The expanding pathways of autoinflammation: a lesson from the first 100 genes related to autoinflammatory manifestations

Abstract

AutoInflammatory Diseases (AIDs) are a group of innate immune system disorders characterized by sterile inflammation without evidence of pathogenic autoantibodies or auto-reactive T lymphocytes. An expanding spectrum of genes and molecular pathways are associated with AIDs. Inflammasomopathies are secondary to dysregulation of multi-protein complexes, called inflammasomes, leading to an excessive maturation and secretion of IL1β and IL18. Patients present with persistent or recurrent systemic inflammation, abdominal and chest pain, skin rashes and are sensible to IL1 inhibitors. Unfolded proteins response causes a small number of AIDs that we propose to call immuno-proteinopathies, characterized by recurrent fevers and deep tissues inflammation. Other inflammatory conditions can occur in case of abnormalities of actin polymerization and the term of immuno-actinopathies is proposed. Generalized pustular psoriasis is a marker of autoinflammation mainly affecting the keratinocytes. Specific treatment targeting the p40 subunit of IL12 and IL23 or IL-17 are usually effective. Granulomatous inflammation characterizes AIDs related to NOD2 signaling defects. Defects in the ubiquitin-proteasome system cause a group of relopathies and some interferonopathies related to defect of the proteasome function (CANDLE syndrome). Gain of function of proteins regulating the production of type I interferons lead to severe inflammatory conditions, called interferonopathies. The JAK/STAT inhibitors are usually effective in these latter conditions. In conclusions, the identification of the main intracellular pathways involved in rare monogenic AIDs allows not only the proper classification of different conditions, but also highlight a pivotal role of possible novel therapeutic targets for the future.

Keywords: Actin; Autoinflammatory diseases; Caspase recruitment domain; Inflammasome; Interferon; Interleukin receptors; Proteasome system; Ubiquitin; Unfolded proteins response.