The Harlan and Kent Labs Resolved a 30 Year Debate by Locating Beta Cells in People with Type 1 Diabetes That Express Important Immune Pathway Gene Products
The central theme of UMass Chan Diabetes Center of Excellence (DCOE) type 1 diabetes (T1D) research is that the sought-after cure will require a thorough understanding of the processes causing the disease.
Published studies led by UMass Chan DCOE and University of Exeter investigators, in collaboration with Oslo University Hospital, Vanderbilt and Carnegie Mellon, sheds light on a long-standing enigma. That is, by far the greatest genetic risk for T1D is driven by the expression of important immune genes called “human leukocyte antigen class II” (HLA Class II) and yet human beta cells were not thought capable of expressing HLA Class II and other important genes supporting HLA Class II function. The HLA Class II and related gene products are usually expressed only in “professional immune cells.” This new research definitively shows that beta cells from individuals with T1D express these important gene products and thus resolves a three decades long debate.
Study Overview
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 T1D using both bulk-sorted and single beta cells. Consistent with immuno-histological studies, beta cells from donors with T1D 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 macrophage marker, CD68. Immuno-histological study of three independent recent-onset type 1 diabetic donor cohorts showed Class II protein and its transcriptional regulator Class II major histocompatibility complex trans-activator (CIITA) 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 demonstrates 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.
Full Publication in Diabetes
What's next?
Still to be understood is exactly how the HLA Class II pathway gene product expression may play a role in the loss of beta cells underlying T1D. The Harlan and Kent labs at the UMass Chan Diabetes Center of Excellence have developed techniques to study that next piece of the puzzle, thus providing a data-driven game plan to prevent the disease.