C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression.
Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses.
Melendi
Guillermina A
GA
INFANT Fundacion, Buenos Aires, Argentina.
Hoffman
Scott J
SJ
Karron
Ruth A
RA
Irusta
Pablo M
PM
Laham
Federico R
FR
Humbles
Alison
A
Schofield
Brian
B
Pan
Chien-Hsiung
CH
Rabold
Richard
R
Thumar
Bhagvanji
B
Thumar
Adeep
A
Gerard
Norma P
NP
Mitzner
Wayne
W
Barnum
Scott R
SR
Gerard
Craig
C
Kleeberger
Steven R
SR
Polack
Fernando P
FP
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D015926:Complement C3a / Q000378:metabolism; D003182:Complement C5 / Q000172:deficiency / Q000378:metabolism*; D015536:Down-Regulation; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D011024:Pneumonia, Viral / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D011657:Pulmonary Eosinophilia / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D011951:Receptors, Complement / Q000172:deficiency / Q000378:metabolism*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000472:pathogenicity*; D012720:Severity of Illness Index
D003182:Complement C5; D008565:Membrane Proteins; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a