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A role for the C3a anaphylatoxin receptor in the effector phase of asthma

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Abstract

Asthma is a chronic inflammatory disease of the airways and lung mucosa with a strong correlation to atopy and acquired (IgE) immunity1. 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 C5a2. 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 attack2,3. 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 permeability2. 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.

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Figure 1: Targeted disruption of the mouse C3aR gene.
Figure 2: Pulmonary accumulation of inflammatory cells.
Figure 3: Assessment of AHR to inhaled methacholine (MCh) in conscious mice.
Figure 4: Airway responsiveness to intravenous methacholine (MCh) in anaesthetized mice.

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Acknowledgements

We thank T. Martin and J. Drazen for comments and advice; J. Brewer for assistance; D. Zurakowski for help and advice with analysing the statistics; and the staff of ARCH at Children's Hospital for animal care. This work was supported in part by grants from the NIH to N.P.G. and C.G. at the Perlmutter laboratory and Pfizer Central Research.

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Authors and Affiliations

  1. Ina Sue Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, 02115, Massachusetts , USA

    Alison A. Humbles, Bao Lu, Christy A. Nilsson, Norma P. Gerard & Craig Gerard

  2. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Craig Lilly & Elliot Israel

  3. Division of Hematology and Oncology Children's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Yuko Fujiwara

Authors
  1. Alison A. Humbles
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  2. Bao Lu
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  3. Christy A. Nilsson
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  4. Craig Lilly
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  5. Elliot Israel
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  6. Yuko Fujiwara
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  7. Norma P. Gerard
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  8. Craig Gerard
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Correspondence to Craig Gerard.

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Humbles, A., Lu, B., Nilsson, C. et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma . Nature 406, 998–1001 (2000). https://doi.org/10.1038/35023175

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