Autoantibody-defined epitopes on nuclear antigens are conserved, conformation-dependent and active site regions

Antinuclear antibodies in the systemic rheumatic diseases have been powerful reagents for identifying and characterizing nuclear antigens and for elucidating immune mechanisms which drive the autoimmune response. Concepts which have emerged from these studies include the following: the autoimmune response is antigen driven, autoantigens are components of subcellular particles, autoantigens are involved in important biosynthetic functions and epitopes recognized by autoantibodies are active sites or functional domain regions. PCNA (proliferating cell nuclear antigen) is a nuclear protein of 36 kDa and autoantibodies are present in patients 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. Studies have shown that epitopes on PCNA recognized by lupus antibodies are conformation-dependent. Composite peptides synthesized by joining discontinuous linear sequences were used to immunize rabbits and one such composite peptide induced antibodies with properties strikingly similar to human autoantibodies. Immunogens in the systemic autoimmune diseases are likely to be intranuclear or other intracellular particles composed of protein-protein or protein-nucleic acid complexes which are involved in cellular biosynthetic functions.