Respiratory viral infection in lung transplantation induces exosomes that trigger chronic rejection.
Aged
Animals
Antigens, Viral
/ metabolism
Autoantigens
/ metabolism
Case-Control Studies
Exosomes
/ metabolism
Female
Graft Rejection
/ etiology
HLA Antigens
/ metabolism
Humans
Lung Transplantation
/ adverse effects
Male
Mice
Mice, Inbred C57BL
Middle Aged
Proteasome Endopeptidase Complex
/ metabolism
Respiratory Tract Infections
/ complications
Virus Diseases
/ complications
antibodies
antigens
chronic rejection
exosomes
graft rejection
lung transplantation
respiratory viral infection
Journal
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
ISSN: 1557-3117
Titre abrégé: J Heart Lung Transplant
Pays: United States
ID NLM: 9102703
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
26
04
2019
revised:
25
11
2019
accepted:
29
12
2019
pubmed:
9
2
2020
medline:
18
9
2020
entrez:
9
2
2020
Statut:
ppublish
Résumé
Respiratory viral infections can increase the risk of chronic lung allograft dysfunction after lung transplantation, but the mechanisms are unknown. In this study, we determined whether symptomatic respiratory viral infections after lung transplantation induce circulating exosomes that contain lung-associated self-antigens and assessed whether these exosomes activate immune responses to self-antigens. Serum samples were collected from lung transplant recipients with symptomatic lower- and upper-tract respiratory viral infections and from non-symptomatic stable recipients. Exosomes were isolated via ultracentrifugation; purity was determined using sucrose cushion; and presence of lung self-antigens, 20S proteasome, and viral antigens for rhinovirus, coronavirus, and respiratory syncytial virus were determined using immunoblot. Mice were immunized with circulating exosomes from each group and resulting differential immune responses and lung histology were analyzed. Exosomes containing self-antigens, 20S proteasome, and viral antigens were detected at significantly higher levels (p < 0.05) in serum of recipients with symptomatic respiratory viral infections (n = 35) as compared with stable controls (n = 32). Mice immunized with exosomes from recipients with respiratory viral infections developed immune responses to self-antigens, fibrosis, small airway occlusion, and significant cellular infiltration; mice immunized with exosomes from controls did not (p < 0.05). Circulating exosomes isolated from lung transplant recipients diagnosed with respiratory viral infections contained lung self-antigens, viral antigens, and 20S proteasome and elicited immune responses to lung self-antigens that resulted in development of chronic lung allograft dysfunction in immunized mice.
Sections du résumé
BACKGROUND
Respiratory viral infections can increase the risk of chronic lung allograft dysfunction after lung transplantation, but the mechanisms are unknown. In this study, we determined whether symptomatic respiratory viral infections after lung transplantation induce circulating exosomes that contain lung-associated self-antigens and assessed whether these exosomes activate immune responses to self-antigens.
METHODS
Serum samples were collected from lung transplant recipients with symptomatic lower- and upper-tract respiratory viral infections and from non-symptomatic stable recipients. Exosomes were isolated via ultracentrifugation; purity was determined using sucrose cushion; and presence of lung self-antigens, 20S proteasome, and viral antigens for rhinovirus, coronavirus, and respiratory syncytial virus were determined using immunoblot. Mice were immunized with circulating exosomes from each group and resulting differential immune responses and lung histology were analyzed.
RESULTS
Exosomes containing self-antigens, 20S proteasome, and viral antigens were detected at significantly higher levels (p < 0.05) in serum of recipients with symptomatic respiratory viral infections (n = 35) as compared with stable controls (n = 32). Mice immunized with exosomes from recipients with respiratory viral infections developed immune responses to self-antigens, fibrosis, small airway occlusion, and significant cellular infiltration; mice immunized with exosomes from controls did not (p < 0.05).
CONCLUSIONS
Circulating exosomes isolated from lung transplant recipients diagnosed with respiratory viral infections contained lung self-antigens, viral antigens, and 20S proteasome and elicited immune responses to lung self-antigens that resulted in development of chronic lung allograft dysfunction in immunized mice.
Identifiants
pubmed: 32033844
pii: S1053-2498(20)30012-7
doi: 10.1016/j.healun.2019.12.009
pmc: PMC7102671
mid: NIHMS1550591
pii:
doi:
Substances chimiques
Antigens, Viral
0
Autoantigens
0
HLA Antigens
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
379-388Subventions
Organisme : NHLBI NIH HHS
ID : K23 HL143050
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL056643
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL092514
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI123034
Pays : United States
Informations de copyright
Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Références
J Thorac Cardiovasc Surg. 1998 Oct;116(4):617-23
pubmed: 9766590
Clin Infect Dis. 2016 Feb 1;62(3):313-319
pubmed: 26565010
Curr Protoc Cell Biol. 2006 Apr;Chapter 3:Unit 3.22
pubmed: 18228490
Am J Transplant. 2012 Aug;12(8):2164-71
pubmed: 22568593
J Immunol. 2008 Apr 1;180(7):4487-94
pubmed: 18354170
Am J Transplant. 2014 Oct;14(10):2359-66
pubmed: 25220332
Am J Transplant. 2011 Feb;11(2):320-8
pubmed: 21219569
Sci Transl Med. 2015 Dec 16;7(318):318ra200
pubmed: 26676607
J Heart Lung Transplant. 2002 May;21(5):559-66
pubmed: 11983546
J Heart Lung Transplant. 2014 Feb;33(2):127-33
pubmed: 24374027
J Immunol. 2018 Apr 15;200(8):2535-2541
pubmed: 29491008
Int J Cancer. 2007 Oct 1;121(7):1494-506
pubmed: 17546597
J Immunol. 2009 Feb 1;182(3):1548-59
pubmed: 19155503
Chest. 2003 Jun;123(6):1825-31
pubmed: 12796156
Am J Transplant. 2017 Feb;17(2):474-484
pubmed: 27278097
Ann Thorac Surg. 2010 Nov;90(5):1637-44; discussion 1644
pubmed: 20971279
Am J Respir Crit Care Med. 2007 Mar 1;175(5):507-13
pubmed: 17158279
J Heart Lung Transplant. 2011 Jun;30(6):624-31
pubmed: 21414808
J Heart Lung Transplant. 2007 Dec;26(12):1229-42
pubmed: 18096473
J Heart Lung Transplant. 2011 Jul;30(7):735-42
pubmed: 21419659
J Heart Lung Transplant. 2013 Aug;32(8):807-14
pubmed: 23856218
Pathog Dis. 2014 Jul;71(2):109-20
pubmed: 24449527
N Engl J Med. 1999 Apr 8;340(14):1081-91
pubmed: 10194239
Semin Respir Crit Care Med. 2010 Apr;31(2):208-21
pubmed: 20354933
J Virol. 2018 Nov 27;92(24):
pubmed: 30282711
J Heart Lung Transplant. 2013 Oct;32(10):1034-40
pubmed: 23953920
J Heart Lung Transplant. 2016 Jul;35(7):946-7
pubmed: 27235268
J Immunol. 2011 Jan 1;186(1):73-82
pubmed: 21106852
Expert Rev Respir Med. 2017 May;11(5):377-383
pubmed: 28388307
Ann Thorac Surg. 2010 Oct;90(4):1094-101
pubmed: 20868794
Am J Respir Crit Care Med. 2004 Jul 15;170(2):181-7
pubmed: 15130908
Transplantation. 2013 Jan 27;95(2):383-8
pubmed: 23444472
J Immunol. 2009 Jan 1;182(1):309-18
pubmed: 19109162
Am J Transplant. 2018 Jul;18(7):1626-1635
pubmed: 29316217