The role of X-chromosome inactivation in female predisposition to autoimmunity

A reduction in the sex ratio (male : female) is characteristic of most autoimmune disorders. The increased prevalence in females ranges from a modest 2:1 for multiple sclerosis [ 1 ], to approximately 10:1 for systemic lupus erythematosus [ 2 ]. This tendency towards autoimmunity in females is often ascribed to hormonal differences because, in a number of experimental disease models, estrogens exacerbate disease and androgens can inhibit disease activity [ 3 , 4 ]. However, human studies have failed to demonstrate a clear-cut influence of hormonal environment on disease susceptibility to lupus or other autoimmune disorders. In addition, many childhood forms of autoimmunity, such as juvenile rheumatoid arthritis, exhibit female predominance [ 5 ]. Interestingly, juvenile (type 1) diabetes is an exception to this general trend, with a sex ratio close to 1 in most studies [ 6 ]. Therefore, it is reasonable to consider alternative explanations for the increased prevalence of autoimmune diseases in human females.