Type 1 interferopathies: keys to understanding clinical and tissue variations

The type I interferonopathies are rare genetic diseases associated with a disturbance in type 1 interferon (IFN I) signalling (interferons representing our first line of immune defence against viral infections). The type I interferonopathies are characterised by variable tissue/clinical expression, with central nervous system involvement, lung and skin features varying between these disorders. The Laboratory of Neurogenetics and Neuroinflammation, led at the Imagine Institute by Yanick Crow, in collaboration with clinicians from the Hôpital Necker-Enfants malades AP-HP, the Hôpital Robert DebréAP-HP and other hospitals, has uncovered one explanation for such variation. In a publication in the Journal of Clinical Immunology, the team showed that differential tissue/clinical involvement is determined, at least party, on the main production site of IFN I in the body.

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The laboratory of Neurogenetics and Neuroinflammation directed by Yanick Crow is interested in understanding the type I interferonopathies i.e. Mendelian diseases characterised by increased production of type I interferons (IFN I). Whilst up-regulation of type I interferon signalling is common across the type I interferonopathies, central nervous system involvement varies between these disorders, the basis of which remains unclear. The work performed by the Crow laboratory, in particular by the Master student Lorenzo Lodi and Drs Marie-Louise Frémond and Isabelle Melki, in close collaboration with Darragh Duffy's team (Institut Pasteur) and clinicians from the Hôpital Necker-Enfants maladies AP-HP, the Hôpital Robert Debré and other hospitals, has enabled us to begin to address this question.

Using the state-of-the-art Simoa technology (ultra-sensitive digital ELISA), interferon alpha protein was measured in the cerebrospinal fluid of patients with two monogenic type I interferonopathies (Aicardi-Goutières syndrome and STING-associated vasculopathy with onset in infancy, SAVI), and in individuals with systemic lupus erythematosus with neuropsychiatric features (a disease in which type I interferons are also considered to contribute to pathogenesis). Cerebrospinal fluid of patients with non-inflammatory hydrocephalus was used as control (thanks to a biobank resource developed in collaboration with Professeur Thomas Blauwblomme, Necker Hospital, and the team of Edor Kabashi, Imagine Institute).

Levels of interferon alpha in the cerebrospinal fluid of patients with monogenic type I interferonopathies and systemic lupus erythematosus with neuropsychiatric features were elevated as compared to controls. Interestingly, in patients with Aicardi-Goutières syndrome, where central nervous system involvement is predominant, interferon alpha levels were higher in the cerebrospinal fluid than in paired serum samples. The opposite was observed in SAVI, which mainly involves peripheral organs (skin and lung) and systemic inflammation. Given these data, we suggest that it is the primary site of type I interferon production in type I interferonopathies which determines, at least in part, the differential tissue/clinical involvement. As such, these results have the potential to inform the diagnosis of, and future therapeutic approach to, monogenic and multifactorial type I interferonopathies.