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1.
Nat Immunol ; 24(6): 1036-1048, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37106040

RESUMO

Allergic diseases are a major global health issue. Interleukin (IL)-9-producing helper T (TH9) cells promote allergic inflammation, yet TH9 cell effector functions are incompletely understood because their lineage instability makes them challenging to study. Here we found that resting TH9 cells produced IL-9 independently of T cell receptor (TCR) restimulation, due to STAT5- and STAT6-dependent bystander activation. This mechanism was seen in circulating cells from allergic patients and was restricted to recently activated cells. STAT5-dependent Il9/IL9 regulatory elements underwent remodeling over time, inactivating the locus. A broader 'allergic TH9' transcriptomic and epigenomic program was also unstable. In vivo, TH9 cells induced airway inflammation via TCR-independent, STAT-dependent mechanisms. In allergic patients, TH9 cell expansion was associated with responsiveness to JAK inhibitors. These findings suggest that TH9 cell instability is a negative checkpoint on bystander activation that breaks down in allergy and that JAK inhibitors should be considered for allergic patients with TH9 cell expansion.


Assuntos
Hipersensibilidade , Inibidores de Janus Quinases , Humanos , Interleucina-9/genética , Linfócitos T Auxiliares-Indutores , Fator de Transcrição STAT5/genética , Cromatina/genética , Inflamação , Hipersensibilidade/genética , Diferenciação Celular , Fator de Transcrição STAT6
3.
PLoS One ; 11(1): e0146955, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26785352

RESUMO

Peripheral B lymphocyte survival requires the B cell receptor (BCR) and B cell activating factor (BAFF) binding to its receptor (BAFF-R). Deletion of the BCR, or its signal transducing chaperone Igß, leads to rapid loss of mature B cells, indicating that signals initiated at the BCR are crucial for B cell survival. BAFF or BAFF-R deficiency also significantly reduces the numbers of mature B cells despite normal BCR expression. Together, these observations indicate that continued BCR and BAFF-R signaling are essential for the survival of mature resting B cells in the periphery. Here we demonstrate that tonic BCR signals up-regulate p100 (Nfkb2) as well as Mcl-1 protein expression at a post-transcriptional level via a PI3K-dependent pathway. p100 expression is mTOR-independent, whereas Mcl-1 expression is mTOR-dependent. BAFF treatment further elevated Mcl-1 levels by an mTOR-independent pathway, while consuming p100. Accordingly, Mcl-1 induction by BAFF is abrogated in Nfkb2-/- B cells. We propose that the cumulative effects of the BCR and BAFF-R signaling pathways increase Mcl-1 levels beyond the threshold required for B cell survival.


Assuntos
Linfócitos B/citologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Subunidade p52 de NF-kappa B/genética , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Fator Ativador de Células B/farmacologia , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Sobrevivência Celular , Células Cultivadas , Camundongos , Proteínas Proto-Oncogênicas c-bcr/metabolismo , Transdução de Sinais
4.
Forensic Sci Int ; 133(3): 254-5, 2003 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-12787661

RESUMO

Allele frequencies for 11 short tandem repeats (STRs) loci (CSF1PO, TPOX, TH01, F13A01, FESFPS, vWA, D16S539, D7S820, D13S317, F13B and LPL) were obtained from a sample of 225 unrelated individuals born in the Entre Ríos state of Argentina.


Assuntos
Frequência do Gene , Genética Populacional , Sequências de Repetição em Tandem , Argentina , Impressões Digitais de DNA/métodos , Humanos , Reação em Cadeia da Polimerase
5.
J Interferon Cytokine Res ; 34(1): 28-34, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24171456

RESUMO

Enhanced endogenous interferon (IFN) stimulated gene (ISG) signature has been associated with nonresponsiveness to hepatitis C treatment using pegylated-IFNα (pegIFNα) and ribavirin (RBV) in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected patients. Using a proteomic approach, we identified high levels of IFNα receptor 2a (IFNαR2a) in the serum of null responders to pegIFNα/RBV. IFNαR2a inhibited antiviral activity of all formulations of IFNα in JFH/Huh7.5 cells. Furthermore, serum from null responders, but not from those who achieved sustained virologic response, suppressed IFN-signaling and ISG expression in IFNα-stimulated PBMCs of healthy donors in an IFNαR2a specific fashion. An IFNαR2a transgenic mice model (C57BL/6) was generated that had significantly higher levels of IFNαR2a in the serum than the controls (P=0.001). Total ISG expression in the lymph nodes was significantly higher compared to wild-type mice (P value=0.0016). In addition, IFITM1 and SP110 had significantly increased expression in the liver, IFITM1 and ISG15 in the lymph node, and ISG15 and PLSCR1 in the spleen (P value<0.05). The underlying mechanism of resistance to hepatitis C treatment may involve transsignaling of the JAK/STAT pathway by the sIFNαR2a-IFNα/ß complex and result in the enhanced ISG signature observed in null responders. In this regard, the transgenic mice model simulated nonresponders to IFNα therapy and provides valuable insights into the role of sIFNαR2a-IFNα interactions in vivo.


Assuntos
Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Interferon-alfa/uso terapêutico , Receptor de Interferon alfa e beta/imunologia , Ribavirina/uso terapêutico , Animais , Coinfecção , HIV/imunologia , Infecções por HIV/virologia , Hepacivirus/imunologia , Hepatite C/virologia , Humanos , Interferon-alfa/imunologia , Interferon-alfa/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Interferon alfa e beta/sangue , Ribavirina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
6.
[Montevideo]; Presidencia de la República. Junta Nacional de Drogas; [2024?]. 30 p.
Monografia em Espanhol | LILACS, UY-BNMED, BNUY | ID: biblio-1566691
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