Increased noncanonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes.
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.
Ng
Bernard
B
Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA.
Yang
Fan
F
Huston
David P
DP
Yan
Yan
Y
Yang
Yu
Y
Xiong
Zeyu
Z
Peterson
Leif E
LE
Wang
Hong
H
Yang
Xiao-Feng
XF
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
D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D020033:Protein Isoforms