Molecular, metabolic and immune evidence suggests that systemic autoimmune disease is antigen-mediated

Abstract Patients with systemic lupus erythematosus generate a sustained immune response against self. The tools of modern molecular biology have been applied to cell activities and elements/signals of the immune system, but a structural or regulatory defect has not been found. When deoxyribonucleic acids for autoantibodies were cloned and sequenced, they were like other autoantibody DNA sequences; when genetic materials for autoantibodies were inserted into transgenic mice, cells secreting the antibodies were subject to normal control mechanisms and eliminated. A failure to clear self-reactive antibody producing thymocytes has not been demonstrated in human systemic lupus erythematosus. Molecular analyses of the efferent side of the immune response have been largely normal in systemic lupus erythematosus. The structure of autoantibodies suggests that they have been generated by selection pressures and the presence of endogenous antigens. If the immune system attack on self was secondary, structural changes and metabolic reactions capable of generating antigens should be found in systemic lupus erythematosus cells. Structural changes have been found in deoxyribonucleic acid from phytohaemagglutinin-stimulated systemic lupus erythematosus lymphocytes in the form of S1 nuclease-sensitive deoxyribonucleic acid breaks. Altered cellular macromolecules could result from endogenous metabolic processes, particularly oxygen free radicals and arachidonic acid metabolites. Excess free-radical species, generating positive nitroblue tetrazolium-reacting material and positive chemiluminescence, have been found in most but not all phytohaemagglutinin-stimulated lupus lymphocyte samples. If endogenous metabolic processes act on endogenous deoxyribonucleic acid, endogenous cell DNA breakdown may lead to low molecular weight deoxyribonucleic acids and deoxyribonucleic acid/immune complexes in systemic lupus erythematosus sera that are potentially immunogenic. These combined findings suggest that the exaggerated immune responses of systemic lupus erythematosus may be a normal response to protect the host from a perceived antigenic threat.