title: Increased noncanonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ng
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: David P
authors.initials: DP
authors.lastname: Huston
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Xiong
authors.forename: Leif E
authors.initials: LE
authors.lastname: Peterson
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
mesh_terms: D017398:Alternative Splicing; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000235:genetics*; D015551:Autoimmunity; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D020033:Protein Isoforms