Is autoimmunity a matter of sex?

Autoimmune diseases include several conditions that cumulatively are estimated to affect over 5% of the US population with a striking female predominance reported for most of them. The cause and mechanisms of this sex bias remains unknown despite multiple proposed hypotheses. Indeed, it is well established in several experimental settings that the human immune system exhibits sexual dimorphism with basic immune responses differing between females and males. Among candidate factors to explain these differences we note that particular attention has been primarily devoted to sex hormones, yet data have been inconclusive or have not been confirmed. The same seems to apply to the hypothesis of fetal microchimerism. Most recently, sex chromosome abnormalities and skewed X chromosome inactivation have been suggested as novel players, particularly in later-onset diseases. We review herein the most recent data on the mechanisms proposed for the female predominance. We also attempt to determine whether observed sex ratios are in fact the result of sex-biased awareness in case-finding studies.