An Update on Autoinflammatory Diseases: Inflammasomopathies

Autoinflammatory diseases are driven by abnormal innate immune activation. In the case of inflammasomopathies, these are all attributable to activation of an inflammasome complex, nucleated by an innate immune sensor such as NLRP3. This review will focus on recent advances that have helped to elucidate the role of three other sensors (NLRP1, NLRC4 and pyrin) which can also cause inflammasomopathies.

Mutations in pyrin (S242R or E244K) destroy an inhibitory 14-3-3 binding site and result in the newly characterised disease pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Moreover, a separate autoinflammatory disease driven by mevalonate kinase deficiency leads to defective RhoGTPase prenylation and subsequent loss of pyrin S242R phosphorylation, suggesting a shared mechanism of disease. Other inflammasomes such as NLRP1 and NLRC4 have had novel mutations described recently, which inform about the specific domains required for activation and autoinhibition. This review covers recent advances in the study of inflammasomopathies, focussing on gene discoveries that elucidate new pathogenic mechanisms.