The lupus autoantigens and the pathogenesis of systemic lupus erythematosus.

Thus, the nucleosome, the U1 snRNP, and the Ro scRNP appear to elicit hierarchies of antibodies in patients with SLE, just as any complex foreign protein might do when injected into an experimental animal. There must be a permissive factor in operation that allows these normally weak antigens (the great paradox of SLE!) to escape tolerance mechanisms. That factor could be an exogenous agent, such as a chemical that structurally alters selected macromolecules. Such a mechanism seems likely in patients with drug-induced lupus in whom autoimmune responses are focused against the same histone epitopes that are recognized by sera from patients with spontaneous SLE. Alternatively, foreign substances may elicit cross-reactive antibodies that recognize "self" determinants, or endogenous metabolic disturbances might enhance exposure of selected macromolecules to the immune system. In any case, it now seems clear that the result in SLE patients is autoimmunity with a repetitive focus. Future research should concentrate on the 3 particles described here in order to identify common denominators that set them apart from other cellular elements and which predispose them to a role as autoantigens, to determine the extent to which these particles make contact with the immune system, and to learn how structural, humoral, or metabolic alterations might predispose individuals to respond to them immunologically.