Increased noncanonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes

• Published in: Journal of Allergy and Clinical Immunology Vol. 114; no. 6; pp. 1463 - 1470
• Main Authors: Ng, Bernard, Yang, Fan, Huston, David P., Yan, Yan, Yang, Yu, Xiong, Zeyu, Peterson, Leif E., Wang, Hong, Yang, Xiao-Feng
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.12.2004; Elsevier; Elsevier Limited
• Subjects: Alternative Splicing; Amino acids; antigen epitopes; Autoantibodies - immunology; Autoantigens; Autoantigens - genetics; Autoimmune diseases; Autoimmunity; Biological and medical sciences; Colorectal cancer; Epitopes, T-Lymphocyte; exons; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genes; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class II - immunology; Humans; immune tolerance; immunogenicity; Immunopathology; isoforms; Lupus; Medical sciences; Pathogenesis; Protein Isoforms; Protein Processing, Post-Translational; Proteins; Raynaud disease; Scleroderma; Studies; autoimmune diseases; ORF; alternative splicing; exons; EST; EAE; Autoantigens; isoforms; DM; immunogenicity; immune tolerance; PLP; NCBI; antigen epitopes; IA-2; Autoimmunity; Immunopathology; Alternative splicing; Molecular form; Immune response; Antigenic determinant; Autoimmune disease; Antigen; Immunology; Autoantigen; Exon; Messenger RNA; Gene; Immunogenicity; Immune tolerance
• ISSN: 0091-6749; 1097-6825; 1365-2567
• DOI: 10.1016/j.jaci.2004.09.006

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). These studies suggest that noncanonical alternative splicing may be an important mechanism for the generation of untolerized epitopes that may lead to autoimmunity. Furthermore, the product of a transcript that does not undergo alternative splicing is unlikely to be a target antigen in autoimmunity.