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Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology
Kidney transplant injury processes are associated with molecular changes in kidney tissue, primarily related to immune cell activation and infiltration. How these processes are reflected in the circulating immune cells, whose activation is targeted by strong immunosuppressants, is poorly understood....
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231008/ https://www.ncbi.nlm.nih.gov/pubmed/35526671 http://dx.doi.org/10.1016/j.kint.2022.03.026 |
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author | Van Loon, Elisabet Lamarthée, Baptiste de Loor, Henriette Van Craenenbroeck, Amaryllis H. Brouard, Sophie Danger, Richard Giral, Magali Callemeyn, Jasper Tinel, Claire Cortés Calabuig, Álvaro Koshy, Priyanka Sprangers, Ben Kuypers, Dirk Gwinner, Wilfried Anglicheau, Dany Marquet, Pierre Naesens, Maarten |
author_facet | Van Loon, Elisabet Lamarthée, Baptiste de Loor, Henriette Van Craenenbroeck, Amaryllis H. Brouard, Sophie Danger, Richard Giral, Magali Callemeyn, Jasper Tinel, Claire Cortés Calabuig, Álvaro Koshy, Priyanka Sprangers, Ben Kuypers, Dirk Gwinner, Wilfried Anglicheau, Dany Marquet, Pierre Naesens, Maarten |
author_sort | Van Loon, Elisabet |
collection | PubMed |
description | Kidney transplant injury processes are associated with molecular changes in kidney tissue, primarily related to immune cell activation and infiltration. How these processes are reflected in the circulating immune cells, whose activation is targeted by strong immunosuppressants, is poorly understood. To study this, we analyzed the molecular alterations in 384 peripheral blood samples from four European transplant centers, taken at the time of a kidney allograft biopsy, selected for their phenotype, using RNA-sequencing. In peripheral blood, differentially expressed genes in 136 rejection and 248 no rejection samples demonstrated upregulation of glucocorticoid receptor and nucleotide oligomerization domain-like receptor signaling pathways. Pathways enriched in antibody-mediated rejection (ABMR) were strongly immune-specific, whereas pathways enriched in T cell-mediated rejection were less immune related. In polyomavirus infection, upregulation of mitochondrial dysfunction and interferon signaling pathways was seen. Next, we integrated the blood results with transcriptomics of 224 kidney allograft biopsies which showed consistently upregulated genes per phenotype in both blood and biopsy. In single-cell RNASeq (scRNASeq) analysis of seven kidney allograft biopsies, the consistently overexpressed genes in ABMR were mostly expressed by infiltrating leukocytes in the allograft. Similarly, in peripheral blood scRNASeq analysis, these genes were overexpressed in ABMR in immune cell subtypes. Furthermore, overexpression of these genes in ABMR was confirmed in independent cohorts in blood and biopsy. Thus, our results highlight the immune activation pathways in peripheral blood leukocytes at the time of kidney allograft pathology, despite the use of current strong immunosuppressants, and provide a framework for future therapeutic interventions. |
format | Online Article Text |
id | pubmed-9231008 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-92310082022-07-01 Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology Van Loon, Elisabet Lamarthée, Baptiste de Loor, Henriette Van Craenenbroeck, Amaryllis H. Brouard, Sophie Danger, Richard Giral, Magali Callemeyn, Jasper Tinel, Claire Cortés Calabuig, Álvaro Koshy, Priyanka Sprangers, Ben Kuypers, Dirk Gwinner, Wilfried Anglicheau, Dany Marquet, Pierre Naesens, Maarten Kidney Int Clinical Investigation Kidney transplant injury processes are associated with molecular changes in kidney tissue, primarily related to immune cell activation and infiltration. How these processes are reflected in the circulating immune cells, whose activation is targeted by strong immunosuppressants, is poorly understood. To study this, we analyzed the molecular alterations in 384 peripheral blood samples from four European transplant centers, taken at the time of a kidney allograft biopsy, selected for their phenotype, using RNA-sequencing. In peripheral blood, differentially expressed genes in 136 rejection and 248 no rejection samples demonstrated upregulation of glucocorticoid receptor and nucleotide oligomerization domain-like receptor signaling pathways. Pathways enriched in antibody-mediated rejection (ABMR) were strongly immune-specific, whereas pathways enriched in T cell-mediated rejection were less immune related. In polyomavirus infection, upregulation of mitochondrial dysfunction and interferon signaling pathways was seen. Next, we integrated the blood results with transcriptomics of 224 kidney allograft biopsies which showed consistently upregulated genes per phenotype in both blood and biopsy. In single-cell RNASeq (scRNASeq) analysis of seven kidney allograft biopsies, the consistently overexpressed genes in ABMR were mostly expressed by infiltrating leukocytes in the allograft. Similarly, in peripheral blood scRNASeq analysis, these genes were overexpressed in ABMR in immune cell subtypes. Furthermore, overexpression of these genes in ABMR was confirmed in independent cohorts in blood and biopsy. Thus, our results highlight the immune activation pathways in peripheral blood leukocytes at the time of kidney allograft pathology, despite the use of current strong immunosuppressants, and provide a framework for future therapeutic interventions. Elsevier 2022-07 /pmc/articles/PMC9231008/ /pubmed/35526671 http://dx.doi.org/10.1016/j.kint.2022.03.026 Text en © 2022 International Society of Nephrology. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Clinical Investigation Van Loon, Elisabet Lamarthée, Baptiste de Loor, Henriette Van Craenenbroeck, Amaryllis H. Brouard, Sophie Danger, Richard Giral, Magali Callemeyn, Jasper Tinel, Claire Cortés Calabuig, Álvaro Koshy, Priyanka Sprangers, Ben Kuypers, Dirk Gwinner, Wilfried Anglicheau, Dany Marquet, Pierre Naesens, Maarten Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology |
title | Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology |
title_full | Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology |
title_fullStr | Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology |
title_full_unstemmed | Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology |
title_short | Biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology |
title_sort | biological pathways and comparison with biopsy signals and cellular origin of peripheral blood transcriptomic profiles during kidney allograft pathology |
topic | Clinical Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231008/ https://www.ncbi.nlm.nih.gov/pubmed/35526671 http://dx.doi.org/10.1016/j.kint.2022.03.026 |
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