We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
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.
- Authors
Diez, Juan; Park, Yongsoo; Zeller, Markus; Brown, Douglas; Garza, David; Ricordi, Camillo; Hutton, John; Eisenbarth, George S.; Pugliese, Alberto; Diez, J; Park, Y; Zeller, M; Brown, D; Garza, D; Ricordi, C; Hutton, J; Eisenbarth, G S; Pugliese, A
- Abstract
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.
- Subjects
AUTOIMMUNITY; GENE expression; DIABETES
- Publication
Diabetes, 2001, Vol 50, Issue 4, p895
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.50.4.895