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The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell-mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.
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Linfocitos T CD4-Positivos/inmunología , Regulación de la Expresión Génica/inmunología , Redes Reguladoras de Genes/inmunología , Interleucina-2/biosíntesis , Proteínas Proto-Oncogénicas c-maf/inmunología , Animales , Interleucina-2/inmunología , RatonesRESUMEN
There is no unified place where genomics researchers can search through all available raw genomic data in a way similar to OMIM for genes or Uniprot for proteins. With the recent increase in the amount of genomic data that is being produced and the ever-growing promises of precision medicine, this is becoming more and more of a problem. DNAdigest is a charity working to promote efficient sharing of human genomic data to improve the outcome of genomic research and diagnostics for the benefit of patients. Repositive, a social enterprise spin-out of DNAdigest, is building an online platform that indexes genomic data stored in repositories and thus enables researchers to search for and access a range of human genomic data sources through a single, easy-to-use interface, free of charge.
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Bases de Datos Genéticas , Genómica , Difusión de la InformaciónRESUMEN
Amyloid A amyloidosis is a protein misfolding disease characterized by deposition of extracellular aggregates derived from the acute-phase reactant serum amyloid A protein. If untreated, amyloid A amyloidosis leads to irreversible damage of various organs, including the kidneys, liver, and heart. Amyloid A deposits regress upon reduction of serum amyloid A concentration, indicating that the amyloid can be efficiently cleared by natural mechanisms. Clearance was proposed to be mediated by humoral immune responses to amyloid. Here, we report that amyloid clearance in mice lacking complement factors 3 and 4 (C3C4(-/-)) was equally efficient as in wild-type mice (C57BL/6), and was only slightly delayed in agammaglobulinemic mice (J(H-/-)). Hence, antibodies or complement factors are not necessary for natural amyloid clearance, implying the existence of alternative physiological pathways for amyloid removal.