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A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients

BACKGROUND: Chronic kidney disease (CKD) patients present a complex interaction between the innate and adaptive immune systems, in which immune activation (hypercytokinemia and acute-phase response) and immune suppression (impairment of response to infections and poor development of adaptive immunit...

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Autores principales: Zaza, Gianluigi, Granata, Simona, Rascio, Federica, Pontrelli, Paola, Dell’Oglio, Maria Pia, Cox, Sharon Natasha, Pertosa, Giovanni, Grandaliano, Giuseppe, Lupo, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655909/
https://www.ncbi.nlm.nih.gov/pubmed/23663527
http://dx.doi.org/10.1186/1755-8794-6-17
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author Zaza, Gianluigi
Granata, Simona
Rascio, Federica
Pontrelli, Paola
Dell’Oglio, Maria Pia
Cox, Sharon Natasha
Pertosa, Giovanni
Grandaliano, Giuseppe
Lupo, Antonio
author_facet Zaza, Gianluigi
Granata, Simona
Rascio, Federica
Pontrelli, Paola
Dell’Oglio, Maria Pia
Cox, Sharon Natasha
Pertosa, Giovanni
Grandaliano, Giuseppe
Lupo, Antonio
author_sort Zaza, Gianluigi
collection PubMed
description BACKGROUND: Chronic kidney disease (CKD) patients present a complex interaction between the innate and adaptive immune systems, in which immune activation (hypercytokinemia and acute-phase response) and immune suppression (impairment of response to infections and poor development of adaptive immunity) coexist. In this setting, circulating uremic toxins and microinflammation play a critical role. This condition, already present in the last stages of renal damage, seems to be enhanced by the contact of blood with bioincompatible extracorporeal hemodialysis (HD) devices. However, although largely described, the cellular machinery associated to the CKD- and HD-related immune-dysfunction is still poorly defined. Understanding the mechanisms behind this important complication may generate a perspective for improving patients outcome. METHODS: To better recognize the biological bases of the CKD-related immune dysfunction and to identify differences between CKD patients in conservative (CKD) from those in HD treatment, we used an high-throughput strategy (microarray) combined with classical bio-molecular approaches. RESULTS: Immune transcriptomic screening of peripheral blood mononuclear cells (1030 gene probe sets selected by Gene-Ontology) showed that 275 gene probe sets (corresponding to 213 genes) discriminated 9 CKD patients stage III-IV (mean ± SD of eGFR: 32.27±14.7 ml/min) from 17 HD patients (p < 0.0001, FDR = 5%). Seventy-one genes were up- and 142 down-regulated in HD patients. Functional analysis revealed, then, close biological links among the selected genes with a pivotal role of PTX3, IL-15 (up-regulated in HD) and HLA-G (down-regulated in HD). ELISA, performed on an independent testing-group [11 CKD stage III-IV (mean ± SD of eGFR: 30.26±14.89 ml/min) and 13 HD] confirmed that HLA-G, a protein with inhibition effects on several immunological cell lines including natural killers (NK), was down-expressed in HD (p = 0.04). Additionally, in the testing-group, protein levels of CX3CR1, an highly selective chemokine receptor and surface marker for cytotoxic effector lymphocytes, resulted higher expressed in HD compared to CKD (p < 0.01). CONCLUSION: Taken together our results show, for the first time, that HD patients present a different immune-pattern compared to the un-dialyzed CKD patients. Among the selected genes, some of them encode for important biological elements involved in proliferation/activation of cytotoxic effector lymphocytes and in the immune-inflammatory cellular machinery. Additionally, this study reveals new potential diagnostic bio-markers and therapeutic targets.
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spelling pubmed-36559092013-05-17 A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients Zaza, Gianluigi Granata, Simona Rascio, Federica Pontrelli, Paola Dell’Oglio, Maria Pia Cox, Sharon Natasha Pertosa, Giovanni Grandaliano, Giuseppe Lupo, Antonio BMC Med Genomics Research Article BACKGROUND: Chronic kidney disease (CKD) patients present a complex interaction between the innate and adaptive immune systems, in which immune activation (hypercytokinemia and acute-phase response) and immune suppression (impairment of response to infections and poor development of adaptive immunity) coexist. In this setting, circulating uremic toxins and microinflammation play a critical role. This condition, already present in the last stages of renal damage, seems to be enhanced by the contact of blood with bioincompatible extracorporeal hemodialysis (HD) devices. However, although largely described, the cellular machinery associated to the CKD- and HD-related immune-dysfunction is still poorly defined. Understanding the mechanisms behind this important complication may generate a perspective for improving patients outcome. METHODS: To better recognize the biological bases of the CKD-related immune dysfunction and to identify differences between CKD patients in conservative (CKD) from those in HD treatment, we used an high-throughput strategy (microarray) combined with classical bio-molecular approaches. RESULTS: Immune transcriptomic screening of peripheral blood mononuclear cells (1030 gene probe sets selected by Gene-Ontology) showed that 275 gene probe sets (corresponding to 213 genes) discriminated 9 CKD patients stage III-IV (mean ± SD of eGFR: 32.27±14.7 ml/min) from 17 HD patients (p < 0.0001, FDR = 5%). Seventy-one genes were up- and 142 down-regulated in HD patients. Functional analysis revealed, then, close biological links among the selected genes with a pivotal role of PTX3, IL-15 (up-regulated in HD) and HLA-G (down-regulated in HD). ELISA, performed on an independent testing-group [11 CKD stage III-IV (mean ± SD of eGFR: 30.26±14.89 ml/min) and 13 HD] confirmed that HLA-G, a protein with inhibition effects on several immunological cell lines including natural killers (NK), was down-expressed in HD (p = 0.04). Additionally, in the testing-group, protein levels of CX3CR1, an highly selective chemokine receptor and surface marker for cytotoxic effector lymphocytes, resulted higher expressed in HD compared to CKD (p < 0.01). CONCLUSION: Taken together our results show, for the first time, that HD patients present a different immune-pattern compared to the un-dialyzed CKD patients. Among the selected genes, some of them encode for important biological elements involved in proliferation/activation of cytotoxic effector lymphocytes and in the immune-inflammatory cellular machinery. Additionally, this study reveals new potential diagnostic bio-markers and therapeutic targets. BioMed Central 2013-05-10 /pmc/articles/PMC3655909/ /pubmed/23663527 http://dx.doi.org/10.1186/1755-8794-6-17 Text en Copyright © 2013 Zaza et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Zaza, Gianluigi
Granata, Simona
Rascio, Federica
Pontrelli, Paola
Dell’Oglio, Maria Pia
Cox, Sharon Natasha
Pertosa, Giovanni
Grandaliano, Giuseppe
Lupo, Antonio
A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients
title A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients
title_full A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients
title_fullStr A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients
title_full_unstemmed A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients
title_short A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients
title_sort specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655909/
https://www.ncbi.nlm.nih.gov/pubmed/23663527
http://dx.doi.org/10.1186/1755-8794-6-17
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