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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

¹ Immunogenetics Program and the
² Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, Florida
³ Division of Endocrinology and Metabolism, Department of Internal Medicine, Hanyang University Hospital, Kuri, Kyunggi-Do, Korea
⁴ Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Colorado

Type 1 diabetes results from the autoimmune destruction of pancreatic ß-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.

Abbreviations: AEC, aminoethyl carbazole; JM, juxta-membrane; PBS-T, phosphate-buffered saline, 0.1%; Tween-20; RT-PCR, reverse transcriptase–polymerase chain reaction; TM, transmembrane

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