Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers

• Published in: Antioxidants Vol. 10; no. 6; p. 891
• Main Authors: Chiriaco, Maria, Salfa, Irene, Ursu, Giorgiana Madalina, Cifaldi, Cristina, Di Cesare, Silvia, Rossi, Paolo, Di Matteo, Gigliola, Finocchi, Andrea
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.06.2021; MDPI
• Subjects: Age; Asymptomatic; CD19 antigen; CD4 antigen; CD8 antigen; Chronic granulomatous disease; chronic granulomatous disease (CGD); Cytokines; Data analysis; dihydrorhodamine (DHR) assay; Disease; Ethics; Females; Genes; Infections; Inflammation; Inflammatory bowel disease; Investigations; Leukocytes (neutrophilic); Lupus; Lymphocytes B; Lymphocytes T; Middle age; Monocytes; Mutation; NAD(P)H oxidase; Natural killer cells; Neutrophils; nicotinamide dinucleotide phosphate oxidase (NADPH); Pathogens; Phagocytes; Protein expression; Proteins; reactive oxygen species (ROSs); Software; X chromosomes; X-chromosome inactivation; X-chromosome inactivation (XCI); X-linked CGD carrier; Young adults; United States > US
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox10060891

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.