title: Airway fibrinogenolysis and the initiation of allergic inflammation.
abstract: The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E-mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B- and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention.
authors.affiliation: 1 Translational Biology and Molecular Medicine Program.
authors.forename: Valentine Ongeri
authors.initials: VO
authors.lastname: Millien
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.forename: Garbo
authors.initials: G
authors.lastname: Mak
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Yuan
authors.forename: J Morgan
authors.initials: JM
authors.lastname: Knight
authors.forename: Paul
authors.initials: P
authors.lastname: Porter
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
mesh_terms: D000485:Allergens / Q000276:immunology*; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D007111:Immunity, Cellular; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D012137:Respiratory System / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D016207:Cytokines; D005340:Fibrinogen
keywords: Th2 cells; asthma; fibrinogen; proteolysis; sinusitis