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1.
Eur J Immunol ; 48(4): 720-723, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29293266

RESUMO

The Mediator complex is known to orchestrate transcription. Here we show that B cell conditional deficient mice for the Med1 subunit display robust somatic hypermutation. Nevertheless, the mutation frequency at A residues is decreased and the expected A/T ratio is abolished, implicating Mediator in the second phase of somatic hypermutation.


Assuntos
Linfócitos B/citologia , Subunidade 1 do Complexo Mediador/deficiência , Subunidade 1 do Complexo Mediador/genética , Hipermutação Somática de Imunoglobulina/genética , Animais , Linfócitos B/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Camundongos , Camundongos Transgênicos
2.
Front Immunol ; 12: 790455, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35058929

RESUMO

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.


Assuntos
Anormalidades Múltiplas , Síndrome Linfoproliferativa Autoimune , Face/anormalidades , Doenças Hematológicas , Doenças da Imunodeficiência Primária , Doenças Vestibulares , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Doenças Hematológicas/imunologia , Humanos , Lactente , Masculino , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Estudos Prospectivos , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/genética , Doenças Vestibulares/imunologia
3.
Front Immunol ; 11: 620046, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33519826

RESUMO

STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.


Assuntos
Agamaglobulinemia/genética , Anemia Hemolítica Autoimune/genética , Mutação com Ganho de Função , Transtornos Linfoproliferativos/genética , Fator de Transcrição STAT3/genética , Espectrina/deficiência , Agamaglobulinemia/imunologia , Idade de Início , Anemia Hemolítica Autoimune/imunologia , Criança , Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Ciclosporina/uso terapêutico , Citocromo P-450 CYP3A/genética , Feminino , Mutação em Linhagem Germinativa , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transtornos do Crescimento/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/imunologia , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Prednisolona/uso terapêutico , Hemorragia Retiniana/induzido quimicamente , Fator de Transcrição STAT3/fisiologia , Espectrina/genética , Doadores não Relacionados
4.
J Exp Med ; 213(3): 303-12, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26903242

RESUMO

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to Ig switch regions (S regions). During CSR, the IgH locus undergoes dynamic three-dimensional structural changes in which promoters, enhancers, and S regions are brought to close proximity. Nevertheless, little is known about the underlying mechanisms. In this study, we show that Med1 and Med12, two subunits of the mediator complex implicated in transcription initiation and long-range enhancer/promoter loop formation, are dynamically recruited to the IgH locus enhancers and the acceptor regions during CSR and that their knockdown in CH12 cells results in impaired CSR. Furthermore, we show that conditional inactivation of Med1 in B cells results in defective CSR and reduced acceptor S region transcription. Finally, we show that in B cells undergoing CSR, the dynamic long-range contacts between the IgH enhancers and the acceptor regions correlate with Med1 and Med12 binding and that they happen at a reduced frequency in Med1-deficient B cells. Our results implicate the mediator complex in the mechanism of CSR and are consistent with a model in which mediator facilitates the long-range contacts between S regions and the IgH locus enhancers during CSR and their transcriptional activation.


Assuntos
Switching de Imunoglobulina/genética , Cadeias Pesadas de Imunoglobulinas/genética , Subunidade 1 do Complexo Mediador/metabolismo , Complexo Mediador/metabolismo , Recombinação Genética/genética , Ativação Transcricional/genética , Animais , Linfócitos B/metabolismo , Células Cultivadas , Técnicas de Silenciamento de Genes , Loci Gênicos , Camundongos , Ligação Proteica , Transcrição Gênica
5.
J Exp Med ; 210(12): 2495-502, 2013 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-24145512

RESUMO

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to switch regions and by the subsequent generation of double-stranded DNA breaks (DSBs). These DNA breaks are ultimately resolved through the nonhomologous end joining (NHEJ) pathway. We show that during CSR, AID associates with subunits of cohesin, a complex previously implicated in sister chromatid cohesion, DNA repair, and the formation of DNA loops between enhancers and promoters. Furthermore, we implicate the cohesin complex in the mechanism of CSR by showing that cohesin is dynamically recruited to the Sµ-Cµ region of the IgH locus during CSR and that knockdown of cohesin or its regulatory subunits results in impaired CSR and increased usage of microhomology-based end joining.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Switching de Imunoglobulina , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Proteínas Cromossômicas não Histona/genética , Citidina Desaminase/metabolismo , Reparo do DNA por Junção de Extremidades , Técnicas de Silenciamento de Genes , Camundongos , Recombinação Genética , Coesinas
6.
J Exp Med ; 209(11): 2099-111, 2012 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-23008333

RESUMO

Antibody diversification requires the DNA deaminase AID to induce DNA instability at immunoglobulin (Ig) loci upon B cell stimulation. For efficient cytosine deamination, AID requires single-stranded DNA and needs to gain access to Ig loci, with RNA pol II transcription possibly providing both aspects. To understand these mechanisms, we isolated and characterized endogenous AID-containing protein complexes from the chromatin of diversifying B cells. The majority of proteins associated with AID belonged to RNA polymerase II elongation and chromatin modification complexes. Besides the two core polymerase subunits, members of the PAF complex, SUPT5H, SUPT6H, and FACT complex associated with AID. We show that AID associates with RNA polymerase-associated factor 1 (PAF1) through its N-terminal domain, that depletion of PAF complex members inhibits AID-induced immune diversification, and that the PAF complex can serve as a binding platform for AID on chromatin. A model is emerging of how RNA polymerase II elongation and pausing induce and resolve AID lesions.


Assuntos
Diversidade de Anticorpos , Linfócitos B/metabolismo , Citidina Desaminase/metabolismo , Proteínas Nucleares/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Citidina Desaminase/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Células HeLa , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Switching de Imunoglobulina , Imunoglobulinas/genética , Imunoprecipitação , Proteínas Nucleares/genética , Ligação Proteica , Interferência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/metabolismo
7.
J Leukoc Biol ; 87(3): 433-42, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19892847

RESUMO

Besides lowering circulating cholesterol, statins act as immunomodulators. Although the effects of statins on lymphocyte activation and differentiation have been clearly defined, there is no consensus as to effects of these drugs on phagocytes. We have addressed the outcome of simvastatin treatment on the activation and effector function of human macrophages in the pathophysiologically relevant context of challenge with an opportunistic pathogen. We provide evidence that: simvastatin blocks the biological effects rapidly triggered by IgG-opsonized bacteria (phagocytosis and oxidative burst) while enhancing the delayed effects elicited by FcgammaR stimulation (production of proinflammatory mediators); these opposite effects of simvastatin result from enhancement of the JNK pathway and concomitant impairment of other signaling modules activated by FcgammaR engagement; and these activities are dependent on the capacity of simvastatin to block protein prenylation. The results provide novel mechanistic insight into the activities of statins on phagocytes and are of relevance to the assessment of potential side-effects in patients undergoing long-term hypocholesterolemic therapy.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Viabilidade Microbiana/efeitos dos fármacos , Proteínas Opsonizantes/imunologia , Sinvastatina/farmacologia , Staphylococcus aureus/imunologia , Actinas/metabolismo , Animais , Linhagem Celular , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Humanos , Inflamação/microbiologia , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Camundongos , Fagocitose/efeitos dos fármacos , Prenilação de Proteína/efeitos dos fármacos , Receptores de IgG/metabolismo , Explosão Respiratória/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Staphylococcus aureus/citologia , Staphylococcus aureus/efeitos dos fármacos , Proteínas ras/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo
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