The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies

Abstract

Despite recent progress in the understanding of systemic lupus erythematosus (SLE), the striking 9:1 female to male ratio of disease incidence remains largely unexplained. In addition, peak SLE incidence rates occur during the early reproductive years in women. Studies which illuminate potential causes underlying this sex difference and characteristic onset during the reproductive years have the potential to fundamentally advance our understanding of disease pathogenesis in SLE. Similarly, progress in this area will likely inform human reproductive immunology. Studies of sex hormone function in the immune system are of obvious importance; however, it seems likely that many other types of sex-related genetic and immunological differences will contribute to SLE. In this review, we will focus on recent work in sex-related differences in cytokine pathways and genetics of these pathways as they relate to SLE pathogenesis. It seems quite possible that many of these sex-related differences could be important to reproductive fitness, which may explain the conservation of these immune system features and the observed female predominance of SLE.

Fig. 1

IFN-α levels and age of onset of SLE. Average serum IFN-α levels by age in a large SLE cohort stratified by sex [22] are shown overlaid upon data regarding the sex-specific age of SLE incidence from a different large population-based study [5]. Serum IFN-α levels seem to correlate with age of SLE onset, as age ranges with higher levels of IFN-α correspond to age ranges of greater SLE incidence. Additionally, there is a time lag for both disease onset and peak serum IFN-α level in men as compared with women. The lines representing average serum IFN-α levels in SLE patients are drawn to approximate the patterns observed in [22], and the bars on the bar graph represent the number of incident SLE cases by age group on the Y axis in the study by Lopez et al. as detailed in [5]