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1.
Clin Exp Immunol ; 188(1): 63-78, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27880975

RESUMO

Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immunopathogenesis. However, a pathogenic role for the T helper type 17 (Th17) axis was demonstrated by many studies, while regulatory T cells (Tregs ) were shown to mediate protection. Recently, we and others characterized a novel and independent T cell population expressing both the Treg characteristic transcription factor forkhead box protein 3 (FoxP3) and the Th17-defining retinoic acid receptor-related orphan nuclear receptor γt (RORγt). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORγt+ FoxP3+ Tregs . This bi-functional nature prompted us to suggest the name 'biTregs '. Importantly, the pathogenic biTreg effects were dependent upon expression of RORγt. We thus aimed to evaluate the contribution of RORγt+ FoxP3+ biTregs to pristane-induced SLE and explored the therapeutic potential of interference with RORγt activation. Our analyses revealed expansion of IL-17 producing biTregs in a distinctive time-course and organ-specific pattern, coincident with the development of autoimmunity and tissue injury. Importantly, specific ablation of RORγt activation in endogenous biTregs resulted in significant amelioration of pristane-induced pulmonary vasculitis and lupus nephritis. As potential mechanisms underlying the observed protection, we found that secretion of IL-17 by biTregs was abrogated completely in FoxP3Cre  × RORCfl/fl mice. Furthermore, Tregs showed a more activated phenotype after cell-specific inactivation of RORγt signalling. Finally, and remarkably, biTregs were found to potently suppress anti-inflammatory Th2 immunity in a RORγt-dependent manner. Our study thus identifies biTregs as novel players in SLE and advocates RORγt-directed interventions as promising therapeutic strategies.


Assuntos
Expressão Gênica , Interleucina-17/metabolismo , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Imunidade Humoral , Imunomodulação , Imunofenotipagem , Pulmão/metabolismo , Pulmão/patologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/etiologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fenótipo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
2.
J Neonatal Perinatal Med ; 7(3): 165-72, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25322993

RESUMO

AIM: To audit clinical practice during transport of very preterm infants (<32 weeks) with acute respiratory distress syndrome (RDS) receiving nasal continuous positive airway pressure (NCPAP). METHODS: Retrospective cohort study. RESULTS: Twenty-seven infants were receiving NCPAP before transport team's arrival, and 23 were commenced on NCPAP after team's arrival. Six infants (12%) failed NCPAP before transfer, 2 infants (4.5%) failed NCPAP less than 24 hours, and 5 infants (11.3%) failed more than 24 hours - 7 days following admission. None died or developed pneumothorax during, or 7 days after admission. We did not observe NCPAP failure during transfer. There was a statistically significant difference between the NCPAP success and NCPAP failure groups for FiO2 at admission (p < 0.05), and the duration of NCPAP (p < 0.05). CONCLUSION: NCPAP is a potentially safe and effective mode of respiratory support for very preterm infants during ground, and air transports.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Transporte de Pacientes/métodos , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Auditoria Médica , Estudos Retrospectivos , Resultado do Tratamento
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