Basic Science
Abstract #1972: Women and Lupus: The Inactive X Awakens
Authors: Qianjin Lu, Laura Tesmer, Ailing Wu, Donna Ray, Bruce Richardson. Second Xiangya Hospital of Central South University, Changsha, China; University of Michigan, Ann Arbor, MI
Objective: That SLE predominantly affects women has been known for many years, but has thus far eluded a convincing explanation. The authors of this study wondered if an epigenetic mechanism thought to contribute to some cases of drug-induced lupus (gene inactivation due to DNA demethylation) might be involved in augmenting immune responses via activation on the “inactive” X chromosome of certain immune response genes like CD40L, a molecule known to be involved in SLE pathogenesis.
Methods: DNA methylation patterns were determined biochemically using T cells from healthy men and women, and from lupus patients. The amount of T cell derived CD40 ligand was determined by real-time PCR and flow cytometry. In vitro demethylation assays using the chemical 5-azacytidine were performed as well.
Results: The CD40L promoter region was noted to be unmethylated in men, and 50% methylated in women. In vitro demethylation of CD40L in T cells from women, but not men, resulted in increased CD40L expression. Strikingly, in all 8 female lupus patients that were examined, decreases in baseline methylation were observed over that seen in healthy women (25% vs. 42%). This correlated with an increase in CD40L activity in these patients which correlated with disease activity.
Significance: This abstract, presented at the 3rd plenary session at the meeting, presents a completely novel and fascinating hypothesis to explain the long-observed gender differences in human SLE. The concept that demethylation-induced activation of an immune response gene found on the “inactive” X chromosome might explain the increased levels of CD40L seen in women with SLE is interesting. It also might explain why men with SLE (who by definition have only 1 X chromosome) often have a more severe phenotype; with all of their CD40L unmethylated at baseline, their T cell activation thresholds might be lower under certain circumstances. All of this clearly needs to be substantiated in larger studies and other important SLE-associated genes need to be examined for methylation patterns as well.
