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.

Rare catastrophes and evolutionary legacies: human germline gene variants in MLKL and the necroptosis signalling pathway

“…It is important to note that some patient mutations reported in the scientific literature may not have been submitted or updated by authors to the ClinVar database at the time of writing and thus are not included here. Disease causing variants in more upstream MLKL signalling modulators including death receptors, pattern recognition receptors, interferons and the NF-κB pathway are not presented here but are described in recent reviews [87][88][89][90]. note that this MLKL mutation also segregated with a homozygous in-frame deletion of one amino acid in the adjacent FA2H gene (fatty acid 2-hydroxylase), and a maternally inherited missense amino acid substitution in the X-linked gene AP1S2 (vesicle sorting and transport) in these patients.…”

A Pro-Inflammatory Signature Constitutively Activated in Monogenic Autoinflammatory Diseases

“…Although common clinical features of mAIDs have already been identified, a general molecular pattern that can characterise the spectrum of the mAIDs remains poorly understood. The mechanism of action of each gene associated with classical mAIDs has been extensively described in a recent review [9]. Although common clinical features of mAIDs have already been identified, a general molecular pattern that can characterise the spectrum of the mAIDs remains poorly understood.…”

“…Although common clinical features of mAIDs have already been identified, a general molecular pattern that can characterise the spectrum of the mAIDs remains poorly understood. The mechanism of action of each gene associated with classical mAIDs has been extensively described in a recent review [9].…”

Pyoderma Gangrenosum, Acne, and Hidradenitis Suppurativa Syndrome: A Case Report and Literature Review

“…The term “autoinflammatory diseases (AIDs)” was first proposed in 1999 to describe autosomal dominant periodic fever syndromes ( 1 ). Traditionally, it represents a group of hereditary recurrent non-invasive inflammatory diseases characterized by a dysfunction or hyperactivation of the innate immune system (lack of autoreactive T-cells and autoantibody production), with mutations in single genes involved in inflammation ( 2 ). As the study of AIDs deepens, it was found that such antigen-independent overactivation of the immune system played a key role in a variety of inflammatory skin diseases ( 3 – 5 ).…”