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Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers

X-linked Granulomatous Disease (XL-CGD) carriers were previously thought to be clinically healthy because random X-chromosome inactivation (XCI) allows approximately half of their phagocytes/monocytes to express functional gp91phox protein. This supports the NADPH oxidase activity necessary for the...

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Autores principales: Chiriaco, Maria, Salfa, Irene, Ursu, Giorgiana Madalina, Cifaldi, Cristina, Di Cesare, Silvia, Rossi, Paolo, Di Matteo, Gigliola, Finocchi, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229314/
https://www.ncbi.nlm.nih.gov/pubmed/34206017
http://dx.doi.org/10.3390/antiox10060891
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author Chiriaco, Maria
Salfa, Irene
Ursu, Giorgiana Madalina
Cifaldi, Cristina
Di Cesare, Silvia
Rossi, Paolo
Di Matteo, Gigliola
Finocchi, Andrea
author_facet Chiriaco, Maria
Salfa, Irene
Ursu, Giorgiana Madalina
Cifaldi, Cristina
Di Cesare, Silvia
Rossi, Paolo
Di Matteo, Gigliola
Finocchi, Andrea
author_sort Chiriaco, Maria
collection PubMed
description X-linked Granulomatous Disease (XL-CGD) carriers were previously thought to be clinically healthy because random X-chromosome inactivation (XCI) allows approximately half of their phagocytes/monocytes to express functional gp91phox protein. This supports the NADPH oxidase activity necessary for the killing of engulfed pathogens. Some XL-CGD carriers suffer from inflammatory and autoimmune manifestations as well as infections, although the skewed-XCI of a mutated allele is reported to be exclusively determinant for infection susceptibility. Indeed, immune dysregulation could be determined by dysfunctional non-phagocytic leukocytes rather than the percentage of functioning neutrophils. Here we investigated in a cohort of 12 X-CGD female carriers at a particular time of their life the gp91phox protein expression/function and how this affects immune cell function. We showed that 50% of carriers have an age-independent skewed-XCI and 65% of them have a misrepresented expression of the wild-type gene. The majority of carriers manifested immune dysregulation and GI manifestations regardless of age and XCI. Immunological investigations revealed an increase in CD19+ B cells, CD56bright-NK cell percentage, a slightly altered CD107a upregulation on CD4+ T cells, and reduced INFγ-production by CD4+ and CD8+ cells. Notably, we demonstrated that the residual level of ROS robustly correlates with INFγ-expressing T cells, suggesting a role in promoting immune dysregulation in carriers.
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spelling pubmed-82293142021-06-26 Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers Chiriaco, Maria Salfa, Irene Ursu, Giorgiana Madalina Cifaldi, Cristina Di Cesare, Silvia Rossi, Paolo Di Matteo, Gigliola Finocchi, Andrea Antioxidants (Basel) Article X-linked Granulomatous Disease (XL-CGD) carriers were previously thought to be clinically healthy because random X-chromosome inactivation (XCI) allows approximately half of their phagocytes/monocytes to express functional gp91phox protein. This supports the NADPH oxidase activity necessary for the killing of engulfed pathogens. Some XL-CGD carriers suffer from inflammatory and autoimmune manifestations as well as infections, although the skewed-XCI of a mutated allele is reported to be exclusively determinant for infection susceptibility. Indeed, immune dysregulation could be determined by dysfunctional non-phagocytic leukocytes rather than the percentage of functioning neutrophils. Here we investigated in a cohort of 12 X-CGD female carriers at a particular time of their life the gp91phox protein expression/function and how this affects immune cell function. We showed that 50% of carriers have an age-independent skewed-XCI and 65% of them have a misrepresented expression of the wild-type gene. The majority of carriers manifested immune dysregulation and GI manifestations regardless of age and XCI. Immunological investigations revealed an increase in CD19+ B cells, CD56bright-NK cell percentage, a slightly altered CD107a upregulation on CD4+ T cells, and reduced INFγ-production by CD4+ and CD8+ cells. Notably, we demonstrated that the residual level of ROS robustly correlates with INFγ-expressing T cells, suggesting a role in promoting immune dysregulation in carriers. MDPI 2021-06-01 /pmc/articles/PMC8229314/ /pubmed/34206017 http://dx.doi.org/10.3390/antiox10060891 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chiriaco, Maria
Salfa, Irene
Ursu, Giorgiana Madalina
Cifaldi, Cristina
Di Cesare, Silvia
Rossi, Paolo
Di Matteo, Gigliola
Finocchi, Andrea
Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers
title Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers
title_full Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers
title_fullStr Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers
title_full_unstemmed Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers
title_short Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers
title_sort immunological aspects of x-linked chronic granulomatous disease female carriers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229314/
https://www.ncbi.nlm.nih.gov/pubmed/34206017
http://dx.doi.org/10.3390/antiox10060891
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