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 language | English |
|---|---|
| Pages (from-to) | 8084-8089 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 103 |
| Issue number | 21 |
| DOIs | |
| Publication status | Published - May 23 2006 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation
AU - Taube, Christian
AU - Thurman, Joshua M.
AU - Takeda, Katsuyuki
AU - Joetham, Anthony
AU - Miyahara, Nobuaki
AU - Carroll, Michael C.
AU - Dakhama, Azzeddine
AU - Giclas, Patricia C.
AU - Holers, V. Michael
AU - Gelfand, Erwin W.
PY - 2006/5/23
Y1 - 2006/5/23
N2 - 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.
AB - 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.
KW - Allergy
KW - Asthma
KW - Innate immunity
KW - Lung
UR - http://www.scopus.com/inward/record.url?scp=33744479974&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33744479974&partnerID=8YFLogxK
U2 - 10.1073/pnas.0602357103
DO - 10.1073/pnas.0602357103
M3 - Article
C2 - 16702544
AN - SCOPUS:33744479974
VL - 103
SP - 8084
EP - 8089
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 21
ER -