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Originally published online as doi:10.1189/jlb.1108710 on May 11, 2009

Published online before print May 11, 2009
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(Journal of Leukocyte Biology. 2009;85:1036-1043.)
© 2009 by Society for Leukocyte Biology

Immune dysregulation in severe influenza

Meredith L. Heltzer*,1, Susan E. Coffin{dagger}, Kelly Maurer*, Asen Bagashev*, Zhe Zhang{ddagger}, Jordan S. Orange* and Kathleen E. Sullivan*,2

Divisions of
* Allergy and Immunology and
{dagger} Infectious Diseases and
{ddagger} Center for Biomedical Informatics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

2 Correspondence: Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA. E-mail: sullivak{at}mail.med.upenn.edu

ABSTRACT

Among previously healthy children with severe influenza, the mechanisms leading to increased pathology are not understood. We hypothesized that children with severe influenza would have high levels of circulating cytokines. To examine this, we recruited patients with severe influenza and examined plasma cytokine levels as well as the ability of peripheral blood cells to respond to stimuli. Ten patients with severe influenza were enrolled during the 2005–2007 influenza seasons. We evaluated plasma cytokine levels, circulating NK cells, and responses to TLR ligands during the illness. We compared these patients with five patients with moderate influenza, six patients with respiratory syncytial virus (RSV), and 24 noninfected controls. Patients with influenza showed depressed responses to TLR ligands when compared with RSV patients and healthy controls (P<0.05). These normalized when retested during a convalescent phase. Plasma levels of IL-6, IL-12, and IFN-{gamma} were elevated in influenza patients compared with controls (P<0.05). A compromised ability to produce TNF-{alpha} was reproduced by in vitro infection, and the magnitude of the effect correlated with the multiplicity of infection and induction of IFN regulatory factor 4 expression. Aberrant, systemic, innate responses to TLR ligands during influenza infection may be a consequence of specific viral attributes such as a high inoculum or rapid replication and may underlie the known susceptibility of influenza-infected patients to secondary bacterial infections.

Key Words: TLR • IRF4 • IFN • NK cells • IL-6 • NKp46




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