Systemic lupus erythematosus: a role for anti-receptor antibodies?

Systemic lupus erythematosus (SLE) is considered by many to represent the best example of human disease where immune complexes play a primary role in the pathogenesis. SLE is thought to have an autoimmune basis; a conclusion based largely upon the propensity of these patients to form antibodies to cell nuclear components. The etiology of SLE remains unknown, as does the mechanism by which nuclear components are rendered autoantigenic. Here we present an argument for considering SLE as an antireceptor autoimmune disease, analogous to Graves' disease or myasthenia gravis. The proposed target of autoimmune attack, the estrogen receptor (ER), is normally resident in the nucleus, physiologically more active in women, and shed from hormonally responsive tissues during the course of the menstrual cycle. Autoantigenicity of ER is enhanced in SLE patients owing to a biochemical abnormality of estrogen metabolism which favors ligand occupancy of the receptor. The spectrum of anti-nuclear antibodies characteristic of SLE arises via normally functioning immune network regulatory mechanisms.