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Systemic lupus erythematosus (SLE), along with systemic sclerosis and Sjogren’s disease, is marked by a striking female predominance, with women representing at least 90% of patients1. Incidence rates for SLE among African-American women peak in the reproductive years (i.e., ages 20–40)2,3, but in other populations, the highest age-specific incidence rates occur after age 40 years4–6. What accounts for this female predominance in these specific diseases? Scientific focus on X- or Y- chromosome genes and on the role of estrogen and testosterone in immune response in animals7 has evolved and expanded during the past 20 years to include DNA methylation and epigenetic alteration of gene expression8. One potential sex-mediated mechanism involves CD40L overexpression, which can occur only in women since CD40L is encoded on the X chromosome9. This type of genetic and molecular research offers promising avenues for understanding the etiology of systemic autoimmune diseases and the development of new therapies. Additional insights into disease risk and pathogenesis can also be gained from an epidemiologic perspective, focusing on the experiences of individuals and populations.In this issue, Ulff-Moller, et al examine the influence of pregnancy and pregnancy outcomes on the risk of SLE10. This cohort study encompasses the entire population of Denmark (about 4.4 million), with a 30-year followup period (1974–2004). The classification of SLE for the purpose of this study was based on a national database … Address correspondence to G.S. Cooper; E-mail: cooper.glinda{at}epa.gov The views expressed in this article are those of the author and do not necessarily reflect the views or policies of the US Environmental Protection Agency.

Unraveling the Etiology of Systemic Autoimmune Diseases: Peering into the Preclinical Phase of Disease