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


METHODS
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.
National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC 20460, USA. cooper.glinda@epa.gov
Glinda S
GS
Cooper
Kathleen M
KM
Gilbert
Eric L
EL
Greidinger
Judith A
JA
James
Jean C
JC
Pfau
Leslie
L
Reinlib
Bruce C
BC
Richardson
Noel R
NR
Rose
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D019175:DNA Methylation; D004781:Environmental Exposure / Q000009:adverse effects*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D008954:Models, Biological; D052638:Particulate Matter / Q000009:adverse effects; D014777:Virus Diseases / Q000150:complications
D052638:Particulate Matter