title: Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation.
abstract: Exposure to inhaled allergens leads to increases in airway hyperresponsiveness (AHR) and inflammation, associated with increased levels of biologically active fragments derived from the complement C3 and C5 family of proteins. Further, complement activation during allergen challenge in sensitized animals is necessary for the development of AHR and airway inflammation. To define the complement pathway involved, we studied mice deficient in complement factor 4 (C4-/-), a critical component of the classical pathway, or factor B (fB-/-), an essential protein in the alternative complement pathway. WT, C4-/-, and fB-/- mice were sensitized to ovalbumin and subsequently exposed to nebulized ovalbumin (1% in saline) on 3 consecutive days. After allergen sensitization and challenge, fB-/- mice demonstrated significantly lower airway responsiveness to methacholine and less airway inflammation. In contrast, C4-/- mice showed no reduction in AHR and airway inflammation compared with WT mice. Tissue inflammation, goblet cell hyperplasia, and IL-4, IL-5, and IL-13 levels in BAL fluid were significantly reduced in fB-/- mice compared with C4-/- and WT mice. The development of AHR and airway inflammation in sensitized fB-/- mice could be restored after intranasal administration of purified factor B before the airway challenge. In addition, administration of a neutralizing anti-factor B mAb to sensitized mice before airway challenge reduced the development of AHR and airway inflammation. These results demonstrate that in sensitized hosts complement activation through the alternative pathway after allergen exposure is critical to the development of AHR and airway inflammation.
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.forename: Anthony
authors.initials: A
authors.lastname: Joetham
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Miyahara
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.forename: Azzeddine
authors.initials: A
authors.lastname: Dakhama
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Giclas
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D003167:Complement Activation; D003181:Complement C4 / Q000737:chemistry*; D003170:Complement Pathway, Alternative; D003165:Complement System Proteins; D007113:Immunity, Innate; D007249:Inflammation / Q000473:pathology*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D012130:Respiratory Hypersensitivity / Q000473:pathology*
chemical_list: D003181:Complement C4; D016210:Methacholine Chloride; D003165:Complement System Proteins