Environmental chemicals are implicated as causative agents of autoimmune diseases (ADs). Our long-term goal is to elucidate the role of lipid peroxidation-derived aldehydes (LPDAs) and reactive nitrogen species (RNS) in the development of ADs induced and/or exacerbated by chemical exposure. Increased production of reactive oxygen and nitrogen species (RONS) has been implicated in the pathogenesis of ADs, and a large number of chemicals are known to produce RONS. Correspondingly, increased lipid peroxidation and protein nitration are also reported in systemic ADs. We hypothesize that increased production of LPDAs and RNS causes structural alterations to endogenous macromolecules, including proteins, through covalent binding and/or oxidation, resulting in the formation of neoantigens. Following antigen processing, these neoantigens can elicit autoimmune responses by stimulating T and B lymphocytes, eventually leading to ADs such as systemic lupus erythematosus (SLE). This hypothesis will be tested through four specific aims to: 1) Delineate the link between oxidative stress and autoimmunity. This will be achieved by exposing autoimmune-prone (MRL+/+) and -resistant (B6C3F1) mice to trichloroethene (TCE, an environmental chemical known to cause lipid peroxidation/RNS). Formation of LPDA-protein adducts (in liver, kidney and spleen) and their corresponding antibodies will be correlated with autoimmune response. The role of oxidative stress in autoimmunity will be further established through iron overload, N-acetylcysteine administration and use of CYP2E1 knockout MRL +/+ mice;2) Establish the role of RNS induced by TCE in autoimmunity. Using iNOS inhibitors and iNOS knockout MRL +/+ mice, we will evaluate the potential of RNS in leading to autoimmunity;3) Elucidate the mechanism(s) of autoimmunity resulting from lipid peroxidation. Utilizing LPDA-protein adducts, the role of T cells in autoimmunity will be elucidated;4) Define oxidative/nitrosative stress signature in the sera of SLE patients. Using sera from SLE patients, a link between oxidative stress markers and disease progression will be established. Our studies should establish oxidative stress as a pathogenic mechanism of ADs, and open important avenues for clinical intervention and medical surveillance through the development of disease markers, and will provide an avenue for mechanism-based risk assessment. Relevance to Public Health: Autoimmune diseases are serious pathological conditions with unknown cause. Our goal is to elucidate the role of oxidative and nitrosative stress in the development of such diseases. The results of this study will provide important insight into the prevention and management of such diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES016302-05S1
Application #
8597487
Study Section
Special Emphasis Panel (ZRG1-DIG-F (02))
Program Officer
Humble, Michael C
Project Start
2007-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$225,000
Indirect Cost
$75,993
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Fan, Xiuzhen; Wang, Gangduo; English, Robert D et al. (2014) Proteomic identification of carbonylated proteins in the kidney of trichloroethene-exposed MRL+/+ mice. Toxicol Mech Methods 24:21-30
Wang, Gangduo; Wang, Jianling; Luo, Xuemei et al. (2014) Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity. PLoS One 9:e98660
Wang, Gangduo; Wang, Jianling; Ma, Huaxian et al. (2013) N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress. Toxicol Appl Pharmacol 273:189-95
Wang, Gangduo; Wang, Jianling; Fan, Xiuzhen et al. (2012) Protein adducts of malondialdehyde and 4-hydroxynonenal contribute to trichloroethene-mediated autoimmunity via activating Th17 cells: dose- and time-response studies in female MRL+/+ mice. Toxicology 292:113-22
Wang, Gangduo; Pierangeli, Silvia S; Papalardo, Elizabeth et al. (2010) Markers of oxidative and nitrosative stress in systemic lupus erythematosus: correlation with disease activity. Arthritis Rheum 62:2064-72
Wang, Gangduo; Wang, Jianling; Ma, Huaxian et al. (2009) Increased nitration and carbonylation of proteins in MRL+/+ mice exposed to trichloroethene: potential role of protein oxidation in autoimmunity. Toxicol Appl Pharmacol 237:188-95
Wang, Gangduo; Konig, Rolf; Ansari, G A S et al. (2008) Lipid peroxidation-derived aldehyde-protein adducts contribute to trichloroethene-mediated autoimmunity via activation of CD4+ T cells. Free Radic Biol Med 44:1475-82
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