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 MA, Redick SD, Blodgett D, Babon JA, Yang C, Kent SC, Derr AG, Kucukural A, Garber M, Harlan DM. (2019). 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 Bioinformatics and Integrative Biology Publications and Presentations. https://doi.org/10.2337/db18-0686. Retrieved from https://escholarship.umassmed.edu/bioinformatics_pubs/149