Glinda S. Cooper,1 Kathleen M. Gilbert,2 Eric L. Greidinger,3 Judith A. James,4 Jean C. Pfau,5 Leslie Reinlib,6 Bruce C. Richardson,7 and Noel R. Rose8
1National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, USA; 2Department of Microbiology and Immunology, University of Arkansas for Medical Sciences/Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, USA; 3Division of Rheumatology, University of Miami Miller School of Medicine, Miami Department of Veterans Affairs Medical Center, Miami, Florida, USA; 4Arthritis and Immunology Program, Oklahoma Medical Research Foundation, and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; 5Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana, USA; 6Division of Extramural Research and Training, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; 7University of Michigan and Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA; 8Department of Pathology, Johns Hopkins Center for Autoimmune Disease Research, Johns Hopkins University, Baltimore, Maryland, USA
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.
Key words: adjuvant effect, apoptosis, autoimmune diseases, bystander effect, demethylation, epigenetics, Epstein-Barr virus, silica, systemic lupus erythematosus, trichloroethylene. Environ Health Perspect 116:695–702 (2008) . doi:10.1289/ehp.11092 available via http://dx.doi.org/ [Online 5 March 2008]
