Role of complement activation in obliterative bronchiolitis post-lung transplantation.
Obliterative bronchiolitis (OB) post-lung transplantation involves IL-17-regulated autoimmunity to type V collagen and alloimmunity, which could be enhanced by complement activation. However, the specific role of complement activation in lung allograft pathology, IL-17 production, and OB is unknown. The current study examines the role of complement activation in OB. Complement-regulatory protein (CRP) (CD55, CD46, complement receptor 1-related protein y/CD46) expression was downregulated in human and murine OB; and C3a, a marker of complement activation, was upregulated locally. IL-17 differentially suppressed complement receptor 1-related protein y expression in airway epithelial cells in vitro. Neutralizing IL-17 recovered CRP expression in murine lung allografts and decreased local C3a production. Exogenous C3a enhanced IL-17 production from alloantigen- or autoantigen (type V collagen)-reactive lymphocytes. Systemically neutralizing C5 abrogated the development of OB, reduced acute rejection severity, lowered systemic and local levels of C3a and C5a, recovered CRP expression, and diminished systemic IL-17 and IL-6 levels. These data indicated that OB induction is in part complement dependent due to IL-17-mediated downregulation of CRPs on airway epithelium. C3a and IL-17 are part of a feed-forward loop that may enhance CRP downregulation, suggesting that complement blockade could be a therapeutic strategy for OB.
Duke Scholars
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- Receptors, Complement 3b
- Receptors, Complement
- Mice, Inbred C57BL
- Mice
- Membrane Cofactor Protein
- Lymphocyte Culture Test, Mixed
- Lung Transplantation
- Interleukin-6
- Interleukin-17
- Immunology
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Receptors, Complement 3b
- Receptors, Complement
- Mice, Inbred C57BL
- Mice
- Membrane Cofactor Protein
- Lymphocyte Culture Test, Mixed
- Lung Transplantation
- Interleukin-6
- Interleukin-17
- Immunology