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
Program in Molecular Medicine, Diabetes Center of Excellence; Division of Diabetes, Department of Medicine; Program in Bioinformatics and Integrative Biology; Garber Lab
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Bioinformatics | Computational Biology | Endocrine System Diseases | Genetic Phenomena | Immune System Diseases | Immunopathology | Integrative Biology | Nucleic Acids, Nucleotides, and Nucleosides | Nutritional and Metabolic Diseases | Systems Biology
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.
DOI of Published Version
Diabetes. 2019 May;68(5):988-1001. doi: 10.2337/db18-0686. Epub 2019 Mar 4. Link to article on publisher's site
Russell, Mark A.; Redick, Sambra D.; Blodgett, David; Babon, Jenny Aurielle B.; Yang, Chaoxing; Kent, Sally C.; Derr, Alan G.; Kucukural, Alper; Garber, Manuel; and Harlan, David M., "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" (2019). Program in Bioinformatics and Integrative Biology Publications and Presentations. 149.