MOLECULAR, METABOLIC AND IMMUNE EVIDENCE SUGGESTS THAT SYSTEMIC AUTOIMMUNE-DISEASE IS ANTIGEN-MEDIATED

Patients with systemic lupus erythematosus generate a sustained immune response against serf. The tools of modern molecular biology have bee n applied to cell activities and elements/signals of the immune system , but a structural or regulatory defect has not been found. When deoxy ribonucleic acids for autoantibodies were cloned and sequenced, they w ere 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 an alyses of the efferent side of the immune response have been largely n ormal 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 g enerating antigens should be found in systemic lupus erythematosus cel ls. Structural changes have been found in deoxyribonucleic acid from p hytohaemagglutinin-stimulated systemic lupus erythematosus lymphocytes in the form of S1 nuclease-sensitive deoxyribonucleic acid breaks. Al tered cellular macromolecules could result from endogenous metabolic p rocesses, particularly oxygen free radicals and arachidonic acid metab olites. Excess free-radical species, generating positive nitroblue tet razolium-reacting material and positive chemiluminescence, have been f ound in most but not all phytohaemagglutinin-stimulated lupus lymphocy te samples. If endogenous metabolic processes act on endogenous deoxyr ibonucleic acid, endogenous cell DNA breakdown may lead to low molecul ar weight deoxyribonucleic acids and deoxyribonucleic acid/immune comp lexes in systemic lupus erythematosus sera that are potentially immuno genic. These combined findings suggest that the exaggerated immune res ponses of systemic lupus erythematosus may be a normal response to pro tect the host from a perceived antigenic threat.