The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies

Abstract

Monogenic autoinflammatory diseases encompass a distinct and growing clinical entity of multisystem inflammatory diseases with known genetic defects in the innate immune system. The diseases present clinically with episodes of seemingly unprovoked inflammation (fever, rashes, and elevation of acute phase reactants). Understanding the genetics has led to discovery of new molecules involved in recognizing exogenous and endogenous danger signals, and the inflammatory response to these stimuli. These advances have furthered understanding of innate inflammatory pathways and spurred collaborative research in rheumatology and infectious diseases. The pivotal roles of interleukin (IL)-1beta in cryopyrin-associated periodic syndromes, tumor necrosis factor (TNF) in TNF receptor-associated periodic syndrome, and links to inflammatory cytokine dysregulation in other monogenic autoinflammatory diseases have resulted in effective therapies targeting proinflammatory cytokines IL-1beta and TNF and uncovered other new potential targets for anti-inflammatory therapies.

Figure 1

Proposed mechanism of activation of proinflammatory signaling pathways in cryopyrin-associated periodic syndromes(CAPS); familial Mediteranean fever (FMF); pediatric granulomatous arthritis (PGA); pyogenic arthritis, pyoderma gangrenosum, and acne(PAPA) syndrome; and tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS). A, Unlike wild-type NALPS, mutated NALP3 (which causes CAPS) is constitutively activated and thought to oligomerize and bind to adapter molecules ASC and CARDINAL to form an active catalytic complex with two pro–caspase-1 molecules, Via autocatalysis, this complex generates active caspase-1, which cleaves inactive pro–interleukin(II)-1β to its active form, IL-1β. Wild-type pyrin can inhibit inflammasome activation by sequestraton of ASC or by direct binding to caspase-1. Mutated pyrin (which causes FMF) cannot exert its inhibitory effect on the inflammasome, leading to unoposed nflammasome activation. Wild-type PSTPIPI, another regulatory molecule of the NALP3 inflammasome, binds to pyrin. Mutated PSTPIP1 (which causes PAPA) cannot dissociate from its binding to pyrin, leading to uninhibited inflammasome activity. B, Bacterial peptidoglycans stimulate the NOD2 nflammasome. RIP2 is recruited, leading to activation of nuclear factor (NF)-κB and mitogen activated protein kinease (MAPK) signaling pathways. Mutations in the NACHT domain (which cause PGA) lead to presumed autoactivation of NOD2 and constitutive activation NF-κB and proinflammatory cytokines C, TNFR1 molecules are transported from endoplasmic reticulum (ER) to the Golgi and then to the cell surface. Wild type TNFR1 complexes are bound to extracellular TNF, leading to NF-κB activation. Receptor cleavage from the cell surface abrogates; receptor signaling and the soluble receptor can buffer soluble TNF. Mutated TNFR1 (which causes TRAPS) is misfolded and cannot be transported to the cell surface. Misfolded TNFR1 is sequestered in the ER, where it may lead to abnormal signaling.