A Reg Family Protein Is Overexpressed in Islets From a Patient With New-Onset Type 1 Diabetes and Acts as T-Cell Autoantigen in NOD Mice
| Autor: | Conchi Mora, Margaret Shaw, Li Wen, Werner Gurr, Laurence Christa, Reza Yavari, Robert S. Sherwin |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
endocrine system
medicine.medical_specialty Adoptive cell transfer T-Lymphocytes Endocrinology Diabetes and Metabolism medicine.medical_treatment T cell Gene Expression Nerve Tissue Proteins Pancreatitis-Associated Proteins Mice SCID medicine.disease_cause Autoantigens Autoimmunity Islets of Langerhans Mice Antigens Neoplasm Mice Inbred NOD Lectins Internal medicine Lithostathine Biomarkers Tumor Internal Medicine medicine Animals Humans Lectins C-Type Pancreas NOD mice Mice Knockout geography geography.geographical_feature_category Interleukin-6 business.industry Pancreatic islets Calcium-Binding Proteins Proteins Islet Adoptive Transfer Mice Inbred C57BL Diabetes Mellitus Type 1 Endocrinology medicine.anatomical_structure Cytokine Gene Expression Regulation Multigene Family business Spleen CD8 |
| Zdroj: | Diabetes. 51:339-346 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/diabetes.51.2.339 |
| Popis: | Genes overexpressed in pancreatic islets of patients with new-onset type 1 diabetes are potential candidates for novel disease-related autoantigens. RT-PCR-based subtractive hybridization was used on islets from a patient who died at the onset of type 1 diabetes, and it identified a type 1 diabetes-related cDNA encoding hepatocarcinoma-intestine-pancreas/pancreatic-associated protein (HIP/PAP). This protein belongs to the family of Reg proteins implicated in islet regeneration; its gene contains a putative interleukin-6 (IL-6) response element. Islets from healthy cadaveric human donors released HIP/PAP protein into the culture medium, and this release was enhanced by the addition of IL-6. The expression pattern of mouse homologues of HIP/PAP was determined in pancreata of prediabetic and diabetic NOD mice. Both groups showed positive immunostaining for HIP/PAP in islets and ductal epithelium. To test whether HIP/PAP is a target of islet-directed autoimmunity, we measured splenic T-cell responses against HIP/PAP in NOD mice. Spontaneous proliferation was detected after 4 weeks. Lymphocytes from islet infiltrates and pancreatic lymph nodes from 7- to 10-week-old NOD mice were used to establish an HIP/PAP-specific I-Ag7-restricted T-cell line, termed WY1, that also responded to mouse islets. WY1 cells homed to islets of NOD-SCID mice and adoptively transferred disease when coinjected with purified CD8+ cells from diabetic NOD mice. Our conclusion was that differential cloning of Reg from islets of a type 1 diabetic patient and the response of Reg to the cytokine IL-6 suggests that HIP/PAP becomes overexpressed in human diabetic islets because of the local inflammatory response. HIP/PAP acts as a T-cell autoantigen in NOD mice. Therefore, autoimmunity to HIP/PAP might create a vicious cycle, accelerating the immune process leading to diabetes. |
| Databáze: | OpenAIRE |
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