Yanick Crow

Neurogenetics and neuroinflammation

Publish at 18.11.2019

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Yanick Crow

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Our work has concentrated on the Mendelian inflammatory disorder Aicardi-Goutières syndrome (AGS). Clinical and genetic studies of this severe disease have helped to define a cell-intrinsic mechanism for the initiation of autoinflammation / autoimmunity by interferon-stimulatory nucleic acids, and have further emphasised the importance of type I interferon metabolism in the pathogenesis of certain non-Mendelian disorders, particularly systemic lupus erythematosus. A combination of clinical, genetic and immunological perspectives have led us to suggest that monogenic disorders associated with an upregulation of type I interferons represent a novel set of inborn errors of immunity due to abnormal sensing, inappropriate stimulation, or defective negative regulation of the type I interferon system – the so-called type I interferonopathies (Figure). This concept immediately suggests the possibility of ‘anti-interferon’ / ‘anti-inflammatory’ therapies, and has important implications for fundamental research into mechanisms of self / non-self discrimination and viral immunity.

 

Possible mechanisms leading to a type I interferonopathy

1. Inappropriate stimulation of the type I interferon response machinery due to an abnormal accumulation of an endogenous nucleic acid ligand

2. Inappropriate stimulation of the type I interferon response machinery due to a change in the composition of an endogenous nucleic acid ligand

3. Enhanced sensitivity or ligand-independent (constitutive) activation of a nucleic acid receptor signalling to the type I interferon pathway

4. Enhanced sensitivity or ligand-independent (constitutive) activation of a non-nucleic acid receptor component (e.g. an adaptor molecule) of the interferon-signalling pathway

5. Defective negative regulation of a nucleic-acid dependent type I interferon response

6. Mutations in other genes involved in non-nucleic acid related stimulation / regulation of the type I interferon pathway (including components of the adaptive immune response)

Abstract 09

Research: a scientific adventure

Our goal: to better understand genetic diseases to better treat them.