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Diabetes. 2019 May;68(5):988-1001. doi: 10.2337/db18-0686. Epub 2019 Mar 4.

HLA Class II Antigen Processing and Presentation Pathway Components Demonstrated by Transcriptome and Protein Analyses of Islet β-Cells From Donors With Type 1 Diabetes.

Author information

1
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, U.K.
2
Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA.
3
Division of Diabetes, Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA.
4
Math and Science Division, Babson College, Wellesley, MA.
5
Pediatric Department, Oslo University Hospital, and Faculty of Medicine, University of Oslo, Oslo, Norway.
6
Institute of Cellular Therapeutics, Allegheny-Singer Research Institute Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA.
7
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
8
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
9
Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN.
10
Program in Bioinformatics, University of Massachusetts Medical School, Worcester, MA.
11
Division of Diabetes, Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA david.harlan@umassmemorial.org.

Abstract

Type 1 diabetes studies consistently generate data showing islet β-cell dysfunction and T cell-mediated anti-β-cell-specific autoimmunity. To explore the pathogenesis, we interrogated the β-cell transcriptomes from donors with and without type 1 diabetes using both bulk-sorted and single β-cells. Consistent with immunohistological studies, β-cells from donors with type 1 diabetes displayed increased Class I transcripts and associated mRNA species. These β-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- β-cells, specifically found in islets with lymphocytic infiltrates. β-Cell surface expression of HLA Class II was detected on a portion of CD45-insulin+ β-cells from donors with type 1 diabetes by immunofluorescence and flow cytometry. Our data demonstrate that pancreatic β-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. β-Cell expression of Class II molecules suggests that β-cells may interact directly with islet-infiltrating CD4+ T cells and may play an immunopathogenic role.

PMID:
30833470
PMCID:
PMC6477908
[Available on 2020-05-01]
DOI:
10.2337/db18-0686
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