Contribution of deficient A-to-I RNA editing of dsRNA to aberrant immune activity in type 1 diabetes and autoimmune disorders

Despite their high prevalence, very little is known about the core mechanisms causing autoimmune disorders. Therefore, effective treatments for this common condition are rare to nonexistent.

RNA editing is a site-specific modification, altering the sequence of RNA transcripts from that encoded in the genome. Adenosine-to-inosine (A-to-I) conversion is the most common form of editing, and it is mediated by a family of double-stranded RNA (dsRNA)-specific adenosine deaminases. Editing deficiencies promote the accumulation of long endogenous dsRNAs in the cell, as editing tends to unwind the secondary structure of dsRNA. Cellular misrecognition of these transcripts as viral dsRNA can activate an interferon response, resembling the process featured in type 1 diabetes and other autoimmune disorders.

Largescale, comprehensive research of A-to-I RNA editing in dsRNA is yet an unmet challenge. Here, we set out to understand the role of dsRNA in initiating the innate autoimmune reaction. We conducted a largescale genomic study of A-to-I RNA editing in dsRNA using the Genotype-Tissue Expression (GTEx) project.

We show that editing in hyper-edited regions is negatively correlated with length and expression, pointing to the danger these potentially proinflammatory regions present. We found that hyper-edited regions are more likely to form dsRNA in comparison to synthesized control regions. Surprisingly, hyper-edited regions appear to be more conserved than control group regions. We are currently establishing the link between highly edited genomic regions and autoimmune conditions using GWAS data.

This suggested mechanism may revolutionize our understanding of autoimmunity and expose the unexplained process behind autoimmune disorders.