Role of complement activation in obliterative bronchiolitis post-lung transplantation

Hidemi Suzuki, Mark E. Lasbury, Lin Fan, Ragini Vittal, Elizabeth A. Mickler, Heather L. Benson, Rebecca Shilling, Qiang Wu, Daniel J. Weber, Sarah R. Wagner, Melissa Lasaro, Denise Devore, Yi Wang, George E. Sandusky, Kelsey Lipking, Pankita Pandya, John Reynolds, Robert Love, Thomas Wozniak, Hongmei GuKrista M. Brown, David S. Wilkes

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4431-4439
Number of pages9
JournalJournal of Immunology
Volume191
Issue number8
DOIs
StatePublished - Oct 15 2013

Fingerprint

Bronchiolitis
Lung Transplantation
Interleukin-17
Complement Activation
Complement System Proteins
Collagen Type V
Complement C1
Complement Receptors
Down-Regulation
Allografts
Lung
Isoantigens
Autoantigens
Autoimmunity
Interleukin-6
Proteins
Epithelium
Epithelial Cells
Lymphocytes
Pathology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Suzuki, H., Lasbury, M. E., Fan, L., Vittal, R., Mickler, E. A., Benson, H. L., ... Wilkes, D. S. (2013). Role of complement activation in obliterative bronchiolitis post-lung transplantation. Journal of Immunology, 191(8), 4431-4439. https://doi.org/10.4049/jimmunol.1202242

Role of complement activation in obliterative bronchiolitis post-lung transplantation. / Suzuki, Hidemi; Lasbury, Mark E.; Fan, Lin; Vittal, Ragini; Mickler, Elizabeth A.; Benson, Heather L.; Shilling, Rebecca; Wu, Qiang; Weber, Daniel J.; Wagner, Sarah R.; Lasaro, Melissa; Devore, Denise; Wang, Yi; Sandusky, George E.; Lipking, Kelsey; Pandya, Pankita; Reynolds, John; Love, Robert; Wozniak, Thomas; Gu, Hongmei; Brown, Krista M.; Wilkes, David S.

In: Journal of Immunology, Vol. 191, No. 8, 15.10.2013, p. 4431-4439.

Research output: Contribution to journalArticle

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 2013, 'Role of complement activation in obliterative bronchiolitis post-lung transplantation', Journal of Immunology, vol. 191, no. 8, pp. 4431-4439. https://doi.org/10.4049/jimmunol.1202242
Suzuki H, Lasbury ME, Fan L, Vittal R, Mickler EA, Benson HL et al. Role of complement activation in obliterative bronchiolitis post-lung transplantation. Journal of Immunology. 2013 Oct 15;191(8):4431-4439. https://doi.org/10.4049/jimmunol.1202242
Suzuki, Hidemi ; Lasbury, Mark E. ; Fan, Lin ; Vittal, Ragini ; Mickler, Elizabeth A. ; Benson, Heather L. ; Shilling, Rebecca ; Wu, Qiang ; Weber, Daniel J. ; Wagner, Sarah R. ; Lasaro, Melissa ; Devore, Denise ; Wang, Yi ; Sandusky, George E. ; Lipking, Kelsey ; Pandya, Pankita ; Reynolds, John ; Love, Robert ; Wozniak, Thomas ; Gu, Hongmei ; Brown, Krista M. ; Wilkes, David S. / Role of complement activation in obliterative bronchiolitis post-lung transplantation. In: Journal of Immunology. 2013 ; Vol. 191, No. 8. pp. 4431-4439.
@article{8493ca897f954cd5905b870ac114013f,
title = "Role of complement activation in obliterative bronchiolitis post-lung transplantation",
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 = "Hidemi Suzuki and Lasbury, {Mark E.} and Lin Fan and Ragini Vittal and Mickler, {Elizabeth A.} and Benson, {Heather L.} and Rebecca Shilling and Qiang Wu and Weber, {Daniel J.} and Wagner, {Sarah R.} and Melissa Lasaro and Denise Devore and Yi Wang and Sandusky, {George E.} and Kelsey Lipking and Pankita Pandya and John Reynolds and Robert Love and Thomas Wozniak and Hongmei Gu and Brown, {Krista M.} and Wilkes, {David S.}",
year = "2013",
month = "10",
day = "15",
doi = "10.4049/jimmunol.1202242",
language = "English (US)",
volume = "191",
pages = "4431--4439",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "8",

}

TY - JOUR

T1 - Role of complement activation in obliterative bronchiolitis post-lung transplantation

AU - Suzuki, Hidemi

AU - Lasbury, Mark E.

AU - Fan, Lin

AU - Vittal, Ragini

AU - Mickler, Elizabeth A.

AU - Benson, Heather L.

AU - Shilling, Rebecca

AU - Wu, Qiang

AU - Weber, Daniel J.

AU - Wagner, Sarah R.

AU - Lasaro, Melissa

AU - Devore, Denise

AU - Wang, Yi

AU - Sandusky, George E.

AU - Lipking, Kelsey

AU - Pandya, Pankita

AU - Reynolds, John

AU - Love, Robert

AU - Wozniak, Thomas

AU - Gu, Hongmei

AU - Brown, Krista M.

AU - Wilkes, David S.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84885460691&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885460691&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1202242

DO - 10.4049/jimmunol.1202242

M3 - Article

C2 - 24043901

AN - SCOPUS:84885460691

VL - 191

SP - 4431

EP - 4439

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 8

ER -