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

Bernard Ng, Fan Yang, David P. Huston, Yan Yan, Yu Yang, Zeyu Xiong, Leif E. Peterson, Hong Wang, Xiao Feng Yang

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1463-1470
Number of pages8
JournalJournal of Allergy and Clinical Immunology
Volume114
Issue number6
DOIs
StatePublished - Dec 2004

Keywords

  • alternative splicing
  • antigen epitopes
  • Autoantigens
  • autoimmune diseases
  • exons
  • immune tolerance
  • immunogenicity
  • isoforms

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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