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

  • Russell, Mark A.
  • Redick, Sambra D.
  • Blodgett, David
  • Babon, Jenny Aurielle B.
  • Yang, Chaoxing
  • Kent, Sally C.
  • Derr, Alan G.
  • Kucukural, Alper
  • Garber, Manuel
  • Harlan, David M.
Publication Date
May 01, 2019
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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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