The sex bias in systemic sclerosis: on the possible mechanisms underlying the female disease preponderance

Systemic sclerosis is a multifactorial and heterogeneous disease. Genetic andenvironmental factors are known to interplay in the onset and progression ofsystemic sclerosis. Sex plays an important and determinant role in thedevelopment of such a disorder. Systemic sclerosis shows a significant femalepreponderance. However, the reason for this female preponderance is incompletely understood. Hormonal status, genetic and epigenetic differences, and lifestylehave been considered in order to explain female preponderance in systemicsclerosis. Sex chromosomes play a determinant role in contributing to systemicsclerosis onset and progression, as well as in its sex-biased prevalence. It isknown, in fact, that X chromosome contains many sex- and immuno-related genes,thus contributing to immuno tolerance and sex hormone status. This review focusesmainly on the recent progress on epigenetic mechanisms--exclusively linked to theX chromosome--which would contribute to the development of systemic sclerosis.Furthermore, we report also some hypotheses (dealing with skewed X chromosomeinactivation, X gene reactivation, acquired monosomy) that have been proposed in order to justify the female preponderance in autoimmune diseases. However,despite the intensive efforts in elucidating the mechanisms involved in thepathogenesis of systemic sclerosis, many questions remain still unanswered.