Lipid peroxidation-derived aldehyde–protein adducts contribute to trichloroethene-mediated autoimmunity via activation of CD4+ T cells

Abstract

Lipid peroxidation is implicated in the pathogenesis of various autoimmune diseases. Lipid peroxidation-derived aldehydes (LPDAs) such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are highly reactive and bind to proteins, but their role in eliciting an autoimmune response and contribution to disease pathogenesis remains unclear. To investigate the role of lipid peroxidation in the induction and/or exacerbation of autoimmune response, 6-week-old autoimmune-prone female MRL +/+ mice were treated for 4 weeks with trichloroethene (TCE; 10 mmol/kg, i.p., once a week), an environmental contaminant known to induce lipid peroxidation. Sera from TCE-treated mice showed significant levels of antibodies against MDA-and HNE-adducted proteins along with antinuclear antibodies. This suggested that TCE exposure not only caused increased lipid peroxidation, but also accelerated autoimmune responses. Furthermore, stimulation of cultured splenic lymphocytes from both control and TCE-treated mice with MDA-adducted mouse serum albumin (MDA-MSA) or HNE-MSA for 72 h showed significant proliferation of CD4 + T cells in TCE-treated mice as analyzed by flow cytometry. Also, splenic lymphocytes from TCE-treated mice released more IL-2 and IFN-γ into cultures when stimulated with MDA-MSA or HNE-MSA, suggesting a Th1 cell activation. Thus, our data suggest a role for lipid peroxidation-derived aldehydes in TCEmediated autoimmune responses and involvement of Th1 cell activation.

Plasma malondialdehyde levels and CXCR4 expression in peripheral blood cells of breast cancer patients

“…Data obtained by Wang et al (2008) suggest a role for lipid peroxidation-derived aldehydes in trichloroethene-mediated autoimmune responses and the involvement of Th1 cell activation.…”

Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease

“…Protein carbonylation is a heterogeneous event, and it is unlikely that only one particular carbonyl modification will impart antigenicity to a protein, as demonstrated here by the immunoreactivity toward protein modified by several different carbonylating species. Carbonylated proteins can also modulate adaptive immune responses (29,30) as well as activate T cells and promote Th1-type responses through their uptake and presentation by antigenpresenting cells (31).…”

“…We have demonstrated that carbonyl adducts, which are potent antigens formed as a result of exposure to chronic oxidative stress (27), such as cigarette smoking or ozone exposure, can trigger an antibody-mediated immune response. Using in vivo models, two groups have shown that oxidant stress and carbonyl-modified protein can lead to autoimmunity (28,31) with specific T cell activation and corresponding antibody production, a prerequisite for any immune response. Similarly, we found that oxidant-stressed mice after chronic ozone exposure exhibited higher antibody titers against carbonyl-modified protein as well as increased activation of their splenocytes in response to stimulation with carbonyl-modified protein.…”

Environmental risk factors of systemic sclerosis

“…MRL+/+ mice, when exposed to trichloroethylene, develop higher levels of overall serum IgG and increased prevalence of antinuclear antibodies [54]. Other experimental models have shown that exposure to trichloroethylene led to (1) protein modifications [55][56][57][58][59]; (2) synthesis of higher levels of IL-17 and IL-21 by splenocytes in trichloroethylene-treated mice [60]; (3) production of reactive oxygen species and increased nitric oxide by nitric oxide synthase in cultured human epidermal keratinocytes [61]; (4) Th1 T cell activation in MRL+/+ mice [62]; (5) inhibition of cellular apoptosis of naïve CD4+ and CD8+ T cells in MRL+/+ mice [63]; and (6) DNA hypermethylation on rat cardiac myoblasts [64]. Furthermore, other experimental studies have shown that exposure to benzene resulted in (1) decreased T cell population in wild/captive American kestrel birds [65]; (2) reduced number of CD4+/CD8+ T cells and B cells in exposed workers [66]; (3) increased reactive oxygen species and induction of DNA fragmentation in pump workers [67]; and (4) changes in gene transcription involved in apoptosis, oxidative stress, cellular cycle, and cytokine production in benzene-treated mice [68].…”