Selective Small Antigenic Structures are Capable of Inducing Widespread Autoimmunity which Closely Mimics the Humoral Fine Specificity of Human SLE

Recent data have suggested that autoantibodies in lupus can progress from simple immunity against a few antigenic structures to a complex response against multiple autoantigens. Our aim was to determine whether these diverse epitope patterns can indeed be generated by antigenic challenge with a single, small structure. Rabbits were immunized with either a 60 kDa Ro peptide commonly antigenic in human systemic lupus erythematosus (SLE) (Ro 274–289) or one which is rarely a humoral target (Ro 500–515). Rabbits immunized with the antigenic peptide (Ro 274–289) not only developed antibodies to multiple epitopes of 60 kDa Ro and La, as has been described, but also produced non‐cross‐reactive antibodies to the common spliceosomal proteins Sm B′ and D1, and nRNP A and C. Rabbits immunized with the Ro 274–289 peptide also mount a progressive, diversified immune response to the sequential antigenic regions of these proteins (60 kDa Ro, Sm B′ and D1, nRNP A and C), which is nearly identical to that seen in human SLE. Animals immunized with the nonantigenic peptide Ro 500–515 develop antibodies only to 60 kDa Ro. These results demonstrate that loss of tolerance to select single, small antigenic structures can begin a cascade which virtually recreates, at the epitope level, the humoral autoimmune specificity seen in human SLE.