Recent Advances and Opportunities in Research on Lupus: Environmental Influences and Mechanisms of Disease

Abstract

ObjectivesIn this review we summarize research on mechanisms through which environmental agents may affect the pathogenesis of lupus, discuss three exposures that have been the focus of research in this area, and propose recommendations for new research initiatives.Data sources and synthesisWe examined studies pertaining to key mechanistic events and specific exposures. Apoptosis leading to increased production or decreased clearance of immunogenic intracellular self-antigens and defective apoptosis of autoreactive immune cells both have been implicated in the loss of self-tolerance. The adjuvant or bystander effect is also needed to produce a sustained autoimmune response. Activation of toll-like receptors is one mechanism through which these effects may occur. Abnormal DNA methylation may also contribute to the pathogenesis of lupus. Each of the specific exposures we examined—Epstein-Barr virus, silica, and trichloroethylene—has been shown, in humans or in mice, to act upon one or more of these pathogenic steps. Specific recommendations for the continued advancement of our understanding of environmental influences on lupus and other autoimmune diseases include the development and use of mouse models with varying degrees of penetrance and manifestations of disease, identification of molecular or physiologic targets of specific exposures, development and use of improved exposure assessment methodologies, and multisite collaborations designed to examine understudied environmental exposures in humans.ConclusionsThe advances made in the past decade concerning our understanding of mechanisms involved in the development of lupus and the influence of environmental agents on this process provide a strong foundation for further developments in this field.

Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus

“…In addition, anti-Ro60 antibodies are considered pathogenic in cutaneous and neonatal lupus (5–7). Among extrinsic factors, infectious agents such as viruses have been implicated in the pathogenesis of lupus either as innate stimuli, cross-reactive agents, or sources for exogenous nucleic acids that promote flares (50). The constant triggers of this lifelong disease remain elusive, particularly in those individuals without any evidence of pathogenic infection.…”

Erionite induces production of autoantibodies and IL-17 in C57BL/6 mice

“…When macrophages internalize erionite and asbestos fibers, they tend to produce reactive oxygen species (ROS) (Carbone et al 2012; Hogg et al 1996), which contribute to carcinogenicity and may also play a role in the pathogenesis of autoimmune diseases. The oxygen radicals may alter self-antigens in a way that causes the immune system to lose self-tolerance and mount an attack on those antigens (Cooper et al 2008). Erionite treatment for 48 hr caused a decrease in BMDM survival in cell culture similar to other fibers, but only a slight decrease was seen at the experimental concentration of 35 μg/cm 2 .…”

Bisphenol A (BPA) stimulates the interferon signaling and activates the inflammasome activity in myeloid cells

“…BPA, an environmental estrogen and an endocrine disruptor, is widely used in the manufacture of polycarbonate plastics and epoxy resins found in food containers (Rao and Richardson, 1999; Melnick et al, 2002; vom Saal, 2007; Cooper et al, 2008). Human exposure to the BPA occurs through a variety of sources by consumption of contaminated food and drinking waters.…”

“…However, in European waters, the levels are estimated to be 3-times higher (up to 40 nM) (Rogers et al, 2013). BPA-induced signaling in cells involves estrogen receptors (ERs)-dependent and independent mechanisms (Rao and Richardson, 1999; vom Saal, 2007; Cooper et al, 2008; Rogers et al, 2013). ERs-dependent signaling modulates the transcription of ER-responsive genes (Melnick et al, 2002; vom Saal, 2007; Rogers et al, 2013).…”