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Emphysema-associated Autoreactive Antibodies Exacerbate Post–Lung Transplant Ischemia–Reperfusion Injury

Emphysema-associated Autoreactive Antibodies Exacerbate Post–Lung Transplant Ischemia–Reperfusion Injury

Authors :
Carl Atkinson
Valeria Montalvo-Calero
Qi Cheng
Sarah E. Stephenson
Satish N. Nadig
Martin Goddard
D. Patterson Allen
Chentha Vasu
Changhai Li
Scott Esckilsen
J. Kilkenny
Ryan Finnegan
Kunal Patel
Source :
American Journal of Respiratory Cell and Molecular Biology. 60:678-686
Publication Year :
2019
Publisher :
American Thoracic Society, 2019.

Abstract

Chronic obstructive pulmonary disease-associated chronic inflammation has been shown to lead to an autoimmune phenotype characterized in part by the presence of lung autoreactive antibodies. We hypothesized that ischemia-reperfusion injury (IRI) liberates epitopes that would facilitate preexisting autoantibody binding, thereby exacerbating lung injury after transplant. We induced emphysema in C57BL/6 mice through 6 months of cigarette smoke (CS) exposure. Mice with CS exposure had significantly elevated serum autoantibodies compared with non-smoke-exposed age-matched (NS) mice. To determine the impact of a full preexisting autoantibody repertoire on IRI, we transplanted BALB/c donor lungs into NS or CS recipients and analyzed grafts 48 hours after transplant. CS recipients had significantly increased lung injury and immune cell infiltration after transplant. Immunofluorescence staining revealed increased IgM, IgG, and C3d deposition in CS recipients. To exclude confounding alloreactivity and confirm the role of preexisting autoantibodies in IRI, syngeneic Rag1-/- (recombination-activating protein 1-knockout) transplants were performed in which recipients were reconstituted with pooled serum from CS or NS mice. Serum from CS-exposed mice significantly increased IRI compared with control mice, with trends in antibody and C3d deposition similar to those seen in allografts. These data demonstrate that pretransplant CS exposure is associated with increased IgM/IgG autoantibodies, which, upon transplant, bind to the donor lung, activate complement, and exacerbate post-transplant IRI.

Details

ISSN :
15354989 and 10441549
Volume :
60
Database :
OpenAIRE
Journal :
American Journal of Respiratory Cell and Molecular Biology
Accession number :
edsair.doi...........2e0f164af37cd9544a320fee9016b202
Full Text :
https://doi.org/10.1165/rcmb.2018-0224oc