Elsevier

Autoimmunity Reviews

Volume 7, Issue 7, July 2008, Pages 567-573
Autoimmunity Reviews

Autoimmunity and oxidatively modified autoantigens

https://doi.org/10.1016/j.autrev.2008.04.019Get rights and content

Abstract

Oxidative damage mediated by reactive oxygen species results in the generation of deleterious by-products. The oxidation process itself and the proteins modified by these molecules are important mediators of cell toxicity and disease pathogenesis. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immunogenic. Proteins modified in this manner have been shown to induce pathogenic antibodies in a variety of diseases including systemic lupus erythematosus (SLE), alcoholic liver disease, diabetes mellitus (DM) and rheumatoid arthritis (RA). 8-oxodeoxyguanine (oxidatively modified DNA) and oxidized low-density lipoproteins (LDL) occur in SLE, a disease in which premature atherosclerosis is a serious problem. In addition, immunization with 4-hydroxy-2-nonenal (HNE) modified 60 kD Ro autoantigen induces an accelerated epitope spreading in an animal model of SLE. Advanced glycation end product (AGE) pentosidine and AGE modified IgG have been shown to correlate with RA disease activity. Oxidatively modified glutamic acid decarboxylase is important in type 1 DM, while autoantibodies against oxidized LDL are prevalent in Behcet's disease. The fragmentation of scleroderma specific autoantigens occurs as a result of oxidative modification and is thought to be responsible for the production of autoantibodies through the release of cryptic epitopes. The administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease, particularly on account of the overwhelming evidence for the involvement of oxidative damage in autoimmunity. However, this should be viewed in the light of disappointing results obtained with the use of antioxidants in cardiovascular disease.

Section snippets

Free radicals

Reactive oxygen species (ROS) are oxygen-based molecules possessing high chemical reactivity. These include free radicals (superoxide and hydroxyl radicals) and non-radical species (hydrogen peroxide) which can be produced even at basal conditions by a number of ways. Free radicals are active species containing atoms or molecules with one or more unpaired electrons occupying an outer orbital. They can arise either by the univalent pathway of oxygen reduction or as a consequence of

Antioxidant defense

Enzymatic (superoxide dismutase (SOD), catalase and the peroxidases) and non-enzymatic (ascorbic acid, reduced glutathione and vitamin E) antioxidant defense systems control ROS production by scavenging or decreasing ROS levels, thereby maintaining an appropriate cellular redox balance. Alterations of this normal balance resulting from elevated ROS production and/or decreased antioxidant levels lead to a state of oxidative stress and thus an enhanced susceptibility of membranes and biological

Lipid peroxidation

Stress or any other factor that compromises the activity of antioxidant enzymes may trigger a potentially dangerous pathway of peroxidative damage. Peroxidative damage brought about by free radicals has been shown to be involved in the pathogenesis of several diseases. Increased oxidant stress has been associated with the observed increase in lipid peroxidation in these diseases. Lipid peroxidation has been defined as oxidative degeneration of polyunsaturated fatty acids, set into motion by

Phases of lipid peroxidation

Oxidation of any polyunsaturated fatty acid is a chain reaction process and can be divided into three stages: initiation, propagation and termination (Fig. 1). In the initiation phase a primary reactive radical (xradical dot), abstracts a hydrogen atom from a methylene group of a polyunsaturated fatty acid to start the peroxidation. This leaves an unpaired electron on the carbon, resulting in the formation of a conjugated diene. The carbon-centered fatty acid radicals combine with molecular oxygen, in the

Reactive oxygen species and protein modification

The process of lipid peroxidation releases aldehydic products of lipid peroxidation (α, β-unsaturated aldehydes), mainly the 4-hydroxy-2-alkenals, that can form adducts with free amino groups of lysine and other amino acids. Aldehyde-modified proteins are highly immunogenic [3], [4], [5], [6], [7].

4-hydroxy-2-nonenal is the most studied molecule, among the 4-hydroxy-2-alkenals. 4-hydroxy-2-nonenal, and related compounds, possess two very reactive electrophilic sites: the alkene bond and the

Oxidation and immune response

Rabbits and mice immunized with oxidized LDL particles (oxLDL) develop autoantibodies directed against epitopes in malondialdehyde and 4-hydroxy-2-nonenal nonenal-modified low-density lipoproteins (LDL). The presence of antibodies against oxLDL or malondialdehyde-LDL in atherosclerotic plaques and oxidation-specific antigens on surface of apoptotic cells has been demonstrated by numerous investigators The presence of antioxidized LDL is associated with more rapid progression of atherosclerosis.

Oxidative modification of proteins in autoimmune disease

Several human diseases are autoimmune in nature resulting from the abrogation of self-tolerance. Autoimmune disease may be either organ-specific or tissue specific. Organ specific diseases include type 1 diabetes, thyroiditis, myasthenia gravis, primary biliary cirrhosis and Goodpasture's syndrome while systemic diseases include rheumatoid arthritis, progressive systemic sclerosis and systemic lupus erythematosus. Nearly all these diseases are characterized by the presence of autoantibodies.

Conclusion

The role of free radicals in the pathogenesis and development of diseases is well documented. Generation of ROS and enzymatic and non-enzymatic control of these harmful molecules is an ongoing process. Antibodies to antioxidant enzymes could result in the disruption in this balance resulting in oxidative stress, which is turn leads to pathological changes. This could lead to oxidatively modified autoantigens that serve as neo-antigens in promoting loss of tolerance to self. Immunization with

Take-home messages

  • Protein, DNA and lipid particles are oxidatively damaged in systemic lupus erythematosus with a decrease in free radical defense enzymes, especially super oxide dismutase.

  • Immunization with oxidatively modified lupus autoantigens leads to more rapid epitope spreading and disease in mice.

  • Oxygen radicals are found in joints of rheumatoid arthritis patients and correlate with levels of serum TNF.

  • In RA IgG is modified by advanced glycation end products.

  • In type 1 diabetes there is free radical damage

Acknowledgements

Supported by NIH grant ARO1844 to RHS and Oklahoma Center for the Advancement of Science and Technology to BTK.

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