Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen.
Type 1 diabetes results from the autoimmune destruction of pancreatic beta-cells in genetically susceptible individuals. Growing evidence suggests that genetically determined variation in the expression of self-antigens in thymus may affect the shaping of the T-cell repertoire and susceptibility to autoimmunity. For example, both allelic variation and parent-of-origin effects influence the thymic expression of insulin (a known type 1 diabetes autoantigen), and insulin gene transcription levels in thymus inversely correlate with susceptibility in both humans and transgenic models. It is unclear why patients lose tolerance to IA-2 (insulinoma-associated tyrosine phosphatase-like protein, or islet cell antigen 512 [ICA512]), especially because IA-2 polymorphisms are not associated with type 1 diabetes. We report that alternative splicing determines differential IA-2 expression in islets compared with thymus and spleen. Islets express full-length mRNA and two alternatively spliced transcripts, whereas thymus and spleen exclusively express an alternatively spliced transcript lacking exon 13. This encodes for the transmembrane (TM) and juxta-membrane (JM) domains that comprise several type 1 diabetes target epitopes, supporting the concept that tolerance to IA-2 epitopes not expressed in lymphoid organs may not be achieved. We propose differential splicing as a regulatory mechanism of gene expression playing a permissive role in the development of autoimmune responses to IA-2. Our findings also show that candidate gene expression studies can help in dissecting the complex genetic determinants of a multifactorial disease such as type 1 diabetes.
Diez
J
J
Immunogenetics Program and the Diabetes Research Institute, University of Miami, Florida 33136, USA.
Park
Y
Y
Zeller
M
M
Brown
D
D
Garza
D
D
Ricordi
C
C
Hutton
J
J
Eisenbarth
G S
GS
Pugliese
A
A
D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics*; D001483:Base Sequence / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005333:Fetus; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008221:Lymphoid Tissue / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010179:Pancreas / Q000503:physiopathology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012326:RNA Splicing; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
D001324:Autoantigens; D008565:Membrane Proteins; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8