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.
Mark A RussellSambra D RedickDavid M BlodgettSarah J RichardsonPia LeeteLars KrogvoldKnut Dahl-JørgensenRita BottinoMarcela BrissovaJason M SpaethJenny Aurielle B BabonRachana HaliyurSimeon I TaylorChaoxing YangSally C KentAlan G DerrAlper KucukuralManuel G GarberNoel G MorganDavid M HarlanPublished in: Diabetes (2019)
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.
Keyphrases
- type diabetes
- induced apoptosis
- cell cycle arrest
- single cell
- oxidative stress
- cell therapy
- cardiovascular disease
- endoplasmic reticulum stress
- flow cytometry
- stem cells
- signaling pathway
- machine learning
- poor prognosis
- cell death
- binding protein
- kidney transplantation
- protein protein
- big data
- immune response
- small molecule
- cell surface
- toll like receptor
- cell proliferation
- nuclear factor
- amino acid
- heat shock protein
- case report
- pi k akt
- skeletal muscle