Impaired RNA editing in β-cells: a potential link to Type 1 Diabetes

In type 1 Diabetes (T1D), autoimmunity destructs β-cells in pancreatic islets. Although a role for genetic and environmental factors is recognized, the etiology of the disease remains unknown. We investigate a possible link between impaired RNA editing in β-cells and autoimmunity.

A GWAS study revealed rare variants of IFIH1 protecting against T1D. IFIH1 is a cytosolic receptor that recognizes double-stranded RNA (dsRNA) and elicits an inflammatory response. dsRNA, commonly introduced during viral infections, is also produced endogenously by retroelements and is dismantled by the adenosine-to-inosine editing enzyme ADAR1. Thus ADAR1 activity can prevent endogenous dsRNA from triggering an IFIH1-mediated inflammatory response.

Epidemiological studies indicate that T1D is preceded by a type-1-interferon transcriptional signature, but the evidence of viral infection is sparse. We therefore hypothesize that impaired RNA editing in β-cells might play a role in activating IFIH1 and triggering an innate immune response, contributing to autoimmune destruction of β-cells.

To assess a potential role for impaired RNA editing in T1D, we are using two models: ADAR1 knockdown in a human β-cell line and β-cell-specific ADAR1 knockout in mice. Preliminary experiments suggest that ADAR1 is required for proper cytokinesis in proliferating human β-cells. In-vivo, ADAR1 deletion in developing mouse β-cells results in a selection against mutated cells. Ongoing work uses a conditional model to inactivate Adar in adult β-cells, to assess the role of ADAR1 in preventing autoinflammation in adult islets.