Circulating exosomes with lung self-antigens as a biomarker for chronic lung allograft dysfunction: A retrospective analysis

Sharma, Monal; Gunasekaran, Muthukumar; Ranjithkumar, R.; Fisher, Cynthia E.; Limaye, Ajit P.; Hu, Chengcheng; McDyer, John F.; Kaza, Vaidehi; Bharat, Ankit; Tokman, Sofya; Omar, Ashraf; Arjuna, A.; Walia, Rajat; Bremner, Ross M.; Smith, Michael A.; Hachem, Ramsey R.; Mohanakumar, Thalachallour

doi:10.1016/j.healun.2020.07.001

Cited by 25 publications

(19 citation statements)

References 35 publications

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“…Our earlier studies, have demonstrated that lung SAgs (Collagen V [Col-V] and Kα1 Tubulin [Kα1T]) containing circulating exosome can predict patients at risk for developing BOS. 33 A novel finding in the current study is that circulating exosomes isolated from BOS LTxRs contain lower levels of LKB1 both at the mRNA and protein level as compared to stable LTxRs (Figure 2B,C). We also showed LKB1 is the upstream regulator of mTOR, a key role of LKB1 is to negatively regulate the activity of mTOR complex 1.…”

Section: Discussionsupporting

confidence: 49%

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Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction

Rahman

Ranjithkumar

Bansal

et al. 2022

American Journal of Transplantation

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Epithelial-mesenchymal transition (EMT) has been implicated to play a role in chronic lung allograft dysfunction (CLAD). Liver kinase B1 (LKB1), a tumor suppressor gene, can regulate EMT. However, its role in CLAD development following lung transplantation remains unknown. Using qRT-PCR, biopsies from lung transplant recipients with bronchiolitis obliterans syndrome (BOS) demonstrated significant downregulation of LKB1 (p = .0001), compared to stable biopsies. To determine the role of LKB1 in EMT development, we analyzed EMT in human bronchial epithelial cell line BEAS-2B.Knockdown of LKB1 by siRNA significantly dysregulated mesenchymal markers expression in BEAS-2B cells. Following incubation of human primary bronchial epithelial cell or BEAS-2B cells with exosomes isolated from BOS or stable lung transplant recipients, LKB1 expression was inhibited when incubated with BOS-exosome. Incubation with BOS-exosomes also decreased LKB1 expression and induced EMT markers in air-liquid interface culture method. Our results provide novel evidence that exosomes released from transplanted lungs undergoing chronic rejection are associated with inactivated tumor suppressor gene LKB1 and this loss induces EMT leading to the pathogenesis of CLAD following human lung transplantation. K E Y W O R D S basic (laboratory) research/science, biomarker, bronchiolitis obliterans (BOS), lung (allograft) function/dysfunction, molecular biology 1 | INTRODUC TI ON Lung transplantation (LTx) is a therapeutic option for patients with advanced lung diseases. Long-term survival after LTx is limited by chronic lung allograft dysfunction (CLAD). CLAD commonly manifests as bronchiolitis obliterans syndrome (BOS), defined by a sustained reduction in the forced expiratory volume in first second of expiration. 1 BOS occurs in 50% of recipients within 5 years post-LTx

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Section: Discussionsupporting

confidence: 49%

“…Western blotting was performed on the protein extracts from exosome and cell lysate samples as previously described. 33 The detailed protocols are provided in the supplemental methods.…”

Section: Western Blot Analysismentioning

confidence: 99%

Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction

Rahman

Ranjithkumar

Bansal

et al. 2022

American Journal of Transplantation

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“…SEVs are involved in several biological and immune processes ( 115 ). Our group has recently validated the use of circulating sEVs with lung TaAgs as a potential biomarker in the early diagnosis of BOS after LTx ( 116 ). In addition, different clinical conditions after LTx that increase the risk for CLAD, e.g., PGD, AR, HLA-DSAs, and respiratory viral infections, can induce circulating sEVs with lung TaAgs ( 117 ).…”

Section: Evs: Role For Eliciting Immune Responses To Taagsmentioning

confidence: 99%

“…Based on this finding, we analyzed plasma samples collected from LTx recipients 6 and 12 months before the clinical diagnosis of BOS from two different LTx centers. Increased levels of lung TaAgs were detected in sEVs isolated from these samples 12 months before the clinical diagnosis of BOS, indicating that circulating sEVs with lung TaAgs can be a viable noninvasive biomarker for identifying patients at risk for developing CLAD ( 116 ). The determination of Col-V or Kα1T in circulating sEVs by western blot followed by semi-quantitation provides a higher positive predictive value with excellent sensitivity and specificity.…”

Section: Sevs With Tissue-associated Ags As a Biomarker For Cladmentioning

confidence: 99%

Extracellular Vesicles Mediate Immune Responses to Tissue-Associated Self-Antigens: Role in Solid Organ Transplantations

et al. 2022

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Transplantation is a treatment option for patients diagnosed with end-stage organ diseases; however, long-term graft survival is affected by rejection of the transplanted organ by immune and nonimmune responses. Several studies have demonstrated that both acute and chronic rejection can occur after transplantation of kidney, heart, and lungs. A strong correlation has been reported between de novo synthesis of donor-specific antibodies (HLA-DSAs) and development of both acute and chronic rejection; however, some transplant recipients with chronic rejection do not have detectable HLA-DSAs. Studies of sera from such patients demonstrate that immune responses to tissue-associated antigens (TaAgs) may also play an important role in the development of chronic rejection, either alone or in combination with HLA-DSAs. The synergistic effect between HLA-DSAs and antibodies to TaAgs is being established, but the underlying mechanism is yet to be defined. We hypothesize that HLA-DSAs damage the transplanted donor organ resulting in stress and leading to the release of extracellular vesicles, which contribute to chronic rejection. These vesicles express both donor human leukocyte antigen (HLA) and non-HLA TaAgs, which can activate antigen-presenting cells and lead to immune responses and development of antibodies to both donor HLA and non-HLA tissue-associated Ags. Extracellular vesicles (EVs) are released by cells under many circumstances due to both physiological and pathological conditions. Primarily employing clinical specimens obtained from human lung transplant recipients undergoing acute or chronic rejection, our group has demonstrated that circulating extracellular vesicles display both mismatched donor HLA molecules and lung-associated Ags (collagen-V and K-alpha 1 tubulin). This review focuses on recent studies demonstrating an important role of antibodies to tissue-associated Ags in the rejection of transplanted organs, particularly chronic rejection. We will also discuss the important role of extracellular vesicles released from transplanted organs in cross-talk between alloimmunity and autoimmunity to tissue-associated Ags after solid organ transplantation.

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“…Exosomes are dual-layer membrane vesicles which can contain HLA and lung self-antigens, adhesion and costimulatory molecules, MHC class II molecules, transcription factors, and 20S-proteasome. They are shed from allograft cells after lung injury and are highly efficient in presenting antigens to the immune system [100][101][102]. Exosomes have been shown to induce T-cell-mediated immune responses, and the induction and continuous release of exosomes from the allograft may stimulate the process of CLAD [21].…”

Section: Exosomesmentioning

confidence: 99%

Immune processes in the pathogenesis of chronic lung allograft dysfunction: identifying the missing pieces of the puzzle

et al. 2022

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Lung transplantation is the optimal treatment for selected patients with end-stage chronic lung diseases. However, chronic lung allograft dysfunction remains the leading obstacle to improved long-term outcomes. Traditionally, lung allograft rejection has been considered primarily as a manifestation of cellular immune responses. However, in reality, an array of complex, interacting and multifactorial mechanisms contribute to its emergence. Alloimmune-dependent mechanisms, including T-cell-mediated rejection and antibody-mediated rejection, as well as non-alloimmune injuries, have been implicated. Moreover, a role has emerged for autoimmune responses to lung self-antigens in the development of chronic graft injury. The aim of this review is to summarise the immune processes involved in the pathogenesis of chronic lung allograft dysfunction, with advanced insights into the role of innate immune pathways and crosstalk between innate and adaptive immunity, and to identify gaps in current knowledge.

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Circulating exosomes with lung self-antigens as a biomarker for chronic lung allograft dysfunction: A retrospective analysis

Cited by 25 publications

References 35 publications

Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction

Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction

Extracellular Vesicles Mediate Immune Responses to Tissue-Associated Self-Antigens: Role in Solid Organ Transplantations

Immune processes in the pathogenesis of chronic lung allograft dysfunction: identifying the missing pieces of the puzzle

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