Sex hormones have long been implicated in autoimmune diseases because women 
account for 80% of cases. The mechanism of hormonal action in autoimmunity is 
unknown. Drawing on genetic studies of autoimmune disease, this article 
discusses how both genes and sex hormones may exert their effects through the 
same general mechanism, dysregulation of transcription factor NF-kappaB, an 
immunoregulatory protein. Gene and hormone alterations of the NF-kappaB 
signaling cascade provide a unifying hypothesis to explain the wide-ranging 
human and murine autoimmune disease phenotypes regulated by NF-kappaB, including 
cytokine balance, antigen presentation, lymphoid development, and lymphoid 
repertoire selection by apoptosis.