Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling

Abstract

Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.

A molecular signature for delayed graft function

“…Immunological response to “danger signals” may lead to excessive activation of proinflammatory cytokines and chemokines, consequently leading to organ damage over time, as observed in the case of autoimmune diseases, where there is a loss in ability to downregulate/attenuate proinflammatory signalling (de Jesus, Canna, Liu, & Goldbach‐Mansky, 2015). This suggests that donor characteristics are important for DGF occurrence and may be linked to organismal/organ stress levels in relation to the type of organ donation (Bon et al, 2012; Morrissey & Monaco, 2014).…”

Interleukin-1β/Interleukin10 Ratio Produced by Monocytes as a Biomarker of Neuroinflammation in Autism

“…Certain auto-inflammatory syndromes are caused by gene mutations that result in dysregulated, excessive IL-1β production 36. These subjects are known to manifest various neuropsychiatric symptoms and seizures [36,37]. In rodent models of seizures, treatment-resistant seizures were shown to be associated with neuro-inflammation triggered by IL-1β [38].…”

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

“…89 Genetic variants in IL-1-related genes associate with the risk for ESRD. 90,91 The pathogenic concept of CAPS was verified by dramatic clinical responses to IL-1 inhibitors such as the IL-1b neutralizing antibody canakinumab (Ilaris), the soluble decoy receptor rilonacept (Arcalyst), and the recombinant human IL-1Ra (Kineret).…”

“…90,91 The pathogenic concept of CAPS was verified by dramatic clinical responses to IL-1 inhibitors such as the IL-1b neutralizing antibody canakinumab (Ilaris), the soluble decoy receptor rilonacept (Arcalyst), and the recombinant human IL-1Ra (Kineret). 89 Important for nephrologists is renal amyloidosis secondary to CAPS or any other hereditary systemic (auto-) inflammatory disorder that responds well to therapeutic IL-1 inhibition (Table 4). [92][93][94][95][96] Numerous other IL-1b-, IL-1a-, or IL-1R1-specific biologic drug candidates and one oral caspase-1 inhibitor are currently in clinical trials.…”