Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis

Abstract

Purpose of review: The genetic and clinical characterizations of monogenic autoinflammatory syndromes have led to ground breaking insights into the regulation of inflammatory responses to endogenous and exogenous inducers or triggers of inflammation and continue to uncover key inflammatory pathways of the innate immune system. This article summarizes recent progress in the clinical aspects and understanding of the pathogenesis of this growing spectrum of diseases.

Recent findings: The understanding of the spectrum of organ manifestations in autoinflammation was expanded by the discovery of two novel monogenic diseases both caused by the absence of an anti-inflammatory signal and added evidence that increased IL-1 signaling can cause aseptic osteolytic bone lesions and that the absence of IL-10 signaling causes inflammatory enterocolitis in neonates. New knock in animal models for TNF-receptor-associated periodic syndrome, and familial Mediterranean fever and cryopyrin-associated periodic syndromes allow insights into the complexity of the dysregulated immune pathways. Exploring 'triggers' of the NLRP3 inflammasome spurred studies of tissue inflammation in diseases including gout and those that previously have not been considered inflammatory in nature such as diabetes, fibrosing lung disease and possibly coronary artery disease.

Summary: The genetic characterization of a growing number of monogenic autoinflammatory diseases has provided important insights into the phenotypic expression of single gene disorders and the complexity of the dysregulated inflammatory pathways leading to clinical disease. Knowledge obtained from these disorders is pertinent to a number of common disorders and provides new targets for drug development.

Figure 1

CAPS, FMF, and PAPA result in activation of the caspase-1 complex. In CAPS, mutations in NLRP3 result in increased assembly of the NLRP3 inflammasome and active caspase-1 through interactions with cardinal, ASC, and procaspase-1. In PAPA, mutations in PSTPIP1 result in its increased binding to pyrin and activation of active caspase-1. In FMF, mutant pyrin is pro-inflammatory in some conditions and results in caspase-1 activation. Active caspase-1 then cleaves pro-IL-1β to form active IL-1β and IL-18 in CAPS, FMF, and PAPA. In PGA, mutant NOD2 binds RIP-2 leading to increased NF-κB production and the transcription of pro-IL-1β and other inflammatory cytokines. In TRAPS, the mutant TNF receptor (TNFR) is sequestered in the endoplasmic reticulum leading to NF-κB production and transcription of a number of pro-inflammatory cytokines. An inflammatory feedback loop is generated through the production of TNF-α that can bind and signal through the wild-type TNFR on the cell surface. Toll-like receptor (TLR) stimulation in vitro induces pro-IL-1β and other cytokine production and models an essential first step in initiating an inflammatory response.