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Removal and Replacement of Endogenous Ligands from Lipid-Bound Proteins and Allergens
Published on: February 24, 2021
Protein-bound 4-hydroxy-2-nonenal: an endogenous triggering antigen of antI-DNA response
Kazuyo Toyoda1, Ritsuko Nagae, Mitsugu Akagawa
1Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Abstract:
Several lines of evidence indicate that the nonenzymatic oxidative modification of proteins and the subsequent accumulation of the modified proteins have been found in cells during aging and oxidative stress and in various pathological states, including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis. Our previous work suggested the existence of molecular mimicry between antibodies raised against hydroxy-2-nonenal (HNE)-modified protein and anti-DNA autoantibodies, a serologic hallmark of systemic lupus erythematosus (SLE). In the present study, we investigated the possible involvement of HNE-modified proteins as the endogenous source of the anti-DNA antibodies. Accumulation of the antigen recognized by the antibody against the HNE-modified protein was observed in the nucleus of almost all of the epidermal cells from patients with autoimmune diseases, including SLE. The SLE patients also showed significantly higher serum levels of the anti-HNE titer than healthy individuals. To determine if a specific anti-DNA response could be initiated by the HNE-derived epitopes, we immunized BALB/c mice with the HNE-modified protein and observed a progressive increase in the anti-DNA response. Moreover, we generated the monoclonal antibodies, showing recognition specificity toward DNA, and found that they can bind to two structurally distinct antigens (i.e. the native DNA and protein-bound 4-oxo-2-nonenal). The findings in this study provide evidence to suspect an etiologic role for lipid peroxidation in autoimmune diseases.
Insights
Lipid peroxidation products, like hydroxy-2-nonenal (HNE)-modified proteins, may trigger autoimmune diseases such as systemic lupus erythematosus (SLE). This study suggests HNE-modified proteins could be an endogenous source of anti-DNA antibodies, implicating them in disease etiology.
Area of Science:
- Biochemistry
- Immunology
- Pathology
Background:
- Nonenzymatic oxidative modification of proteins accumulates during aging, oxidative stress, and diseases like atherosclerosis.
- Molecular mimicry between antibodies against hydroxy-2-nonenal (HNE)-modified protein and anti-DNA autoantibodies is a hallmark of systemic lupus erythematosus (SLE).
Purpose of the Study:
- To investigate the role of HNE-modified proteins as an endogenous source of anti-DNA antibodies in autoimmune diseases.
- To explore the potential etiologic link between lipid peroxidation and autoimmune conditions.
Main Methods:
- Immunohistochemical analysis of epidermal cells from autoimmune disease patients.
- Quantification of serum anti-HNE antibody titers in SLE patients and healthy individuals.
- Immunization of mice with HNE-modified protein to assess anti-DNA response induction.
- Generation and characterization of monoclonal antibodies for DNA and HNE-modified protein binding.
Main Results:
- Antigen recognized by anti-HNE-modified protein antibody accumulates in the nucleus of epidermal cells from patients with autoimmune diseases, including SLE.
- SLE patients exhibit significantly higher serum anti-HNE antibody titers compared to healthy controls.
- Immunization with HNE-modified protein induced a progressive increase in anti-DNA response in mice.
- Generated monoclonal antibodies recognized both native DNA and protein-bound 4-oxo-2-nonenal.
Conclusions:
- HNE-modified proteins are present in the nucleus of cells in patients with autoimmune diseases, suggesting their involvement.
- Elevated anti-HNE antibody titers in SLE patients support a link between lipid peroxidation and autoimmunity.
- HNE-derived epitopes can initiate an anti-DNA response, indicating a potential mechanism for autoantibody generation in SLE.
- Lipid peroxidation may play an etiologic role in the development of autoimmune diseases.
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