Systemic lupus erythematosus and related autoimmune diseases are antigen-driven, epigenetic diseases

Autoimmune diseases result when cellular stresses (ex UV, cell cycle, hormones, viruses, and/or drugs) induce altered expression of polyamines, leading to chromatin disruption, interference with chromatin methylation, exposure of sequestered genes, and interference with tissue-specific processes. Exposure of previously sequestered Alu and LINE-1 sequences can lead to reverse transcription of Alu-RNA (and other transcripts) by the LINE-1 reverse transcriptase, yielding autoantigenic, hypomethylated DNA fragments. Release from the cell of the hypomethylated DNA fragments, along with polyamine-associated nucleoprotein complexes formed with the fragments, would elicit the autoimmune response. Loss of gene control due to hypomethylation and chromatin disruption by polyamines or other factors can include loss of dosage compensation from the inactive X chromosome for spermine synthase and spermidine/spermine N-1-acetyltransfe rase at Xp22.1. This leads to ongoing altered polyamine levels. Thus, autoimmune diseases result from epigenetic changes that lead to autoantigen generation. (C) 2002 Elsevier Science Ltd. All rights reserved.