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.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Hidemi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lasbury
authors.forename: Lin
authors.initials: L
authors.lastname: Fan
authors.forename: Ragini
authors.initials: R
authors.lastname: Vittal
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mickler
authors.forename: Heather L
authors.initials: HL
authors.lastname: Benson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Shilling
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weber
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Wagner
authors.forename: Melissa
authors.initials: M
authors.lastname: Lasaro
authors.forename: Denise
authors.initials: D
authors.lastname: Devore
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: George E
authors.initials: GE
authors.lastname: Sandusky
authors.forename: Kelsey
authors.initials: K
authors.lastname: Lipking
authors.forename: Pankita
authors.initials: P
authors.lastname: Pandya
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.forename: Robert
authors.initials: R
authors.lastname: Love
authors.forename: Thomas
authors.initials: T
authors.lastname: Wozniak
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gu
authors.forename: Krista M
authors.initials: KM
authors.lastname: Brown
authors.forename: David S
authors.initials: DS
authors.lastname: Wilkes
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001989:Bronchiolitis Obliterans / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid; D018958:CD55 Antigens / Q000096:biosynthesis; D024062:Collagen Type V / Q000276:immunology; D003167:Complement Activation; D015926:Complement C3a / Q000096:biosynthesis; D003182:Complement C5; D015536:Down-Regulation; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D016040:Lung Transplantation / Q000009:adverse effects*; D007959:Lymphocyte Culture Test, Mixed; D051916:Membrane Cofactor Protein / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D011951:Receptors, Complement / Q000096:biosynthesis; D017463:Receptors, Complement 3b
chemical_list: D018958:CD55 Antigens; D024062:Collagen Type V; D003182:Complement C5; C081470:Cr1l protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D051916:Membrane Cofactor Protein; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D015926:Complement C3a
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