Autoinflammatory diseases

Abstract

The quintessence of chronic inflammation consists of a series of rare hereditary diseases characterized by the pathological, sometimes permanent, activation of one or other inflammatory pathway. Their study has made it possible to determine the precise mechanism of many of these diseases, to develop effective targeted therapies and to better understand the physiology of inflammatory responses. This lecture presents the main pathologies associated with either excessive production of IL-1, type I interferon, or multiple cytokines. The former correspond to " inflammasomopathies ", in reference to the disruption of the action of inflammasomes (cf. lecture^no. 1), in particular NLRP3. The functions of modified molecules - pyrin in periodic illness, mevalonate kinase in hyper IgD syndrome, PSTP1 in " PAPA " syndrome, and the TNF receptor type 1 - have been described, along with their abnormalities and consequences. The development of IL-1 neutralization treatments using biotherapies represents a decisive advance in the control of these dreaded chronic inflammatory pathologies.

The " interferonopathies " are a second group of IAMs characterized by excessive production of a second major mediator of inflammation : type I interferons, whose physiological action concerns the control of viral infections. Through multiple mechanisms (some twenty known to date), interferon production is deregulated, causing severe pathologies ranging from prenatal encephalopathies (Aicardi-Goutières syndrome) to lupus-like autoimmune diseases. Novel therapeutic strategies, including inhibition of interferon action by kinase inhibitors (JAK kinase 1 and 2) involved in intracellular signaling, were presented.

Finally, the possible link between these models and more common inflammatory pathologies such as gout, atheroma (cf. lecture 3) and possibly neurodegenerative diseases was discussed.