPS; and SPS presentation with anti-Zic4 antibodies, spasmodic laryngeal stridor and fluctuating eyelid ptosis. Clinical characteristics, CSF findings, neurophysiological features, adequate immunological assays and a high suspicion index are essential for prompt diagnosis and management.


Assuntos
Diversidade de Anticorpos , Autoanticorpos/imunologia , Rigidez Muscular Espasmódica/imunologia , Idoso , Idoso de 80 Anos ou mais , Especificidade de Anticorpos , Autoantígenos/imunologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/imunologia , Diarreia/etiologia , Diplopia/etiologia , Evolução Fatal , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imunossupressores/uso terapêutico , Imunoterapia , Masculino , Pessoa de Meia-Idade , Rigidez Muscular/etiologia , Mioclonia/etiologia , Proteínas do Tecido Nervoso/imunologia , Neuroimagem , Fenótipo , Receptores da Glicina/imunologia , Convulsões/etiologia , Rigidez Muscular Espasmódica/complicações , Rigidez Muscular Espasmódica/diagnóstico por imagem , Rigidez Muscular Espasmódica/terapia , Fatores de Transcrição/imunologia , Tremor/etiologia
14.
Clin Exp Rheumatol ; 38(1): 67-73, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31365334

RESUMO

OBJECTIVES: To investigate anti-TIF1-γ antibodies in longitudinally followed patients with myositis and cancer. METHODS: Serum levels of anti-TIF1-γ antibodies at different time-points in relation to myositis and cancer diagnosis were analysed by ELISA in 79 patients from a Swedish cohort with polymyositis (PM) and dermatomyositis (DM) and a Spanish cohort restricted to DM patients. Anti-TIF1-γ positive and negative patients were compared with Fisher's exact test, student t-tests and Wilcoxon test. RESULTS: Thirty-six patients (17 from cohort 1 and 19 from cohort 2) with myositis and cancer were anti-TIF1-γ antibody positive; all had DM. In 88% of anti-TIF1-γ positive patients, cancer was diagnosed within 3 years from DM diagnosis compared to 63% in anti-TIF1-γ negative. Four DM patients, anti-TIF1-γ positive at cancer diagnosis had positive serum samples even antedating cancer diagnosis up to five years. In cohort 1 the median (interquartile range) antibody level was higher, 2.13 au (1.82-2.15), in the seven patients who died <1 year after cancer diagnosis, compared to the seven that died >1 year after cancer diagnosis, 1.34 au (0.92-1.59), (p=0.004). Three patients were still alive and in remission from cancer and DM 14-16 years after cancer treatment of whom two became negative for anti-TIF1-γ antibodies. In the second cohort remission of cancer coincided with remission of DM and low or negative serum levels of autoantibodies. CONCLUSIONS: Anti-TIF1-γ antibodies may be detected before clinical symptoms of cancer and may disappear after successful treatment of cancer with remission of DM supporting DM being a paramalignant phenomenon.


Assuntos
Autoanticorpos , Dermatomiosite , Miosite , Neoplasias , Proteínas Nucleares , Polimiosite , Fatores de Transcrição , Humanos , Estudos Longitudinais , Miosite/complicações , Miosite/imunologia , Miosite/terapia , Neoplasias/complicações , Neoplasias/imunologia , Neoplasias/terapia , Proteínas Nucleares/imunologia , Fatores de Transcrição/imunologia
15.
J Exp Med ; 217(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31570496

RESUMO

CCR6- group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6- ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6- ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Proteínas Proto-Oncogênicas c-maf/imunologia , Animais , Linhagem da Célula/imunologia , Cromatina/imunologia , Regulação da Expressão Gênica/imunologia , Homeostase/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Fatores de Transcrição/imunologia , Transcriptoma/imunologia
16.
J Exp Med ; 217(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31685531

RESUMO

RORγ+ and Helios+ Treg cells in the colon are phenotypically and functionally distinct, but their origins and relationships are poorly understood. In monocolonized and normal mice, single-cell RNA-seq revealed sharing of TCR clonotypes between these Treg cell populations, potentially denoting a common progenitor. In a polyclonal Treg cell replacement system, naive conventional CD4+ (Tconv) cells, but not pre-existing tTregs, could differentiate into RORγ+ pTregs upon interaction with gut microbiota. A smaller proportion of Tconv cells converted into Helios+ pTreg cells, but these dominated when the Tconv cells originated from preweaning mice. T cells from infant mice were predominantly immature, insensitive to RORγ-inducing bacterial cues and to IL6, and showed evidence of higher TCR-transmitted signals, which are also characteristics of recent thymic emigrants (RTEs). Correspondingly, transfer of adult RTEs or Nur77high Tconv cells mainly yielded Helios+ pTreg cells, recapitulating the infant/adult difference. Thus, CD4+ Tconv cells can differentiate into both RORγ+ and Helios+ pTreg cells, providing a physiological adaptation of colonic Treg cells as a function of the age of the cell or of the individual.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Senescência Celular/imunologia , Colo/imunologia , Proteínas de Ligação a DNA/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Linfócitos T Reguladores/imunologia , Fatores de Transcrição/imunologia , Animais , Diferenciação Celular/imunologia , Feminino , Microbioma Gastrointestinal/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Rheumatology (Oxford) ; 59(3): 469-477, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31883334

RESUMO

Anti-transcription intermediary factor 1 (TIF1)-γ autoantibodies are robustly linked with cancer-associated DM in adults. This review aims to give an overview of the physiological context of TIF1-γ and to determine whether there is a pathophysiological link between anti-TIF1-γ autoantibodies and the occurrence of cancer. Detection of anti-TIF1-γ autoantibodies has a high sensitivity and specificity for cancer-associated DM in adults and is therefore useful for both diagnosis and cancer risk stratification. The function of the autoantigen, TIF1-γ, may provide insight into the mechanism behind this association. TIF1-γ is a ubiquitously present protein involved in various biological pathways, including TGF-ß signalling. In cancer, it can act either as a tumour suppressor or promoter, depending on the cellular context and cancer stage. Evolving data provide pathophysiological insights, linking anti-TIF1-γ autoantibodies to both the anti-tumour response and to muscle and skin damage. TIF1-γ expression is increased in muscle and skin tissue of patients with DM. Mutations or loss-of-heterozygosity in TIF1-γ alleles in malignant tissue may result in the expression of tumour-specific neo-antigens stimulating autoantibody production. The newly formed autoantibodies are hypothesized to cross-react with antigens in muscle and skin, driving the development of DM. Based on the current evidence, anti-TIF1-γ autoantibodies should be considered warning lights of a potential tumour autoantigen and should alert the physician to the possibility of an underlying cancer.


Assuntos
Autoanticorpos , Autoantígenos/imunologia , Dermatomiosite/imunologia , Fatores de Transcrição/imunologia , Humanos
18.
Immunopharmacol Immunotoxicol ; 42(1): 28-36, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31876196

RESUMO

Background: Epidemiological studies have shown that environmental factors accelerate the progress of primary Sjögren's syndrome (pSS). Bisphenol A (BPA), a classic endocrine disrupting chemical, affects the immune system. However, the impact of BPA on pSS has not yet been reported. The present study aimed to evaluate the potential relationship between BPA, estrogen receptor (ER), and pSS.Methods: We studied the impact of BPA on monocyte-derived dendritic cells (moDCs) from pSS patients and age-matched healthy controls (HCs). Morphological effects were observed under inverted microscope. Surface markers were analyzed by flow cytometry. ER and cytokine profiles were assessed using real-time polymerase chain reaction. The ability of moDCs to stimulate CD4+ T cells activation was assessed by mixed lymphocyte reaction (MLR).Results: moDCs from both pSS patients and HCs expressed ERα as well as ERß. After BPA-exposure, expression of ERα increased significantly in pSS patients, while that of ERß remained unchanged. moDCs from BPA-exposed pSS patients showed irregular morphology and reduction in cell aggregation. BPA increased HLA-DR on moDCs of pSS patients via ERα, and promoted the secretion of IL6 and IL12. When co-cultured with BPA-treated moDCs, cytokines (IFN-γ, IL4, IL17, IL10) and transcription factors (T-bet, Gata3, RoR-γt, Foxp3) of CD4+ T cells showed imbalance of Th1/Th2/Th17/Treg polarization, with Th1 and Th17 dominating.Conclusions: BPA altered the function of moDCs through ERα, including antigen capture, secretion of inflammatory factors, and ability to stimulate T cells, as well as accelerated the progression and further deterioration of pSS.


Assuntos
Compostos Benzidrílicos/toxicidade , Células Dendríticas/imunologia , Monócitos/imunologia , Fenóis/toxicidade , Síndrome de Sjogren/imunologia , Idoso , Citocinas/imunologia , Células Dendríticas/patologia , Receptor alfa de Estrogênio/imunologia , Receptor beta de Estrogênio/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Síndrome de Sjogren/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Fatores de Transcrição/imunologia
19.
Med Sci (Paris) ; 35 Hors série n° 2: 18-23, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31859626

RESUMO

Dermatomyositis are rare chronic auto-immune diseases characterized by cutaneous involvement. Diagnosis could be made in childhood or in aldult. There are some different clinical and histological presentation associated with different myositis specific antibody. There are five dermatomyositis specific autoantibodies, anti-Mi2, anti-Tif1-γ, anti-NXP2, anti-MDA5, and anti-SAE. Anti-Mi2 are associated with "classical form" of DM with cutaneous and muscular involvement. Anti-Tif1γ and anti-NXP2 are found in juvenile and adult dermatomyositis, and are associated with recurrent diseases with cutaneous involvement at the forefront. In adults, they are associated with cancer. Anti-MDA5 antibodies are associated with a systemic involvement and an interstitial lung disease. Finally, anti-SAE have been found only in adults, with a classic form.


Assuntos
Autoanticorpos/sangue , Autoanticorpos/isolamento & purificação , Dermatomiosite/classificação , Dermatomiosite/diagnóstico , Terminologia como Assunto , Adenosina Trifosfatases/imunologia , Adulto , Idade de Início , Criança , Proteínas de Ligação a DNA/imunologia , Dermatomiosite/sangue , Dermatomiosite/epidemiologia , Humanos , Helicase IFIH1 Induzida por Interferon/imunologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/imunologia , Fatores de Transcrição/imunologia , Enzimas Ativadoras de Ubiquitina/imunologia
20.
PLoS One ; 14(10): e0217728, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31647813

RESUMO

Regulatory T cells (Tregs) are an immunosuppressive population that are identified based on the stable expression of the fate-determining transcription factor forkhead box P3 (Foxp3). Tregs can be divided into distinct subsets based on whether they developed in the thymus (tTregs) or in the periphery (pTregs). Whether there are unique functional roles that distinguish pTregs and tTregs remains largely unclear. To elucidate these functions, efforts have been made to specifically identify and modify individual Treg subsets. Deletion of the conserved non-coding sequence (CNS)1 in the Foxp3 locus leads to selective impairment of pTreg generation without disrupting tTreg generation in the C57BL/6J background. Using CRISPR-Cas9 genome editing technology, we removed the Foxp3 CNS1 region in the non-obese diabetic (NOD) mouse model of spontaneous type 1 diabetes mellitus (T1D) to determine if pTregs contribute to autoimmune regulation. Deletion of CNS1 impaired in vitro induction of Foxp3 in naïve NOD CD4+ T cells, but it did not alter Tregs in most lymphoid and non-lymphoid tissues analyzed except for the large intestine lamina propria, where a small but significant decrease in RORγt+ Tregs and corresponding increase in Helios+ Tregs was observed in NOD CNS1-/- mice. CNS1 deletion also did not alter the development of T1D or glucose tolerance despite increased pancreatic insulitis in pre-diabetic female NOD CNS1-/- mice. Furthermore, the proportions of autoreactive Tregs and conventional T cells (Tconvs) within pancreatic islets were unchanged. These results suggest that pTregs dependent on the Foxp3 CNS1 region are not the dominant regulatory population controlling T1D in the NOD mouse model.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Linfócitos T Reguladores/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
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