Hypothesis: systemic lupus erythematosus as a disease secondary to polyclonal lymphocyte activation

Systemic lupus erythematosus (SLE) is characterized by the concomitance of B cell polyclonal activation and the production of a wide spectrum of autoantibodies showing a marked preference for nuclear antigens. We propose the hypothesis that the production of the most pathogenic antinuclear antibodies with high affinity and IgG isotype is driven by antigens liberated by the death of rapidly proliferating lymphoid cells. The disease could evolve in three steps: (1) polyclonal B cell activation and proliferation caused by unknown etiologic factors (virus?, mitogen? ...); (2) primary activation of natural antibody-producing clones leading to the appearance in the serum of large amounts of natural autoantibodies with public idiotype; and (3) secondary immunization against molecules synthesized in large quantities during lymphocyte proliferation, released by dying cells and subsequently presented in an immunogenic form to T cells. These molecules include nucleic acids (DNA, RNA), nucleic acid-binding proteins (histones, Ro, La), and parts of the RNA splicing machinery (RNP). Other autoantibody activities could relate to cross-reactivities or the binding properties of DNA-anti-DNA immune complexes.