Monogenic Autoinflammatory Diseases: State of the Art and Future Perspectives

Abstract

Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways. In most cases, they have a strong genetic background, with mutations in single genes involved in inflammation. Therefore, they can derive from different pathogenic mechanisms at any level, such as dysregulated inflammasome-mediated production of cytokines, intracellular stress, defective regulatory pathways, altered protein folding, enhanced NF-kappaB signalling, ubiquitination disorders, interferon pathway upregulation and complement activation. Since the discover of pathogenic mutations of the pyrin-encoding gene MEFV in Familial Mediterranean Fever, more than 50 monogenic autoinflammatory diseases have been discovered thanks to the advances in genetic sequencing: the advent of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have allowed a better understanding of the underlying innate immunologic pathways and pathogenetic mechanisms, thus opening new perspectives in targeted therapies. Moreover, this field of research has become of great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently active or recently concluded, allowing us to hope for considerable acquisitions for the next few years. General paediatricians need to be aware of the importance of this group of diseases and they should consider autoinflammatory diseases in patients with clinical hallmarks, in order to guide further examinations and refer the patient to a specialist rheumatologist. Here we resume the pathogenesis, clinical aspects and diagnosis of the most important autoinflammatory diseases in children.

Keywords: inflammasomopathies; interferonopathies; next generation sequencing; periodic fever; systemic autoinflammatory diseases.

Figure 1

Inflammatory signalling pathways in AIDs. The first step of inflammatory response is the recognition of pathogens’ conserved structures (PAMP) by PPR of intracellular sensors (including NLR domains, ALR and pyrine), with the formation of a multimeric proteic complex, called inflammasome. The inflammasome receptors interact with the adapter protein ASC, leading to the activation of Caspase 1, which converts pro-IL-1β and pro-IL-18 to their bioactive forms. Caspase 1 also cleavages the Gasdermin-D (GSDMD), whose N-terminal domain (GSDMD-N) forms cytotoxic pores in the lipidic cellular membrane, causing pyroptosis. Also, PAMPs are sensed by TLRs (mainly TLR-4) or NOD2 receptors and activate NF-κB pathway, enhancing NLRP-3 transcription. The intra-cytoplasmic accumulation of viral or endogenous nucleic acids is sensed by others proteins, like cGAS, MDA5 and DDX58, which activate STING and therefore IR3-IR7 factors. These latter translocate to the nucleus, stimulating the transcription of type I IFN genes. STING also directly activates NFkB signalling. Most of the described signalling pathways activate NF-κB signalling, thus stimulating the transcription of NF-κB-dependent genes (NLRP3, pro-IL-β, pro-IL-18, and IL-6) and promoting a positive feedback effect. Alterations at different levels of this complex mechanism are associated with the development different AIDs. Abbreviations: PAMP (pathogen associated molecular patterns); PRR (pattern recognition receptors); NLR (Nucleotide-binding oligomerization domain (NOD)-like receptors); ALR (Absence in melanoma 2 (AIM2)-like receptors); NLRP-3 (NLR family pyrin domain containing 3); NF-κB (NF-kappaB); IFN (interferon); IRF (IFN regulatory factor); CGAS (cyclic GMP-AMP synthase); MDA5 (melanoma differentiation-associated protein 5; DDX58 (DExD/H box RNA helicase); STING (Stimulator of interferon genes).