Clinical and Experimental Rheumatology 2005; 23: 133-136. EDITORIAL Inherited autoinflammatory Inherited autoinflammatory syndromes neous and articular syndrome (CINCA, syndromes: An expanding (IAS) are a group of recently identified MIM 607115) represent a wide spec- new group of chronic monogenic diseases characterized by trum of autosomic dominant diseases recurrent episodes of systemic inflam- related to different mutations in a sin- inflammatory diseases mation presenting as fever associated gle gene, CIAS1 (cold-induced autoin- with a number of clinical manifesta- flammatory syndrome 1, or NALP-3), M. Gattorno, A. Martini tions such as rash, serositis (peritonitis, encoding a protein called cryopyrin (8, pleuritis), lymphadenopathy and arthri- 9, 10). FCAS is characterized by epi- Marco Gattorno, MD; Alberto Martini, tis. Symptoms may present with differ- sodes of rash, fever and arthralgia after MD, Prof. and Head of Dept. of Pediatrics. Pediatria II, Istituto G. Gaslini, Diparti- ent degrees of severity and vary among exposure to cold. MWS consists of re- mento di Pediatria, Università di Genova, different diseases as well as within the current episodes of urticarial rash, fe- Genova, Italy. same disease. Recurrent episodes and ver and abdominal pain. Sensorineural Please address correspondence to: subclinical chronic inflammation may deafness and amyloidosis may present Prof. Alberto Martini, MD, Department lead to systemic reactive amyloidosis as late complications. CINCA, repre- of Pediatrics, University of Genova, (AA) that, for some of these condi- sents the most severe disorder and is Pediatria II, IRCCS G. Gaslini, Largo tions, represents the most severe long- characterized by neonatal onset urticar- G. Gaslini no. 5, 16147 Genova, Italy. term complication. ial-like skin lesions, persistent systemic Received on April 6, 2005; accepted The discovery of MEFV as the suscep- inflammation, central nervous system on April 7, 2005. tibility gene for autosomal recessive involvement (chronic meningitis) and © Copyright CLINICAL AND EXPERIMEN- familial Mediterranean fever (FMF, growth cartilage alterations leading to TAL RHEUMATOLOGY 2005. MIM 249100) in 1997 represented the severe bone dysmorphisms (11). Key words: Autoinflammatory beginning of a new era for monogenic Two other diseases belonging to the syndromes, TNF-associated periodic IAS (1). FMF is characterized by fever group of IAS are characterized by a syndrome, mevalonate kinase attacks lasting 1 to 3 days accompanied prevalent localization of inflammation deficiency, cryopyrin, interleukin-1, by serositis (peritonitis, pleuritis), arth- to specific organs and tissues. Blau syn- PAPA syndrome, periodic fevers. ritis and erysipelas-like skin lesions. drome (MIM 186580) is an autosomal MEFV is mapped on the chromosome dominant disorder characterized by the 16p13.3 and encodes pyrin (marenos- recurrent granulomatous inflammation trin). Amyloidosis is a frequent and se- of joints, skin and eyes caused by muta- vere complication. tions in the NOD2/CARD 15 gene (12). TNF-receptor associated periodic syn- Pyogenic sterile arthritis, pyoderma gan- drome (TRAPS), previously known as grenosum and acne syndrome (PAPA, Hibernian fever, is an autosomal domi- MIM 604416) is a disorder caused by nant disorder characterized by fever mutations in the CD2-binding protein 1 (often lasting for 3 to 4 weeks) accom- (CD2BP1) and is characterized by re- panied by myalgia, arthralgia, rash and current episodes of aseptic abscesses of abdominal pain. The disease is due to the joints and skin due to the increased mutations in the gene of type I TNF re- recruitment and activation of polymor- ceptor (TNFRSF1A, chromosome 12p- phonuclear leukocytes (13). 13) (2). Reactive amyloidosis occurs in The existence of autoinflammatory about 15-25% of patients (3, 4). conditions caused by mutations of a sin- Hyper-IgD syndrome (HIDS, MIM gle gene represents important evidence 260920) is characterized by periodic that alterations of a limited number of episodes of fevers lasting 3 to 5 days, mechanisms involved in the regulation accompanied by rash, lymphoadenopa- or activation of the inflammatory re- thy and abdominal pain. It is caused by sponse are able to establish complex recessive mutations in the gene of mev- and long-lasting diseases. This issue alonate kinase (MVK, chromosome has also relevant implications for the 12q24) causing moderate enzyme defi- study of the etio-pathogenesis of multi- ciency (5). The occurrence of severe factorial rheumatic disorders. infections and amyloidosis have been Notably, genes involved in almost the recently reported as possible complica- all IAS syndromes encode for proteins tions (6, 7). involved in the control of crucial mech- Muckle-Wells syndrome (MWS, MIM anisms related to inflammation, such as 191900), familial cold autoinflamma- apoptosis and activation or modulation tory syndrome (FCAS, MIM 120100) of pro-inflammatory cytokines, such as and chronic infantile neurological cuta- IL-1β and TNF-α. 133 EDITORIAL Inherited inflammatory syndromes / M. Gattorno & A. Martini The TNF receptor system receptor-associated death domain, and pyrin domain (PYD) (16). In in- The pathogenesis of TRAPS is sup- TRADD) are involved. The activation flammasome the above-mentioned posed to be primarily related to a defect of this particular intracellular pathway functional domains are provided by 2 in the down-modulation of TNF. The leads to the activation of the caspase distinct proteins, the former belongs to binding of circulating TNF-α to mem- cascade that eventually results in cell the so called CATERPILLER family brane (TNFRs) leads to the recruitment apoptosis (14). Thus, it is possible that and consists in a member of the NALP of cytoplasmatic proteins that initiate a lack of control of TNF-induced apop- subfamily (NALP1 or NALP3), the lat- the intracellular signalling leading to tosis could also play a role in the patho- ter is a protein called ASC (apoptosis- the activation of transcriptor factors, genesis of TRAPS. associated speck-like protein contain- such as nuclear factor κB (NF-κB) and ing a CARD) that associates with Cas- activation protein 1 (AP-1) which ulti- Caspase 1 and IL-1β activation pase 1 through the interaction of two mately cause the production of inflam- IL-1β is produced as a 33-kD inactive CARD domains (Fig. 1A) (17). matory mediators and anti-apoptotic cytoplasmatic precursor (proIL1β) that As already mentioned, different muta- proteins (14). Activation of type I and must be cleaved to generate the biolog- tions in the NACTH domain of NALP3 type II TNFRs causes cleavage and ically active 17-kD isoform by a IL-1β- (or CIAS-1) are responsible for the shedding of the extra-cellular portions, converting enzyme, called Caspase 1. FCAS, MWS and CINCA phenotypes, which are able to bind TNF-α in the Factors regulating the activation of which are presumably due to an alter- circulation and therefore act as specific Caspase 1 have been the subject of in- ation in the regulation of caspase 1 acti- inhibitors. It has been suggested that tense investigation in recent years. Cas- vation. some mutations may interfere with the pase 1 can be activated by an intracel- Recent reports have documented in- process of shedding, leading to lack of lular multiprotein complex called in- creased IL-1β release associated with appropriate inhibition of circulating flammasome which is structurally CIAS1 mutations, (18, 19). These stud- TNF and therefore to uncontrolled in- organized in three functional domains: ies led to the therapeutic use of a re- flammation (2). However, TRAPS pa- i) a ligand sensing domain that is com- combinant IL-1 receptor antagonist tients display a normal shedding of posed of multiple repeats of motifs (Anakinra) in patients with FCAS, type II receptor that, in normal condi- such as the leucin-rich repeats (LRR), MWS and CINCA, and a rapid and dra- tions, represent the prevalent circulat- ii) an oligomerization domain (i.e. matic downregulation of the inflamma- ing soluble TNFR and some mutations NACTH) essential for subsequent tory response was seen soon after the are not associated to a defect of TNFR complex activation, iii) a recruitment introduction of the treatment (20-24). shedding (4, 15). domain that interacts directly with Cas- Notably, FMF and PAPA syndrome Notably, in the case of TNFRI the bind- pase 1 through domains of the death- also appear to primarily affect, albeit ing to TNF-α may lead to either fold family, such as the death domain through different mechanisms, the inflammation or apoptosis. In the latter (DD), death-effector domain (DED), function of caspase 1 and therefore are case, different signalling proteins (TNF caspase-recruitment domain (CARD) thought to be closely related to the ab- Fig. 1. Functional relationship among intracellular proteins involved in caspase 1 activation. A) Inflammasome is constituted by the functional interaction between NALP3 (cyropyrin) and ASC that associates and activates caspase 1. B) Pyrin has been proposed to associate with ASC protein and disrupt its inter- action with cryopyrin. C) CD2BP1 protein (mutated in the PAPA syndrome) is able to interact with pyrin, blocking its anti-inflammatory regulatory function (see text for complete explanation). 134 Inherited inflammatory syndromes / M. Gattorno & A. Martini EDITORIAL normal activation and secretion of IL- receptor antibody has been shown to be protein causes familial cold autoinflammato- 1β. a promising therapy (31, 32). However,