Environmental exposures, epigenetic changes and the risk of lupus

Abstract

A dose-dependent combination of environmental exposures, estrogenic hormones and genetic predisposition is thought to be required for lupus to develop and flare, but how the environment modifies the immune system in genetically predisposed people is unclear. Current evidence indicates that environmental agents that inhibit DNA methylation can convert normal antigen-specific CD4+ T lymphocytes into autoreactive, cytotoxic, pro-inflammatory cells that are sufficient to cause lupus-like autoimmunity in animal models, and that the same changes in DNA methylation characterize CD4+ T cells from patients with active lupus. Environmental agents implicated in inhibiting T-cell DNA methylation include the lupus-inducing drugs procainamide and hydralazine, as well as diet, and agents causing oxidative stress, such as smoking, UV light exposure, and infections, which have been associated with lupus onset or disease activity. Other studies demonstrate that demethylated T cells cause only anti-DNA antibodies in mice lacking a genetic predisposition to lupus, but are sufficient to cause lupus-like autoimmunity in genetically predisposed mice and likely people, and that estrogens augment the disease. Collectively, these studies suggest that environmental agents that inhibit DNA methylation, together with lupus genes and estrogens or endocrine disruptors, combine in a dose-dependent fashion to cause lupus flares.

Keywords: Lupus; endocrine disruptors; environment; epigenetics; genetics; mercury; oxidative stress.

Figure 1. Genetic, epigenetic and hormonal interactions in lupus flares

Lupus develops when genetically predisposed people encounter environmental agents that trigger the flares. Any person can inherit from 0 to more than 76 lupus genes, making the genetic contribution variable from person to person (light shading indicates low genetic predisposition; dark shading indicates high genetic predisposition). Endogenous estrogen levels vary in women, as do exposure levels to endocrine disruptors (e.g., diethylstilbesterol, bisphenol-A, and some pesticides), which may provide another variable contribution to flares (low to high also indicated by shading). CD4+ T cell DNA demethylation, caused by certain drugs, diet and oxidative stress, provides a third variable contribution (similarly indicated by shading).