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* Division of Respiratory Diseases and Allergy, Center for Gene Therapeutics and Department of Pathology and Molecular Medicine and
Department of Medicine, McMaster University, Hamilton, Ontario, Canada; and
Department of Inflammation and Autoimmunity, MedImmune, Inc., Gaithersburg, MD 20878
The impact of respiratory viral infections on the emergence of the asthmatic phenotype is a subject of intense investigation. Most experimental studies addressing this issue have used the inert Ag OVA with controversial results. We examined the consequences of exposure to a low dose of the common aeroallergen house dust mite (HDM) during the course of an influenza A infection. First, we delineated the kinetics of the immune-inflammatory response in the lung of mice following intranasal infection with influenza A/PR8/34. Our data demonstrate a peak response during the first 10 days, with considerable albeit not complete resolution at day 39 postinfection (p.i.). At day 7 p.i., mice were exposed, intranasally, to HDM for 10 consecutive days. We observed significantly enhanced eosinophilic inflammation, an expansion in Th2 cells, enhanced HDM-specific IgE and IgG1 responses and increased mucous production. Furthermore, lung mononuclear cells produced enhanced IFN-
and IL-5, unchanged IL-13, and reduced IL-4. These immunologic and structural changes lead to marked lung dysfunction. This allergic phenotype occurs at a time when there is a preferential increase in plasmacytoid dendritic cells over myeloid dendritic cells, activated CD8+ T cells, and increased IFN- production, all of which have been proposed to inhibit allergic responses. In contrast, the inflammatory response elicited by HDM was reduced when exposure occurred during the resolution phase (day 40 p.i.). Interestingly, this was not associated with a reduction in sensitization. Thus, the proinflammatory environment established during an acute influenza A infection enhances Th2-polarized immunity to a low dose of HDM and precipitates marked lung dysfunction.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was partially funded by the Canadian Institute of Health Research and MedImmune, Inc. R.F. is supported by an Ontario Graduate Scholarship in Science and Technology. M.J. is a Senior Canada Research Chair.
2 Address correspondence and reprint requests to Dr. Manel Jordana, Department of Pathology and Molecular Medicine, Division of Respiratory Diseases and Allergy, McMaster University, MDCL Room 4013, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. E-mail address: jordanam{at}mcmaster.ca
3 Abbreviations used in this paper: HDM, house dust mite; BAL, bronchoalveolar lavage; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; RSV, respiratory syncytial virus; p.i., postinfection; PAS, periodic acid-Schiff; MCh, methacholine; Rn, airway resistance; G, tissue resistance; HTE, tissue elastance; MHCII, MHC class II; KLH, keyhole limpet hemocyanin; NES, Nippostrongylus brasiliensis.
4 The online version of this article contains supplemental material.
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