New monogenic autoinflammatory diseases—a clinical overview

Abstract

Translating pathogenic insights gained from monogenic defects that cause autoinflammatory diseases into novel therapies has dramatically improved the lives of patients with these syndromes. The last 15 years have focused on the central role of IL-1 in driving autoinflammatory phenotypes and on therapies blocking IL-1 signaling. Recent discoveries from patients unresponsive to IL-1 blockade have highlighted other key inflammatory mediators and pathways. New genetic discoveries have confirmed unifying mechanisms of autoinflammation, including dysregulation of danger sensing, cell stress, and immune-receptor signaling. Recent gene discovery in novel diseases has demonstrated new concepts. First, several complex clinical syndromes, caused by mutations leading to chronic type I interferon (IFN) production present with organ manifestations different from IL-1 mediated diseases including cerebral calcifications, myositis, and interstitial lung disease and the frequent occurrence of autoantibodies. These disorders introduce type I IFN’s as inflammatory mediators that cause autoinflammatory phenotypes. Second, conditions associated with high IL-18 production may provide a direct link between autoinflammation and macrophage activation syndrome. Third, dysregulation of inflammatory and cell differentiation pathways in nonhematopoietic cells, such as aberrant calcium signaling and impaired endothelial or keratinocyte development, provide an understanding of organ specificity in autoinflammatory disorders. Many of these discoveries highlight the intricate interconnections between autoinflammation, autoimmunity, immunodeficiency, and lymphoproliferation and suggest ways in which we may better diagnose and treat autoinflammatory diseases.

A Report of Novel STIM1 Deficiency and 6-Year Follow-Up of Two Previous Cases Associated with Mild Immunological Phenotype

“…Furthermore, this patient has several clinical features suggestive of autoinflammatory complications. Although he does not have pulmonary involvement (fibrosis) or severe ulceration and necrosis of the skin, which are typical for SAVI, he did have pustular rash developing at the cold exposed areas of the skin and acral surfaces, which have been reported in this condition (16).…”

Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities

“…Recently, the first report appeared of two IFN-c-receptor-deficient patients who acquired HLH in the absence of functional IFN-c-signalling, constituting formal proof that HLH can emerge independent of IFN-c, not only in animal models (Canna et al, 2013), but also in humans (Tesi et al, 2015c). Secondary HLH patients carrying heterozygous NLRC4 mutations have also been described (Canna & Goldbach-Mansky, 2015). Lastly, activating polymorphisms in IRF5, a TLR-signalling molecule and master transcription factor for pro-inflammatory cytokines, were associated with susceptibility to secondary HLH (Yanagimachi et al, 2011a,b).…”

“…Persistent high levels of otherwise NK cell-stimulating cytokines, like IL12 or IL18, might overactivate NK cells, predisposing to activationinduced apoptosis, or cause exhaustion and insensitivity to further cytokine stimulation Canna & Goldbach-Mansky, 2015). Recent evidence indicates chronic IL6 exposure is involved.…”

“…Such mutations result in caspase-1 overactivation, excessive IL18 production and systemic macrophage activation, underscoring the involvement of innate pathways in secondary HLH (Canna & Goldbach-Mansky, 2015).…”

Weathering the Storm: Improving Therapeutic Interventions for Cytokine Storm Syndromes by Targeting Disease Pathogenesis

“…TLRs are not the only innate immune receptor implicated in the development of MAS, as patients with activating mutations in the gene encoding NLRC4 spontaneously develop an autoinflammatory syndrome with a predisposition to the development of MAS, termed NLRC4-MAS (44, 45). NLRC4 can direct the assembly of inflammasomes leading to the activation of the proinflammatory cytokines IL-1 and IL-18, which have been implicated in the pathogenesis of MAS and are produced by cells of the innate immune system (46). These preclinical and clinical data suggest that heightened innate immune responses are sufficient to drive MAS in certain scenarios.…”