A role for the C3a anaphylatoxin receptor in the effector phase of asthma.
Asthma is a chronic inflammatory disease of the airways and lung mucosa with a strong correlation to atopy and acquired (IgE) immunity. However, many features of bronchial asthma, such as smooth muscle contraction, mucus secretion and recruitment of inflammatory cells, are consistent with the actions of complement anaphylatoxins, in particular C3a and C5a. Complement activation forms a central core of innate immune defence against mucosal bacteria, viruses, fungi, helminths and other pathogens. As a system of 'pattern-recognition molecules', foreign surface antigens and immune complexes lead to a proteolytic cascade culminating in a lytic membrane attack. The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability. Here we show that in a murine model of allergic airway disease, genetic deletion of the C3a receptor protects against the changes in lung physiology seen after allergen challenge. Furthermore, human asthmatics develop significant levels of ligand C3a following intra-pulmonary deposition of allergen, but not saline. We propose that, in addition to acquired immune responses, the innate immune system and complement (C3a in particular) are involved in the pathogenesis of asthma.
Humbles
A A
AA
Ina Sue Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Lu
B
B
Nilsson
C A
CA
Lilly
C
C
Israel
E
E
Fujiwara
Y
Y
Gerard
N P
NP
Gerard
C
C
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015926:Complement C3a / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006969:Hypersensitivity, Immediate; D008168:Lung / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D016210:Methacholine Chloride / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010991:Plethysmography; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D015703:Antigens, CD; D008565:Membrane Proteins; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor; D016210:Methacholine Chloride; D015926:Complement C3a