Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

• Published in: International journal of molecular sciences 2021-01, Vol.22 (3), p.1114
• Main Authors: Youness, Ali, Miquel, Charles-Henry, Guéry, Jean-Charles
• Format: Article
• Language: English
• Subjects: Adaptive systems; Animals; Autoimmune diseases; Autoimmune Diseases / genetics; Chromosomes; Chromosomes, Human, X; Cytokines; Dendritic cells; Disease; Embryogenesis; Embryos; Estrogens; Female; Females; Functional plasticity; Gene dosage; Gene expression; Genes; Genetic factors; Histone Demethylases / genetics; Histone Demethylases / immunology; Histone Demethylases / metabolism; Hormones; Humans; Immune system; Immunity / genetics; Immunology; Infections; Intracellular Signaling Peptides and Proteins / genetics; Intracellular Signaling Peptides and Proteins / immunology; Life Sciences; Lupus; Male; Males; Mosaicism; Mutation; Pathogenesis; Pathogens; Polymorphism, Single Nucleotide; Review; RNA, Long Noncoding / genetics; RNA, Long Noncoding / immunology; Scleroderma; sex bias; Sex chromosomes; Sex hormones; Steroid hormones; Steroids; systemic lupus erythematosus; Testes; Toll-Like Receptor 7 / genetics; Womens health; X chromosome inactivation; X chromosomes; Y chromosomes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22031114

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.