Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation

Christian Taube, Joshua M. Thurman, Katsuyuki Takeda, Anthony Joetham, Nobuaki Miyahara, Michael C. Carroll, Azzeddine Dakhama, Patricia C. Giclas, V. Michael Holers, Erwin W. Gelfand

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8084-8089
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number21
DOIs
Publication statusPublished - May 23 2006
Externally publishedYes

Fingerprint

Complement Factor B
Inflammation
Complement C4
Allergens
Alternative Complement Pathway
Ovalbumin
Complement C5
Dimercaprol
Intranasal Administration
Complement C3
Goblet Cells
Interleukin-13
Methacholine Chloride
Complement Activation
Interleukin-5
Interleukin-4
Hyperplasia
Proteins

Keywords

  • Allergy
  • Asthma
  • Innate immunity
  • Lung

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation. / Taube, Christian; Thurman, Joshua M.; Takeda, Katsuyuki; Joetham, Anthony; Miyahara, Nobuaki; Carroll, Michael C.; Dakhama, Azzeddine; Giclas, Patricia C.; Holers, V. Michael; Gelfand, Erwin W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 21, 23.05.2006, p. 8084-8089.

Research output: Contribution to journalArticle

Taube, Christian ; Thurman, Joshua M. ; Takeda, Katsuyuki ; Joetham, Anthony ; Miyahara, Nobuaki ; Carroll, Michael C. ; Dakhama, Azzeddine ; Giclas, Patricia C. ; Holers, V. Michael ; Gelfand, Erwin W. / Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 21. pp. 8084-8089.
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