Journal
DIABETES
Volume 68, Issue 5, Pages 988-1001Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db18-0686
Keywords
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Funding
- nPOD [SCR-014641]
- JDRF (nPOD grant) [5-SRA-2018-557-Q-R]
- Leona M. and Harry B. Helmsley Charitable Trust [2018PG-T1D053]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [SCR-014393, UC4DK-104211, DK-108120, DK-112232, DK-106755]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Vanderbilt Diabetes Research and Training Center grant) [DK-20593]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Department of Veterans Affairs)
- JDRF [5-CDA-2014-221-A-N, 3-PDF-2017-374-A-N]
- Diabetes UK [16/0005480]
- Babson Faculty Research Fund
- South-Eastern Norway Regional Health Authority
- Novo Nordisk Foundation
- PEVNET Study Group - European Union Seventh Framework Programme (FP7/2007-2013) [261441 PEVNET]
- Leona M. and Harry B. Helmsley Charitable Trust
- [DK-116284]
- [DK-105837]
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Type 1 diabetes studies consistently generate data showing islet beta-cell dysfunction and T cell-mediated anti-beta-cell-specific autoimmunity. To explore the pathogenesis, we interrogated the beta-cell transcriptomes from donors with and without type 1 diabetes using both bulk-sorted and single beta-cells. Consistent with immunohistological studies, beta-cells from donors with type 1 diabetes displayed increased Class I transcripts and associated mRNA species. These beta-cells also expressed mRNA for Class II and Class II antigen presentation pathway components, but lacked the macrophage marker CD68. Immunohistological study of three independent cohorts of donors with recent-onset type 1 diabetes showed Class II protein and its transcriptional regulator Class II MHC trans-activator protein expressed by a subset of insulin(+)CD68(-) beta-cells, specifically found in islets with lymphocytic infiltrates. beta-Cell surface expression of HLA Class II was detected on a portion of CD45(-)insulin(+) beta-cells from donors with type 1 diabetes by immunofluorescence and flow cytometry. Our data demonstrate that pancreatic beta-cells from donors with type 1 diabetes express Class II molecules on selected cells with other key genes in those pathways and inflammation-associated genes. beta-Cell expression of Class II molecules suggests that beta-cells may interact directly with islet-infiltrating CD4(+) T cells and may play an immunopathogenic role.
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