Figure 2.

Pathophysiology of autoinflammatory diseases: pathways leading to inflammasome formation and their downstream effects, including pore formation (Gasdermin D; GSDMD), induction of pyroptosis, and secretion of IL-1β and IL-18. Different stimuli for specific inflammasomes (NLRP1, NLRP3, AIM,...) are shown. The proteins associated with heritable autoinflammatory conditions are denoted with yellow lightning bolts. These include MVK (associated with HIDS) and PSTPIP1 (PAPA syndrome) of which the pathways are reported to culminate in derailed Pyrin activity. Pyrin is regulated through Rho-GTPase via PNK1/PNK2. FMF is the most common Pyrin-associated autoinflammatory disease. Besides Pyrin, NLRP1, NLRP3, NLRP12 and NLRC4 are other inflammasomes, respectively associated with NLRP1 deficiency, CAPS, FCAS2, and NLRC4-MAS. Impaired function of Lipin-2, an indirect regulator of NLRP3, leads to Majeed syndrome. Deleterious IL1RN mutations underlie IL-1R antagonist deficiency (DIRA), which is the natural antagonist of the IL-1 receptor. Likewise, mutations in IL36N lead to a defective function of the IL-36 receptor antagonist and cause deficiency of IL-36R antagonist (DITRA). TRAPS is caused by mutations in the TNF receptor (TNFRSF1A) which affects NFκB as a master regulator of transcription of inflammasome-related proteins. Deficiency of RIPK1, a regulator of the NF-κB and MAPK pathways, lead to AIEFL. NOD2 is another protein that activates NFκB and of which deleterious variants underlie Blau syndrome. Created with Biorender.com. Adapted with permission from “Exploring the immune horizon: systemic inflammatory diseases in the era of SARS-CoV-2 and beyond.” by Hoste L. (30). http://hdl.handle.net/1854/LU-01HFQA9EK0NY3S6HEKN4YD1C7P. The PhD thesis of Levi Hoste was published online by Ghent University – Department of Internal Medicine and Pediatrics under the license CC-BY. https://biblio.ugent.be/publication/01HFQA9EK0NY3S6HEKN4YD1C7P.