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A systematic approach to autoinflammatory syndromes: a spelling booklet for the beginner

ABSTRACT Introduction: Hallmark of autoinflammatory syndromes (AIS) is the periodic recurrence of ‘sterile’ inflammatory attacks characterized by fever and organ- or tissue-specific inflammation. Basic research projects over the last two decades have boosted our understanding of pathological pathways, mainly involving interleukin (IL)-1 biosynthesis, and also revealed that their dysregulation results from genetically-heterogeneous inborn errors of innate immunity and leads to multiple inflammatory phenotypes. Starting from the evidence of poor response to IL-1 inhibitors of some patients with multi-organ inflammation, further research studies have disclosed a crucial role for nuclear factor (NF)-κB and type I interferon (IFN) in specific AIS. Presently, new genetically-defined AIS have been identified, following the in-depth analysis of molecular pathways which involve either constitutive NF-κB activation or IFN signaling. Areas covered: This review is intended as a spelling booklet to help clinicians approaching patients with AIS in a simple way, using the component of the innate immunity they mainly affect. AIS have been split into 4 groups: IL-1-mediated disorders, NF-κB-mediated disorders, IFN-mediated disorders, and syndromes with still unraveled pathogenetic mechanisms or without any dominating cytokine involved. This classification has mere scholastic purposes and does not reflect the intimate complexity of each disorder discussed herein. Expert commentary: The understanding of dysregulated molecular pathways driving specific phenotypes in most AIS has prompted numerous projects to discover therapies targeting directly cytokine-mediated manifestations in such problematic patients, hopefully aimed to decrease or cancel inflammation and lead to a drastic change in patients’ lives. The future has only begun.