Autoimmunity and oxidatively modified autoantigens
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 (x), 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
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Protein, DNA and lipid particles are oxidatively damaged in systemic lupus erythematosus with a decrease in free radical defense enzymes, especially super oxide dismutase.
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Immunization with oxidatively modified lupus autoantigens leads to more rapid epitope spreading and disease in mice.
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Oxygen radicals are found in joints of rheumatoid arthritis patients and correlate with levels of serum TNF.
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In RA IgG is modified by advanced glycation end products.
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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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