Faculty Collaboration Database

Role of complement activation in obliterative bronchiolitis post-lung transplantation. J Immunol 2013 Oct 15;191(8):4431-9

Date

09/18/2013

Pubmed ID

24043901

Pubmed Central ID

PMC3873138

DOI

10.4049/jimmunol.1202242

Scopus ID

2-s2.0-84885460691 (requires institutional sign-in at Scopus site)   52 Citations

Abstract

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.

Author List

Suzuki H, Lasbury ME, Fan L, Vittal R, Mickler EA, Benson HL, Shilling R, Wu Q, Weber DJ, Wagner SR, Lasaro M, Devore D, Wang Y, Sandusky GE, Lipking K, Pandya P, Reynolds J, Love R, Wozniak T, Gu H, Brown KM, Wilkes DS

MESH terms used to index this publication - Major topics in bold

Animals
Autoimmunity
Bronchiolitis Obliterans
Bronchoalveolar Lavage Fluid
CD55 Antigens
Collagen Type V
Complement Activation
Complement C3a
Complement C5
Down-Regulation
Graft Rejection
Humans
Interleukin-17
Interleukin-6
Lung Transplantation
Lymphocyte Culture Test, Mixed
Membrane Cofactor Protein
Mice
Mice, Inbred C57BL
Receptors, Complement
Receptors, Complement 3b