Autoimmunity in women: an eXamination of eXisting models

Abstract

Women comprise over 80% of the affected individuals for many autoimmune conditions. Although sex-specific differences in sex hormones are thought to contribute to the female predisposition to autoimmunity, emerging evidence also suggests an intriguing role of both physiological and dysregulated X-chromosome inactivation. Furthermore, recent studies have demonstrated that many immune genes encoded on the X chromosome are expressed biallelically, and the contribution of these sex-specific differences in immune gene dosage to autoimmunity remains to be fully explored. This review highlights recent developments in this field and discusses questions that remain unanswered.

Keywords: Autoimmune disease; Female predilection; Sex disparity; X-chromosome inactivation.

Figure 1.. X chromosome inactivation and X-linked immune genes.

During development, in female cells, X-chromosome inactivation occurs randomly for one of the two X chromosomes, which equalizes the dosage of gene products from the X chromosome between females (XX) and males (XY). Each X chromosome has an equal probability of being silenced. Once established, inactivation of the X chromosome is stable, and perpetuates throughout subsequent division of the daughter cells. Through this process, each female is a mosaic of cells, composed of cells where either the maternally or paternally inherited X is expressed, and the other inherited X is silenced.

Figure 2.. The X chromosome has a high density of immunity-related genes.

Genes from the gene ontology terms GO_REGULATION_OF_IMMUNE_SYSTEM_PROCESS and GO_IMMUNE_RESPONSE that are located on the X chromosome are shown. The genes highlighted in blue have been linked to inherited immune disorders including immunodeficiencies.

Figure 3.. Models of skewed X-chromosome inactivation and reactivation.

In female cells, either the maternal (pink) or paternal (blue) X chromosome is randomly inactivated. Early in development, each cell has two active X chromosomes (gray). (A) Normal XCI is random, res ulting in a 1:1 ratio of cells expressing a maternal or paternal X chromosome. (B) Nonrandom X-inactivation can be primary and arise simply by chance or due to a genetic predisposition, resulting in the preferential inactivation of either the maternal or paternal X. (C) Secondary nonrandom X-inactivation occurs when an X-linked mutation affects cell fitness and inactivation of the mutated allele results in a fitness cost. Though random XCI may have initially occurred, one may find a greater proportion of the cells inactivating the X chromosome associated with the disease allele, through a form of selection in some tissues. (D) Additionally, following random X-inactivation, some cells, notably naive lymphocytes, have been found to reactivate the Xi, expressing both the maternal and paternal X chromosome (purple). A number of genes have also been described to escape X-inactivation and are thus biallelically expressed (inset).