SCHNITZLER AND SAPHO SYNDROMES: A MOLECULAR LINK BETWEEN P2X7 RECEPTOR AND INFLAMMASOME COMPLEX

Autoinflammatory diseases are a group of disorders characterized by recurrent unprovoked inflammatory events in absence of autoantibodies or autoreatcive T cells. At least eight forms are well characterized: 1) Familial Mediteranean Fever (FMF), 2) hypergammaglobulinemia D with periodic fever (HIDS), 3) tumor necrosis factor receptor-associated periodic syndrome (TRAPS), 4) Muckle-Wells syndrome (MWS), 5) familial cold autoinflammatroy syndrome (FCAS), 6) chronica infantile neurologic cutaneous articular (CINCA) syndrome, 7) Pyogenic sterile Arthritis, Pyoderma gangrenosum and Acne syndrome (PAPA) and 8) Blau syndrome. Recently also Schnitzler and SAPHO (Synovitis Acne Pustolosis Hyperostosis Osteitis) syndromes have been added to the list. With the exception of FMF these disorders are rare. In many of these diseases there is a fundamental alteration in the IL-1 (FCAS, MWS, CINCA, HIDS, FMF, PAPA) or TNF pathway (TRAP). Recent advances in molecular genetics of FACS, MWS and CINCA have led to the identification of the likely cause of deregulated IL-1 secretion. Processing and release of IL-1 occur in a macromolecular complex termed inflammasome which includes the proteins the proteins ASC, NALP3, Caspase-1 and Cardinal. The mechanism of inflammasome activation is obscure. However, it is well known that extracellular ATP is the most potent physiological activator so far identified. Extracellular ATP-mediated activation of caspase-1 occurs via a receptor named P2X7 (P2X7R). Mice deficient of constituents of the inflammasome (es ASC) are unresponsive to P2X7R-mediated stimulation but molecular link between P2X7R and inflammasome has not been elucidated. Here we have investigated the role of the P2X7R and of the inflammasome components ASC and NALP3 in the pathogenesis of Schnitzler and SAPHO syndromes. The results show that PBMCs from Schnitzler patients present a defective pathway of IL-1ß processing and secretion which allows substantial IL-1ß release also in the absence of the “second hit” usually required. Therapies aimed at normalizing inflammasome function might help to correct the unbalanced IL-1ß secretion typical of this syndrome. In the SAPHO patient a deregulation of the extracellular ATP-dependent P2X7-IL-1ß axis is suggested, that prompted to begin treatment with the interleukin-1 receptor antagonist (IL-1Ra) anakinra (100mg/day). The blockade of IL-1 signalling had a sustained effect, with remission of signs and symptoms and normalization of acute phase markers. The dosage of anakinra was then gradually reduced and the patient is still symptom-free. In any case, since a positive response to anti-TNFα agents has also been observed, the precise pathogenetic role of IL-1β and TNFα is a matter for further investigations.