Studies on the Structure, Regulation, and Pathogenic Potential of Anti-dsDNA Antibodies

Background: Advanced glycation end products (AGEs) can act as neoantigens to trigger immune responses. Results: Natural IgM antibodies against AGEs recognize multiple molecules, including DNA and chemically modified proteins. Conclusion: There is a close relationship between the formation of AGEs and innate immune responses. Significance: Our findings highlight AGEs and related modified proteins as a source of multispecific natural antibodies.

Section: Discussionmentioning

confidence: 99%

Multispecificity of Immunoglobulin M Antibodies Raised against Advanced Glycation End Products

Chikazawa

Otaki

Shibata

et al. 2013

“…3 Of interest, the anti-DNA mAb raised from the BALB/c mice immunized with the 4-hydroxy-2-nonenal-modified protein has been shown to crossreact with the ONE-modified protein (13). Several different antigenic cross-reactivities have been identified for the anti-DNA antibodies (27). These antibodies share structural similarities with antibodies against bacterial polysaccharide, and some cross-react with the bacterial polysaccharide and protect mice against a lethal bacterial infection (28,29).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Lipid Peroxidation Product as the Source of Oxidation-specific Epitopes Recognized by Anti-DNA Autoantibodies*

Otaki

Chikazawa

Nagae

et al. 2010

Lipid peroxidation in tissue and in tissue fractions represents a degradative process, which is the consequence of the production and the propagation of free radical reactions primarily involving membrane polyunsaturated fatty acids, and has been implicated in the pathogenesis of numerous diseases, including systemic lupus erythematosus (SLE). We have found that bovine serum albumin incubated with peroxidized polyunsaturated fatty acids significantly cross-reacted with the sera from MRLlpr mice, a representative murine model of SLE. To identify the active substances responsible for the generation of autoantigenic epitopes recognized by the SLE sera, we performed the activity-guiding separation of a principal source from 13-hydroperoxy-9Z,11E-octadecadienoic acid and identified 4-oxo-2-nonenal (ONE), a highly reactive aldehyde originating from the peroxidation of 6 polyunsaturated fatty acids, as the source of the autoantigenic epitopes. When the age-dependent change in the antibody titer against the ONE-modified protein was measured in the sera from MRL-lpr mice and control MRL-MpJ mice, all of the MRL-lpr mice developed an anti-ONE titer, which was comparable with the anti-DNA titer. Strikingly, a subset of the anti-DNA monoclonal antibodies generated from the SLE mice showing recognition specificity toward DNA cross-reacted with the ONE-specific epitopes. Furthermore, these dual-specific antibodies rapidly bound and internalized into living cells. These findings raised the possibility that the enhanced lipid peroxidation followed by the generation of ONE may be involved in the pathogenesis of autoimmune disorders.

“…4 In addition, we have examined the affinity of the anti-DNA mAbs D431 and D466 obtained from the 56R and CD40L double transgenic mice (33,34), a spontaneous murine model of SLE, with the ONE-modified protein and have found that, of the two anti-DNA mAbs, mAb D466 cross-reacted with the ONE-modified BSA. 4 Several different antigenic cross-reactivities have been identified for the anti-DNA antibodies (35). These antibodies share structural similarities with antibodies against bacterial polysaccharide, and some cross-react with the bacterial polysaccharide and protect mice against a lethal bacterial infection (36,37).…”

Section: Discussionmentioning

confidence: 99%

Protein-bound 4-Hydroxy-2-nonenal

Toyoda

Nagae

Akagawa

et al. 2007

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.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 (1, 2). It has also been suggested that many of the effects of cellular dysfunction under oxidative stress are mediated by the products of nonenzymatic reactions, such as the peroxidative degradation of polyunsaturated fatty acids (3, 4). Lipid peroxidation leads to the formation of a broad array of different products with diverse and powerful biological activities. Among them are a variety of different aldehydes. The primary products of lipid peroxidation, lipid hydroperoxides, can undergo carbon-carbon bond cleavage via alkoxyl radicals in the presence of transition metals, giving rise to the formation of short chain, unesterified aldehydes of 3-9 carbons in length, and a second class of aldehydes still esterified to the parent lipid (5). These aldehydes generated during the lipid peroxidation have been implicated as causative agents in cytotoxic processes initiated by the exposure of biological systems to oxidizing agents.Some of the lipid peroxidation products exhibit a facile reactivity with proteins, generating a variety of intra-and intermolecular covalent adducts. Such adducts could be the targets of B cell-mediated immune responses a...