International Journal of Molecular Sciences Review Monogenic Autoinflammatory Diseases: State of the Art and Future Perspectives Giulia Di Donato †, Debora Mariarita d’Angelo †, Luciana Breda and Francesco Chiarelli * Department of Pediatrics, University of Chieti, 66100 Chieti, Italy;
[email protected] (G.D.D.);
[email protected] (D.M.d.);
[email protected] (L.B.) * Correspondence:
[email protected]; Tel.: +39-0871-358015; Fax: +39-0871-574538 † These authors contributed equally to this work. 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 Citation: Di Donato, G.; d’Angelo, great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently D.M.; Breda, L.; Chiarelli, F.