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.

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.

• Authors: J Diez, Y Park, M Zeller, D Brown, D Garza, C Ricordi, J Hutton, G S Eisenbarth, A Pugliese
• Journal: Diabetes (Diabetes) Vol. 50 Issue 4 Pg. 895-900 (Apr 2001) ISSN: 0012-1797 [Print] United States
• PMID: 11289059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Autoantigens
• Membrane Proteins
• PTPRN protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Protein Tyrosine Phosphatases
• Receptor-Like Protein Tyrosine Phosphatases, Class 8

Topics

• Adult
• Amino Acid Sequence (genetics)
• Autoantigens (immunology)
• Autoimmunity (genetics)
• Base Sequence (genetics)
• Diabetes Mellitus, Type 1 (genetics, immunology)
• Female
• Fetus
• Humans
• Infant
• Infant, Newborn
• Lymphoid Tissue (physiopathology)
• Male
• Membrane Proteins (genetics)
• Middle Aged
• Molecular Sequence Data
• Pancreas (physiopathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Protein Tyrosine Phosphatases (genetics)
• RNA Splicing
• Receptor-Like Protein Tyrosine Phosphatases, Class 8