Journal
ANTIOXIDANTS
Volume 10, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/antiox10060891
Keywords
chronic granulomatous disease (CGD); X-linked CGD carrier; reactive oxygen species (ROSs); nicotinamide dinucleotide phosphate oxidase (NADPH); dihydrorhodamine (DHR) assay; X-chromosome inactivation (XCI); immune dysregulation
Funding
- E-rare project EURO-CGD
- Italian Telethon Foundation [GGP15109]
- Children's Hospital Bambino Gesu
- [CELL-PID HEALTH-F5-2010-261387]
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XL-CGD carriers, previously thought to be clinically healthy due to random X-chromosome inactivation, may actually manifest immune dysregulation due to dysfunctional non-phagocytic leukocytes, with a potential correlation between residual ROS levels and immune dysregulation.
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 INF gamma-production by CD4+ and CD8+ cells. Notably, we demonstrated that the residual level of ROS robustly correlates with INF gamma-expressing T cells, suggesting a role in promoting immune dysregulation in carriers.
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