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ISSN Print: 1040-8401
ISSN Online: 2162-6472
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Chronic Lung Allograft Dysfunction: Immune Responses Induced by Circulating Exosomes with Lung-Associated Self-Antigens
ABSTRACT
Exosomes, nanovesicles shown to regulate physiological processes in vivo, have been implicated in pathological conditions including cancer, autoimmune disease, infectious disease, neurodegenerative disease, and allograft rejection. Studies of lung transplant recipients with primary graft dysfunction, respiratory viral infection, and (acute) rejection have demonstrated circulating exosomes containing donor-mismatched human leukocyte antigen and lung-associated self-antigens, K-alpha 1 tubulin and collagen V, indicating that exosomes are originating from the transplanted organ. These circulating exosomes likely play a role in activating immune responses that lead to increased risk of chronic lung allograft dysfunction, as exosomes efficiently present their antigens to the immune system by all known pathways of antigen recognition (i.e., direct, indirect, and semidirect pathways). Here, we discuss exosome biogenesis, describe their contents, and address the mechanism of exosome-mediated activation of immune responses that lead to allograft rejection, especially after lung transplantation.
-
Sato M, Hwang DM, Wassell TK, Singer LG, Keshavjes S. Progression pattern of restrictive allograft syndrome after lung transplantation. J Heart Lung Transpl. 2013;32(1):23-30.
-
Ofek E, Sato M, Saito T, Wagnetz U, Roberts HC, . Chaparro C, Waddell TK, Singer LG, Hutcheon 14 MA, Keshavjee S, Hwang DM. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol. 2013;26(3):350-56.
-
Verleden SE, Vaselescu DM, McDonough JE, Ruttens D, Vos R, Vandermeulen E, Bellon H, Geenens R, Verbeken 15 EK, Verschakelen J, Van Raemdonck DE, Wuyts WA, Sokolow Y, Knoop C, Cooper JD, Hogg JC, Verleden GM, Vanaudenaerde BM. Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure. Eur Respir J. 2015;46(5):1430-39.
-
Nath DS, Basha HI, Mohanakumar T. Antihuman leukocyte antigen antibody-induced autoimmunity: role in chronic rejection. Curr Op Organ Transplant. 17. 2010;15(1):16-20.
-
Smirnova NF, Conlon TM, Morrone C, Dorfmuller P, Humbert M, Stathopoulos GT, Umkehrer S, Pfeiffer F, Yildirim AO, Eickelberg O. Inhibition of B cell-dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation. JCI Insight. 2019;4(3):e123971.
-
Bhinder S, Chen H, Sato M, Copes R, Evans GJ, Chow CW, Singer LG. Air pollution and the development of posttransplant chronic lung allograft dysfunction. Am J Transplant. 2014 Dec;14(12):2749-57.
-
Gregson AL, Wang X, Weigt SS, Palchevskiy V, Lynch JP, 3rd, Ross DJ, Kubak BM, Saggar R, Fishbein MC, Ardehali A, Li G, Elashoff R, Belperio JA. Interaction between Pseudomonas and CXC chemokines increases risk of bronchiolitis obliterans syndrome and death in lung transplantation. Am J Respir Crit Care Med. 2013 Mar 1;187(5):518-26.
-
Weigt SS, Elashoff RM, Huang C, Ardehali A, Gregson AL, Kubak B, Fishbein MC, Saggar R, Keane MP, Saggar R, Lynch JP, 3rd, Zisman DA, Ross DJ, Belperio JA. Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome. Am J Transplant. 2009 Aug;9(8):1903-11.
-
Gauthier JM, Hachem RR, Kreisel D. Update on chronic lung allograft dysfunction. Curr Transplant Rep. 2016;3(3):185-91.
-
Tullius SG, Tilney NL Both alloantigen-dependent and independent factors influence chronic allograft rejection. Transplantation. 1995;59(3):313-18.
-
Mauck KA, Hosenpud JD. The bronchial epithelium: a potential allogeneic target for chronic rejection after lung transplantation. J Heart Lung Transplant. 1996 Jul;15(7):709-14.
-
Smith CR, Jaramillo A, Duffy BF, Mohanakumar T. Airway epithelial cell damage mediated by antigen-specific T cells: implications in lung allograft rejection. Hum Immunol. 2000 Oct;61(10):985-92.
-
Webert KE, Blajchman MA. Transfusion-related acute lung injury. Transfus Med Rev. 2003;17(4):252-62.
-
Bharat A, Narayanan K, Street T, Fields RC, Steward N, Aloush A, Meyers B, Schuessler R, Trulock EP, Patterson GA, Mohanakumar T. Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection. Transplantation. 2007 Jan 27;83(2):150-58.
-
Sato M, Hirayama S, Hwang DM, Lara-Guerra H, Wagnetz D, Waddell TK, Liu M, Keshavjee S. The role of intrapulmonary de novo lymphoid tissue in obliterative bronchiolitis after lung transplantation. J Immunol. 2009 Jun 1;182(11):7307-16.
-
Dijke EI, Platt JL, Blair P, Clatworthy MR, Patel JK, Kfoury AG, Cascalho M. B cells in transplantation. J Heart Lung Transpl. 2016 Jun;35(6):704-10.
-
Mehrotra A, Heeger PS. B cells and kidney transplantation: beyond antibodies. J Am Soc Nephrol. 2014 Jul;25(7): 1373-74.
-
Zeng Q, Ng YH, Singh T, Jiang K, Sheriff KA, Ippolito R, Zahalka S, Li Q, Randhawa P, Hoffman RA, Ramaswami B, Lund FE, Chalasani G. B cells mediate chronic allograft rejection independently of antibody production. J Clin Invest. 2014 Mar;124(3):1052-56.
-
Sun Y, Tawara I, Zhao M, Qin ZS, Toubai T, Mathewson N, Tamaki H, Nieves E, Chinnaiyan AM, Reddy P. Allogeneic T cell responses are regulated by a specific miRNA-mRNA network. J Clin Invest. 2013;123(11):4739-54.
-
Shan J, Feng L, Luo L, Wu, W, Li C, Li S, Li Y. Micro-RNAs: potential biomarker in organ transplantation. Transpl Immunol. 2011;24(4):210-15.
-
Harris A, Krams SM, Martinez OM. MicroRNAs as immune regulators: implications for transplantation. Am J Transplant. 2010;10(4):713.
-
Xu Z, Yang W, Steward N, Sweet SC, Danziger-Isakov L, Heeger PS, Mohanakumar T. Role of circulating microRNAs in the immunopathogenesis of rejection after pediatric lung transplantation. Transplantation. 2017;101(10):2461-68.
-
Xu Z, Nayak D, Benshoff N, Hachem R, Gelman AE, Mohanakumar T. De novo-developed antibodies to donor MHC antigens lead to dysregulation of microRNAs and induction of MHC class II. J Immunol. 2015;194(12):6133-43.
-
Anderson HC, Mulhall D, Garimella R. Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis. Lab Invest. 2010;90(11):1549-57.
-
Gunasekaran M, Xu Z, Nayak DK, Sharma M, Hachem R, Walia R, Bremner RM, Smith MA, Mohanakumar T. Donor-derived exosomes with lung self-antigens in human lung allograft rejection. Am J Transpl. 2017;17(2):474-84.
-
Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell. 1983;33(3):967-78.
-
Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicle. 2018;7(1):1535750.
-
Console L, Scalise M, Indiveri C. Exosomes in inflammation and role as biomarkers. Clin Chim Acta. 2019;488:165-71.
-
Ludwig N, Whiteside TL. Potential roles of tumor-derived exosomes in angiogenesis. Expert Opin Ther Targets. 2018;22(5):409-17.
-
Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, Garin J, Amigorena S. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol. 2001;166(12):7309-18.
-
McGough IJ, Vincent JP. Exosomes in developmental signaling. Development. 2016;143(14):2482-93.
-
Huang CC, Narayanan R, Alapati S, Ravindran S. Exosomes as biomimetic tools for stem cell differentiation: applications in dental pulp tissue regeneration. Biomaterials. 2016;111:103-15.
-
Wang X, Omar O, Vazirisani F, Thomsen P, Ekstrom K. Mesenchymal stem cell-derived exosomes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differentiation. PLoS One. 2018;13(2):e0193059.
-
Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, Li H, Liu Z, Shi C, Duan F, Xiao Y. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res. 2016;64(4):831-40.
-
Berditchevski F, Odintsova E. Tetraspanins as regulators of protein trafficking. Traffic. 2007;8(2):89-96.
-
Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H, Raposo G. Cells release prions in association with exosomes. Proc Natl Acad Sci U S A. 2004;101(26):9683-88.
-
Hurley JH. ESCRTs are everywhere. EMBO J. 2015; 34(19):2398-407.
-
Sinha S, Hishino D, Hong NH, Kirkbride KC, Grega-Larson NE, Seiki M, Tyska MJ, Weaver AM. Cortactin promotes exosome secretion by controlling branched actin dynamics. J Cell Biol. 2016;214(2):197-213.
-
Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol. 2005;6(10): 801-11.
-
Gonzalez-Nolasco B, Wang M, Prunevieille A, Benichou G. Emerging role of exosomes in allorecognition and allograft rejection. Curr Op Organ Transplant. 2018;23(1):22-27.
-
Marino J, Paster J, Benichou G. Allorecognition by T lymphocytes and allograft rejection. Front Immunol. 2016;14(7):582.
-
Bansal S, Sharma M, Mohanakumar T. The role of exosomes in allograft immunity. Cell Immunol. 2018 Sep;331:85-92.
-
Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018 Jan;75(2):193-208.
-
Savina A, Vidal M, Colombo MI. The exosome pathway in K562 cells is regulated by Rab11. J Cell Sci. 2002;115(Pt 12):2505-15.
-
Hsu C, Morohashi Y, Yoshimura S, Manrique-Hoyos N, Jung S, Lauterbach MA, Bakhti M, Gronborg M, Mobius W, Rhee J, Barr FA, Simons M. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol. 2010;189(2):223-32.
-
Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010 Jan;12(1):19-30; suppl: 1-13.
-
Grant BD, Donaldson JG. Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol. 2009;10(9):597-608.
-
Blanc L, Vidal M. New insights into the function of Rab GTPases in the context of exosomal secretion. Small GTPases. 2018;9(1-2):95-106.
-
Raposo G, Marks MS, Cutler DF. Ly so some-related organelles: driving post-Golgi compartments into specialisation. Curr Opin Cell Biol. 2007;19(4):394-401.
-
Bharat A, Mohanakumar T. Allopeptides and the alloimmune response. Cell Immunol. 2007;248(1):31-43.
-
Sivaganesh S, Herper SJ, Conlon TM, Callaghan CJ, Saeb-Parsy K, Negus MC, Motallebzadeh R, Bolton EM, Bradley JA, Pettigrew GJ. Copresentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T cells by indirect-pathway CD4 T cells. J Immunol. 2013;190(11):5829-38.
-
Jiang S, Herrera O, Lechler RI. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr Opin Immunol. 2004;16(5):550-57.
-
Thery C, Duban L, Segura E, Veron P, Lantz O, Amigorena S. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol. 2002;3(12):1156-62.
-
Tiriveedhi V, Gautam B, Sarma N, Askar M, Budev M, Aloush A, Hachem R, Trulock R, Myers B, Patterson GA, Mohanakumar T. Pre-transplant antibodies to K-alpha-1 Tubulin and Collagen-V in lung transplantation: clinical correlations. J Heart Lung Transplant. 2013;32(8):807-14.
-
Jaramillo A, Smith MA, Phelan D, Sundaresan S, Trulock EP, Lynch JP, Cooper JD, Patterson GA, Mohanakumar T. Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation. Transplantation. 1999 Apr 27;67(8):1155-61.
-
Jaramillo A, Smith CR, Maruyama T, Zhang L, Patterson GA, Mohanakumar T. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol. 2003;64(5):521-29.
-
Goers TA, Ramachandran S, Aloush A, Trulock E, Patterson GA, Mohanakumar T. De novo production of K-alpha 1 tubulin-specific Abs: role in chronic lung allograft rejection. J Immunol. 2008;180(7):4487-94.
-
Saini D, Weber J, Ramachandran S, Phelan D, Tiriveedhi V, Liu M, Steward N, Aloush A, Hachem R, Trulock E, Meyers B, Patterson GA, Mohanakumar T. Alloimmunity-induced autoimmunity as a potential mechanism in the pathogenesis of chronic rejection of human lung allografts. J Heart Lung Transplant. 2011 Jun;30(6):624-31. PubMed PMID: 21414808. PMCID: Pmc3091959. Epub 2011/03/19. eng.
-
Bharat A, Zheng Z, Sun H, Yeldandi A, DeCamp MM, Perlman H, Budinger GR, Mohanakumar T. Lung-restricted antibodies mediate primary graft dysfunction and prevent allotolerance after murine lung transplantation. Am J Respir Cell Mol Biol. 2016;55(4):532-41.
-
Burlingham WJ, Love RB, Jankowska-Gan E, Haynes LD, Xu Q, Bobadilla JL, Meyer KC, Hayney MS, Braun RK, Greenspan DS, Gopalakrishnan B, Cai J, Brand DD, Yoshida S, Cummings OW, Wilkes DS. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007 Nov;117(11):3498-506.
-
Land WG. The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation. Transplantation. 2005;79(5):505-14.
-
Fukami N, Ramachandran S, Saini D, Walter M, Chapman W, Patterson GA, Mohanakumar T. Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection. J Immunol. 2009 Jan 1;182(1):309-18.
-
Hachem RR, Tiriveedhi V, Patterson GA, Aloush A, Trulock EP, Mohanakumar T. Antibodies to K-alpha 1 tubulin and collagen V are associated with chronic rejection after lung transplantation. Am J Transplant. 2012 Aug;12(8):2164-71.
-
Nayak DK, Zhou F, Xu M, Huang J, Tsuji M, Yu J, Hachem R, Gelman AE, Bremner RM, Smith MA, Mohanakumar T. Zbtb7a induction in alveolar macrophages is obligatory in antihuman leukocyte antigen-mediated lung allograft rejection. Sci Trans Med. 2017;9(398).
-
Xu Z, Ramachandran S, Gunasekaran M, Nayak D, Benshoff B, Hachem R, Gelman AE, Mohanakumar T. B cell-activating transcription factor plays a critical role in the pathogenesis of anti-major histocompatibility complex-induced obliterative airway disease. Am J Transpl. 2016;16(4):1172-82.
-
Mohanakumar T, Sharma M, Bansal S, Ravichandran R, Smith M, Bremner R. A novel mechanism for immune regulation after human lung transplantation. J Thorac Cardiovasc Surg. 2019 May;157(5):2096-106.
-
Mimura T, Walker N, Aoki Y, Manning CM, Murdock BJ, Myers JL, Lagstein A, Osterholzer JJ, Lama VN. Local origin of mesenchymal cells in a murine orthotopic lung transplantation model of bronchiolitis obliterans. Am J Path. 2015;185:1564-74.
-
Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease. N Engl J Med. 2018; 379(22):2180-81.
-
Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161-72.
-
Lundy SK, Klinker MW, Fox DA. Killer B lymphocytes and their fas ligand positive exosomes as inducers of immune tolerance. Front Immunol. 2015;6:122. PubMed PMID: 25852690.
-
Gunasekaran M, Sharma M, Hachem R, Bremner R, Smith MA, Mohanakumar T. Circulating exosomes with distinct properties during chronic lung allograft rejection. J Immunol. 2018;200(8):2535-41.
-
Montecalvo A, Shufesky WJ, Stolz DB, Sulllivan MG, Wang Z, Divito SJ, Papworth GD, Watkins SC, Robbins PD, Larregina AT, Morelli AE. Exosomes as a short-range mechanism to spread alloantigen between dendritic cells during T cell allorecognition. J Immunol. 81 2008;180(5):3081-90.
-
Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci. 2016;17(10):E1712.
-
Hwang B, Chen R, Bryers J, Mulligan MS. Exosome-82 allorecognition in lung transplantation rejection. Immunol Res Ther J. 2018;1(1):114.
-
Amrouche L, Rabant M, Anglicheau D. MicroRNAs as biomarkers of graft outcome. Transplant Rev. 2014;28(3):111-18.
-
Budding K, Rossato M, van de Graaf EA, Kwakkel-van Erp JM, Radstake TRDJ, Otten HG. Serum miRNAs as potential biomarkers for the bronchiolitis obliterans syndrome after lung transplantation. Transpl Immunol. 84 2017;42:1-4.
-
Hussain S, Iqbal T, Javed Q. TNF-alpha-308G>A polymorphism and the risk of familial CAD in a Pakistani population. Hum Immunol. 2015;76(1):13-18.
-
Xu Z, Nayak D, Yang W, Baskaran G, Ramachandran S Sarma N, Aloush A, Trulock E, Hachem R, Patterson GA, Mohanakumar T. Dysregulated microRNA expression and chronic lung allograft rejection in recipients with antobidies to donor HLA. Am J Transpl. 2015;15(7):1933-47.
-
Xu Z, Ramachandran S, Gunasekaran M, Nayak D, Trulock E, Hachem R, Kreisel D, Mohanakumar T. MicroRNA-144 dysregulates the transforming growth factor-beta signaling cascade and contributes to the development of bronchiolitis obliterans syndrome after human lung transplantation. J Heart Lung Transplant. 2015;34(9):1154-62.
-
Soni S, Wilson MR, O'Dea KP, Yoshida M, Katbeh U, Woods SJ, Takata M. Alveolar macrophage-deerived microvesicles mediate acute lung injury. Thorax. 2016;71(11):1020-29.
-
Nayak DK, Zhou F, Xu M, Huang J, Tsuji M, Hachem R, Mohanakumar T. Long-term persistence of donor alveolar macrophages in human lung transplant recipients that influences donor-specific immune responses. Am J Transpl. 2016;16(8):2300-11.
-
Wu Y, Zhou Y, Huan L, Xu L, Shen M, Huang S, Liang L. LncRNA MIR22HG inhibits growth, migration and invasion through regulating the miR-10a-5p/NC0R2 axis in hepatocellular carcinoma cells. Cancer Sci. 2019 Mar;110(3):973-84.
-
Chen LP, Zhang NN, Ren XQ, He J, Li Y. miR-103/miR-195/miR-15b regulate SALL4 and inhibit proliferation and migration in glioma. Molecules. 2018 Nov 10;23(11):2938.
-
Jin LW, Ye HY, Xu XY, Zheng Y, Chen Y. MiR-133a/133b inhibits Treg differentiation in IgA nephropathy through targeting F0XP3. Biomed Pharmacother. 2018 May;101:195-200.
-
Cheng D, Li J, Zhang L, Hu L. miR-142-5p suppresses proliferation and promotes apoptosis of human osteo-sarcoma cell line, HOS, by targeting PLA2G16 through the ERK1/2 signaling pathway. Oncol Lett. 2019 Jan;17(1):1363-71.
-
Mashima R. Physiological roles of miR-155. Immunology. 2015 Jul;145(3):323-33.
-
Yamada Y, Arai T, Kojima S, Sugawara S, Kato M, Okato A, Yamazaki K, Naya Y, Ichikawa T, Seki N. Regulation of antitumor miR-144-5p targets oncogenes: Direct regulation of syndecan-3 and its clinical significance. Cancer Sci. 2018 Sep;109(9):2919-36.
-
Pan JY, Zhang F, Sun CC, Li SJ, Li G, Gong FY, Bo T, He J, Hua RX, Hu WD, Yuan ZP, Wang X, He QQ, Li DJ. miR-134: A human cancer suppressor? Mol Ther Nucleic Acids. 2017 Mar 17;6:140-49.
-
Arjuna Ashwini, Olson Michael T., Walia Rajat, Bremner Ross M., Smith Michael A., Mohanakumar Thalachallour, An update on current treatment strategies for managing bronchiolitis obliterans syndrome after lung transplantation, Expert Review of Respiratory Medicine, 15, 3, 2021. Crossref
-
Frye C. Corbin, Bery Amit I., Kreisel Daniel, Kulkarni Hrishikesh S., Sterile inflammation in thoracic transplantation, Cellular and Molecular Life Sciences, 78, 2, 2021. Crossref
-
Conrad Carol K., Hedlin Haley, Chin Hyunsook, Hayes Don, Heeger Peter S., Faro Albert, Goldfarb Samuel, Melicoff‐Portillo Ernestina, Thalachallour Mohanakumar, Odim Jonah, Schecter Marc, Storch Gregory A., Visner Gary A., Williams Nikki M., Kesler Karen, Danziger‐Isakov Lara, Sweet Stuart C., Auto‐inflammation and auto‐immunity pathways are associated with emergence of BOS in pediatric lung transplantation, Pediatric Transplantation, 26, 4, 2022. Crossref