Grantee Research Project Results

2001 Progress Report: Mechanism(s) of Chloroethylene-Induced Autoimmunity

EPA Grant Number: R826409
Title: Mechanism(s) of Chloroethylene-Induced Autoimmunity
Investigators: Pumford, Neil R. , Gilbert, Kathleen M.
Institution: University of Arkansas for Medical Sciences , University of Arkansas
EPA Project Officer: Aja, Hayley
Project Period: March 25, 1998 through March 24, 2001
Project Period Covered by this Report: March 25, 2000 through March 24, 2001
Project Amount: $374,384
RFA: Exploratory Research - Human Health (1997) RFA Text | Recipients Lists
Research Category: Human Health

Objective:

The overall estimation for the number of people afflicted with autoimmune diseases in the United States exceeds 8.5 million, or approximately 1 in every 31 Americans. The development of autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma) is believed to be multifactorial, involving both genetic and environmental components. Chemical exposures may be a major environmental influence on the development of autoimmune diseases. There is ample evidence supporting an association of chlorinated ethylenes with life-threatening autoimmune disorders such as systemic lupus erythematosus and scleroderma; however, the mechanisms by which chlorinated ethylenes cause autoimmunity are unknown.

We hypothesize that chlorinated ethylenes are metabolized to reactive intermediates that initiate an autoimmune response. The autoimmune response involves the activation of CD4⁺ T-cells that are stimulated by either a specific response against the chlorinated ethylene-modified proteins, or a nonspecific response initiated through the release of serum factors, such as cytokines, growth factors, or unidentified factors. Either pathway will result in the activation of T-cells, which can lead to the development of inflammation.

We have shown previously that chronic exposure to trichloroethylene (TCE) in the water supply at levels commensurate with occupational exposure can promote the development of autoimmune disease (lupus and autoimmune hepatitis) in MRL+/+ mice. TCE-induced autoimmunity was accompanied by the expansion of activated CD4⁺ T-cells secreting increased levels of IFN-g.

Progress Summary:

Because TCE metabolism is required to promote autoimmunity, we investigated whether the immunoregulatory effects of TCE was mediated by one of its major metabolites, trichloroacetaldehyde (TCA). TCA costimulated the proliferation of murine Th1 cells in vitro. In addition to memory T-cells, TCA also activated naïve T-cells, stimulating expression of activation markers on CD4⁺ T-cells from MRL+/+ mice. TCA's stimulatory effects were associated with the formation of a Schiff base on T-cell surface proteins. It is hypothesized that Schiff base formation on T-cells nonspecifically stimulates T-cells, leading to autoimmune disease.

Future Activities:

Grants will be submitted for further funding to both the U.S. Environmental Protection Agency and the National Institutes of Health.

Journal Articles on this Report : 1 Displayed | Download in RIS Format

Publications Views
Other project views:	All 21 publications	6 publications in selected types	All 6 journal articles

Publications
Type	Citation	Project	Document Sources
Journal Article	Griffin JM, Gilbert KM, Lamps LW, Pumford NR. CD4+ T-cell activation and induction of autoimmune hepatitis following trichloroethylene treatment in MRL+/+ mice. Toxicological Sciences, 2000;57(2):345-352.	R826409 (2001) R826409 (Final)	not available

Supplemental Keywords:

volatile organic compounds, VOC, intermediates, metabolism, human health, genetic predisposition, sensitive populations, susceptibility., Health, RFA, Scientific Discipline, Waste, Toxics, Hazardous, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Risk Assessment, Risk Assessments, genetic susceptability, Environmental Chemistry, 33/50, Hazardous Waste, Environmental Microbiology, VOCs, Biochemistry, Disease & Cumulative Effects, Genetics, health effects, scleroderma, chlorinated ethylenes, cytokines, environmental hazard exposures, genetic predisposition, metabolism, sensitive populations, autoimmune diseases, chloroethylenes, immune response, cytochrome P450, Lymphocytes, Tetrachloroethylene, Trichloroethylene, air emissions, human exposure, rheumatoid arthritis, chloroethylene autoimmunity, effects assessment, groundwater, lupus erythematosus, exposure, Vinyl chloride, autoimmunity, air contaminant exposure, environmentally caused disease, gene-environment interaction, occupational exposure, human susceptibility, biomarkers, exposure assessment, chemical releases

Progress and Final Reports:

Original Abstract

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.