Systemic autoinflammatory diseases

Abstract

Systemic autoinflammatory diseases (SAIDs) are a growing group of disorders caused by a dysregulation of the innate immune system leading to episodes of systemic inflammation. In 1997, MEFV was the first gene identified as disease causing for Familial Mediterranean Fever, the most common hereditary SAID. In most cases, autoinflammatory diseases have a strong genetic background with mutations in single genes. Since 1997 more than 30 new genes associated with autoinflammatory diseases have been identified, affecting different parts of the innate immune system. Nevertheless, for at least 40-60% of patients with phenotypes typical for SAIDs, a distinct diagnosis cannot be met, leading to undefined SAIDs (uSAIDs). However, SAIDs can also be of polygenic or multifactorial origin, with environmental influence modulating the phenotype. The implementation of a disease continuum model combining the adaptive and the innate immune system with autoinflammatory and autoimmune diseases shows the complexity of SAIDs and the importance of new methods to elucidate molecular changes and causative factors in SAIDs. Diagnosis is often based on clinical presentation and genetic testing. The timeline from onset to diagnosis takes up to 7.3 years, highlighting the indisputable need to identify new treatment and diagnostic targets. Recently, other factors are under investigation as additional contributors to the pathogenesis of SAIDs. This review gives an overview of pathogenesis and etiology of SAIDs, and summarizes recent diagnosis and treatment options.

Keywords: Inflammasomes; Inflammation; Innate immunity; Periodic fever; Systemic autoinflammatory disease.

Fig. 1. Inflammatory cascade.

Upon recognition of PAMP (see Table 2) and DAMP by intracellular sensors, multimeric protein scaffolds called inflammasomes are formed. As a result of this formation, pro-Caspase-1 is activated by proteolytic cleavage and further converting pro IL-1β and pro IL-18 to their bioactive form, which is released into the bloodstream. IL-1 receptors sense IL-1β and reacts by activating the NF-κB pathway. Active NF-κB is translocated to the nucleus where it promotes the transcription of NF-κB-dependent genes, such as NLRP3, pro-IL-β, pro-IL-18, and IL-6. The compositions of the inflammasome complexes are adapted from Ref. [21]. In the treatment section, different IL-1 blocking agents (Canakinumab, Rilonacept) and anti-IL-1 receptor antagonist (Anakinra) are depicted.