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Definition and characterization of type I interferonopathies

Final Report Summary - T1-IFN (Definition and characterization of type I interferonopathies)

The type I interferonopathy concept was formally introduced into the medical literature in 2011, referring to a novel grouping of Mendelian inborn errors of immunity in which enhanced type I interferon production was posited as directly relevant to pathogenesis, as opposed to representing a simple biomarker. The award of a Consolidator Fellowship to Professor Yanick Crow in 2013 has enabled the PI and his group to further develop this premise, the highlights of which have included the identification of several novel type I interferonopathies (specifically, due to mutations in MDA5, DNASE2, ISG15, USP18, SKIV2l and PNPT1). The funding awarded by the ERC has facilitated work which has refined and expanded the phenotypic spectrum of the type I interferonopathies (for example, to include non-syndrome spastic paraparesis and bilateral striatal necrosis). Importantly, Professor Crow has gone on to develop and utilise novel screening methods to identify patients demonstrating enhanced type I interferon signalling – most recently the characterisation of a digital ELISA single molecule array (Simoa) platform allowing, for the first time, the measurement of protein levels of all interferon alpha subtypes in patient material (most frequently, blood and cerebrospinal fluid). In this way, 26 distinct genotypes are now considered as type I interferonopathies (from a number less than 10 at the start of the project).

Looking broadly at the development of the field over the last five years, this project has led to an appreciation of self / non-self recognition as a fundamental tenet of the type I interferonopathy phenomenon. Thus, recognition of foreign nucleic acids is the primary mechanism by which a type I interferon–mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e. the absolute requirement to reliably differentiate self–nucleic acids from non-self nucleic acids. Thus, Professor Crow suggests that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self / non-self discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states.

Finally, not only has this work provided fundamental new insights in the biology of nucleic acid signalling, it has enabled the possibility of directed therapies. In particular, a significant impact of the Fellowship awarded to Professor Crow has been the use of JAK1 inhibition in the treatment of a number of discrete type I interferonopathies, and an early clinical trial involving the use of reverse transcriptase inhibitors in certain Aicardi-Goutières syndrome related genotypes.