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Allergic Airways Disease Develops after an Increase in Allergen Capture and Processing in the Airway Mucosa¹

Christophe von Garnier^2,3,*, Matthew E. Wikstrom^2,*, Graeme Zosky^*, Debra J. Turner^*, Peter D. Sly^*, Miranda Smith^*, Jennifer A. Thomas^*, Samantha R. Judd^*, Deborah H. Strickland^*, Patrick G. Holt^* and Philip A. Stumbles^3,*,

^* Telethon Institute for Child Health Research and Centre for Child Health Research, School of Pediatrics and Child Health, University of Western Australia, West Perth, Western Australia, Australia; and School of Veterinary and Biomedical Sciences, Division of Health Sciences, Murdoch University, Perth, Western Australia, Australia

Airway mucosal dendritic cells (AMDC) and other airway APCs continuously sample inhaled Ags and regulate the nature of any resulting T cell-mediated immune response. Although immunity develops to harmful pathogens, tolerance arises to nonpathogenic Ags in healthy individuals. This homeostasis is thought to be disrupted in allergic respiratory disorders such as allergic asthma, such that a potentially damaging Th2-biased, CD4⁺ T cell-mediated inflammatory response develops against intrinsically nonpathogenic allergens. Using a mouse model of experimental allergic airways disease (EAAD), we have investigated the functional changes occurring in AMDC and other airway APC populations during disease onset. Onset of EAAD was characterized by early and transient activation of airway CD4⁺ T cells coinciding with up-regulation of CD40 expression exclusively on CD11b^– AMDC. Concurrent enhanced allergen uptake and processing occurred within all airway APC populations, including B cells, macrophages, and both CD11b⁺ and CD11b^– AMDC subsets. Immune serum transfer into naive animals recapitulated the enhanced allergen uptake observed in airway APC populations and mediated activation of naive allergen-specific, airway CD4⁺ T cells following inhaled allergen challenge. These data suggest that the onset of EAAD is initiated by enhanced allergen capture and processing by a number of airway APC populations and that allergen-specific Igs play a role in the conversion of normally quiescent AMDC subsets into those capable of inducing airway CD4⁺ T cell activation.

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 work was supported by National Health and Medical Research Council of Australia. C.v.G. was funded by the Swiss National Fund, Janggen-Poehn-Stiftung, Herrmann-Stiftung, Novartis-Stiftung, and Boehringer Ingelheim.

² C.v.G. and M.E.W. have contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Christophe von Garnier at the current address: Respiratory Medicine, Berne University Hospital, 3010 Berne, Switzerland; E-mail address: christophe.vongarnier{at}insel.ch or Dr. Philip A. Stumbles, Division of Cell Biology, Telethon Institute for Child Health Research, P.O. Box 855, West Perth, Western Australia 6872, Australia; E-mail address: phils{at}ichr.uwa.edu.au

⁴ Abbreviations used in this paper: RT, respiratory tract; DC, dendritic cell; AHR, airway hyperresponsiveness; DLN, draining lymph node; EEAD, experimental allergic airways disease; BLG, -lactoglobulin A; p.n., per nasal; MCh, methacholine; BAL, bronchoalveolar lavage; Alum, AlOH₃; MHC II, MHC class II.