PAPA Syndrome and the Spectrum of PSTPIP1-Associated Inflammatory Diseases

Abstract

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome was the first described autoinflammatory disease caused by mutations in the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1, also known as CD2BP1) gene. However, in the last years, the spectrum of PSTPIP1-associated inflammatory diseases (PAID) has expanded encompassing PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome and the anecdotal description of other clinical phenotypes. Besides dysregulation of IL-1ß release from activated PAPA monocytes that requires activation of the NLRP3 inflammasome, PSTPIP1 mutations have an impact on the formation of podosomes and filopodia which might be an additional pathogenic mechanism. The serum concentrations of the endogenous TLR4 agonists myeloid-related proteins (MRP) 8 and 14 are characteristic features of these diseases and might play a central role in the pathogenesis. Here, we give an overview about the expanding spectrum of autoinflammatory diseases due to mutations in PSTPIP1 and insights into their pathogenesis.