Recent advances and opportunities in research on lupus: environmental influences and mechanisms of disease

Abstract

Objectives: In 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 synthesis: We 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.

Conclusions: The 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.

Keywords: Epstein-Barr virus; adjuvant effect; apoptosis; autoimmune diseases; bystander effect; demethylation; epigenetics; silica; systemic lupus erythematosus; trichloroethylene.

Figure 1

Mechanisms involved in the loss of self-tolerance and development of autoimmune pathology. Activation of innate immune effectors as a danger signal, adjuvant effects, and a decreased clearance of autoreactive cells produce a sustained pathogenic response to the self-antigens that may result from apoptotic debris. Abnormal DNA methylation may also result in increased production and decreased clearance of apoptotic cells through macrophage apoptosis, and overstimulation of B cells.

Figure 2

Putative roles for EBV in the initiation and propagation of SLE. Supportive evidence is available for direct effects (e.g., molecular mimicry with production cross-reactive antibodies) and indirect effects (e.g., bystander effects, inappropriate cytokine production, or gene expression).

Figure 3

Possible immune-related effects of silica in relation to SLE pathogenesis. Apoptosis of macrophages needed for efficient clearance of debris, along with proinflammatory cytokines, results in uptake of apoptotic debris by activated APCs. The self-antigen may be altered structurally or spatially by oxidative stress. Inflammation helps drive both fibrosis and autoimmunity, resulting in reciprocal exacerbation.