AUTOANTIBODY-DEFINED EPITOPES ON NUCLEAR ANTIGENS ARE CONSERVED, CONFORMATION-DEPENDENT AND ACTIVE-SITE REGIONS

Antinuclear antibodies in the systemic rheumatic diseases have been po werful reagents for identifying and characterizing nuclear antigens an d for elucidating immune mechanisms which drive the autoimmune respons e. Concepts which have emerged from these studies include the followin g: the autoimmune response is antigen driven, autoantigens are compone nts of subcellular particles, autoantigens are involved in important b iosynthetic functions and epitopes recognized by autoantibodies are ac tive sites or functional domain regions. PCNA (proliferating cell nucl ear antigen) is a nuclear protein of 36 kDa and autoantibodies are pre sent inpatients with systemic lupus erythematosus. PCNA is a component of the DNA replication complex and is associated with DNA polymerase delta in continuous strand DNA synthesis at the replication fork. Stud ies have shown that epitopes on PCNA recognized by lupus antibodies ar e conformation dependent. Composite peptides synthesized by joining di scontinuous linear sequences were used to immunize rabbits and one suc h composite peptide induced antibodies with properties strikingly simi lar to human autoantibodies. Immunogens in the systemic autoimmune dis eases are likely to be intranuclear or other intracellular particles c omposed of rot ein-protein or protein-nucleic acid complexes which are involved in cellular biosynthetic functions.