Type 1 IFN Induction by Cytosolic Nucleic Acid Is Intact in Neonatal Mononuclear Cells, Contrasting Starkly with Neonatal Hyporesponsiveness to TLR Ligation Due to Independence from Endosome-Mediated IRF3 Activation.

Autor:	Brennan K; National Children's Research Centre, Crumlin, Dublin 12, Ireland.; School of Medicine, Trinity College Dublin, Dublin 2, Ireland., O'Leary BD; National Maternity Hospital, Dublin 2, Ireland., Mc Laughlin D; Department of Paediatric Surgery, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland., Breen EP; School of Medicine, Trinity College Dublin, Dublin 2, Ireland., Connolly E; National Children's Research Centre, Crumlin, Dublin 12, Ireland.; School of Medicine, Trinity College Dublin, Dublin 2, Ireland., Ali N; National Maternity Hospital, Dublin 2, Ireland., O'Driscoll DN; National Maternity Hospital, Dublin 2, Ireland., Ozaki E; National Children's Research Centre, Crumlin, Dublin 12, Ireland.; School of Medicine, Trinity College Dublin, Dublin 2, Ireland., Mahony R; National Children's Research Centre, Crumlin, Dublin 12, Ireland.; School of Medicine, Trinity College Dublin, Dublin 2, Ireland., Mulfaul K; National Children's Research Centre, Crumlin, Dublin 12, Ireland.; School of Medicine, Trinity College Dublin, Dublin 2, Ireland., Ryan AM; National Children's Research Centre, Crumlin, Dublin 12, Ireland., Ni Chianain A; National Maternity Hospital, Dublin 2, Ireland., McHugh A; National Maternity Hospital, Dublin 2, Ireland., Molloy EJ; National Children's Research Centre, Crumlin, Dublin 12, Ireland.; School of Medicine, Trinity College Dublin, Dublin 2, Ireland.; Women and Infants University Hospital, Dublin 8, Ireland., Hogan AE; National Children's Research Centre, Crumlin, Dublin 12, Ireland.; Education and Research Centre and Conway Institute, St. Vincent's University Hospital, University College Dublin, Dublin 4, Ireland; and., Paran S; Department of Paediatric Surgery, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland., McAuliffe FM; National Maternity Hospital, Dublin 2, Ireland.; Obstetrics and Gynaecology, School of Medicine, University College Dublin, National Maternity Hospital, Dublin 2, Ireland., Doyle SL; National Children's Research Centre, Crumlin, Dublin 12, Ireland; sarah.doyle@tcd.ie.; School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2018 Aug 15; Vol. 201 (4), pp. 1131-1143. Date of Electronic Publication: 2018 Jul 06.
DOI:	10.4049/jimmunol.1700956
Abstrakt:	Two million infants die each year from infectious diseases before they reach 12 mo; many of these diseases are vaccine preventable in older populations. Pattern recognition receptors represent the critical front-line defense against pathogens. Evidence suggests that the innate immune system does not fully develop until puberty, contributing to impaired response to infection and impaired vaccine responses in neonates, infants, and children. The activity of the pattern recognition receptor family of cytosolic nucleic acid (CNA) sensors in this pediatric population has not been reported. We show that in direct contrast to weak TLR-induced type I IFN in human cord blood mononuclear cells, cord blood mononuclear cells are capable of initiating a potent response to CNA, inducing both antiviral type I IFN and, unexpectedly, proinflammatory TNF-α. A deficiency in Rab11-GTPase endosome formation and consequent lack of IRF3 activation in neonatal monocytes is at least in part responsible for the marked disparity in TLR-induced IFN production between neonatal and adult monocytes. CNA receptors do not rely on endosome formation, and therefore, these responses remain intact in neonates. Heightened neonatal responses to CNA challenge are maintained in children up to 2 y of age and, in marked contrast to TLR4/9 agonists, result in IL-12p70 and IFN-γ generation. CNA sensors induce robust antiviral and proinflammatory pathways in neonates and children and possess great potential for use as immunostimulants or vaccine adjuvants for targeted neonatal and pediatric populations to promote cell-mediated immunity against invasive infectious disease. (Copyright © 2018 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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