TY - JOUR
T1 - Respiratory viral infection in lung transplantation induces exosomes that trigger chronic rejection
AU - Gunasekaran, Muthukumar
AU - Bansal, Sandhya
AU - Ravichandran, Ranjithkumar
AU - Sharma, Monal
AU - Perincheri, Sudhir
AU - Rodriguez, Francisco
AU - Hachem, Ramsey
AU - Fisher, Cynthia E.
AU - Limaye, Ajit P.
AU - Omar, Ashraf
AU - Smith, Michael A.
AU - Bremner, Ross M.
AU - Mohanakumar, Thalachallour
N1 - Funding Information:
This study was supported by National Institutes of Health grants AI123034 , HL056643 , and HL092514 (TM).
Publisher Copyright:
© 2020 International Society for Heart and Lung Transplantation
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
KW - antibodies
KW - antigens
KW - chronic rejection
KW - exosomes
KW - graft rejection
KW - lung transplantation
KW - respiratory viral infection
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U2 - 10.1016/j.healun.2019.12.009
DO - 10.1016/j.healun.2019.12.009
M3 - Article
C2 - 32033844
AN - SCOPUS:85078834003
VL - 39
SP - 379
EP - 388
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
SN - 1053-2498
IS - 4
ER -