['Alternative splicing is important for increasing the complexity of the human proteome from a limited genome. Previous studies have shown that for some autoantigens, there is differential immunogenicity among alternatively spliced isoforms.', 'Herein, we tested the hypothesis that alternative splicing is a common feature for transcripts of autologous proteins that are autoantigens. The corollary hypothesis tested was that nonautoantigen transcripts have a lower frequency of alternative splicing.', 'The extent of alternative splicing within 45 randomly selected self-proteins associated with autoimmune diseases was compared with 9554 randomly selected proteins in the human genome by using bioinformatics analyses. Isoform-specific regions that resulted from alternative splicing were studied for their potential to be epitopes for antibodies or T-cell receptors.', 'Alternative splicing occurred in 100% of the autoantigen transcripts. This was significantly higher than the approximately 42% rate of alternative splicing observed in the 9554 randomly selected human gene transcripts ( P < .001). Within the isoform-specific regions of the autoantigens, 92% and 88% encoded MHC class I and class II-restricted T-cell antigen epitopes, respectively, and 70% encoded antibody binding domains. Furthermore, 80% of the autoantigen transcripts underwent noncanonical alternative splicing, which is also significantly higher than the less than 1% rate in randomly selected gene transcripts ( P < .001).'] Does increased noncanonical splicing of autoantigen transcripts provide the structural basis for expression of untolerized epitopes?