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 , pyoderma gan- drome (TRAPS), previously known as grenosum and 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 () 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, ry syndrome and Muckle-Wells syndrome. Nat Genet 2001; 29: 301-5. Pyrin-deficient mice show increased interestingly, also familial cold autoin- 9. FELDMANN J, PRIEUR AM, QUARTIER P et activation of caspase-1, resulting in the flammatory syndrome (FCAS), one of al.: Chronic infantile neurological cutaneous enhanced processing and secretion of the CIAS-1/NALP3-related diseases, is and articular syndrome is caused by muta- IL-1 . In fact, pyrin is able to interact characterized by elevated circulating tions in CIAS1, a gene highly expressed in β polymorphonuclear cells and chondrocytes. with the inflammasome component IL-6 levels that normalize after treat- Am J Hum Genet 2002; 71: 198-203. ASC through its PYD domain, which ment with anakinra (20). 10. NEVEN B, CALLEBAUT I, PRIEUR AM et al.: suggests a role for pyrin in the negative The therapeutic effect of anankinra and Molecular basis of the spectral expression of regulation of the inflammatory re- the clinical similarities that exist be- CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders sponse (Fig. 1B) (25). Moreover pyrin- tween autoinflammatory syndromes CINCA/NOMID, MWS, and FCU. Blood deficient mice also display an impaired and systemic JIA raise the possibility 2004; 103: 2809-15. apoptosis of macrophages through an therefore that at least some cases of 11. PRIEUR AM, GRISCELLI C: Arthropathy with rash, chronic meningitis, eye lesions, and IL-1 independent mechanism (25). systemic JIA could be due to gene mu- mental retardation. J Pediatr 1981; 99: 79-83. In patients with PAPA syndrome, an tations leading to uncontrolled IL-1 12. MICELI-RICHARD C, LESAGE S, RYBOJAD increase in IL-1β secretion is also pre- production. M et al.: CARD15 mutations in Blau syn- sent. The CD2BP protein, which is mu- In summary, it is probable that research drome. Nat Genet 2001; 29: 19-20. 13. WISE CA, GILLUM JD, SEIDMAN CE et al.: tated in the PAPA syndrome, has been in the future on the intracellular path- Mutations in CD2BP1 disrupt binding to PTP recently found to bind to pyrin and is ways of IL-1β activation will shed PEST and are responsible for PAPA syn- thought to exert a loss-of-function in- more light on pivotal mechanisms lead- drome, an autoinflammatory disorder. Hum teraction on the IL1β regulatory activi- ing to the persistence of inflammation Mol Genet 2002; 11: 961-9. 14. MUPPIDI JR, TSCHOPP J, SIEGEL RM: Life ty of this latter protein (Fig. 1C) (26). in rheumatic conditions and will allow and death decisions: secondary complexes Indeed, the deregulation of the com- the identification of new disease enti- and lipid rafts in TNF receptor family signal plex intracellular machinery leading to ties. transduction. Immunity 2004; 21: 461-5. caspase 1 and IL-1 activation seems 15. HUGGINS ML, RADFORD PM, MCINTOSH RS β et al.: Shedding of mutant tumor necrosis fac- to be crucial for the development and References tor receptor superfamily 1A associated with maintenance of many autoinflammato- 1. INTERNATIONAL FMF CONSORTIUM: An- receptor-associated ry disorders. cient missense mutations in a new member of periodic syndrome: differences between cell the RoRet gene family are likely to cause types. Arthritis Rheum 2004; 50: 2651-9. familial Mediterranean fever. Cell 1997; 90: 16. MARTINON F, TSCHOPP J: Inflammatory The tip of an iceberg? 797-807. caspases: linking an intracellular innate im- In various centers, including our own, 2. MCDERMOTT MF, AKSENTIJEVICH I, GAL- mune system to autoinflammatory diseases. involved in the genetic diagnosis of au- ON J et al.: Germline mutations in the extra- Cell 2004; 117: 561-74. cellular domains of the 55 kDa TNF receptor, 17. TSCHOPP J, MARTINON F, BURNS K: toinflammatory syndromes, only about TNFR1, define a family of dominantly inher- NALPs: a novel protein family involved in 20% of cases with typical clinical fea- ited autoinflammatory syndromes. Cell 1999; inflammation. Nat Rev Mol Cell Biol 2003; 4: tures submitted for genetic analysis 97: 133-44. 95-104. show mutations in one of the genes 3. MCDERMOTT MF: Autosomal dominant re- 18. AGOSTINI L, MARTINON F, BURNS K, MC- current fevers. Clinical and genetic aspects. DERMOTT MF, HAWKINS PN, TSCHOPP J: thus far associated with the autoinflam- Rev Rhum (Engl Ed.) 1999; 66: 484-91. NALP3 forms an IL-1beta-processing in- matory syndromes. This strongly sug- 4. AKSENTIJEVICH I, GALON J, SOARES M et flammasome with increased activity in Muck- gests the existence of a large number of al.: The tumor-necrosis-factor receptor-asso- le-Wells autoinflammatory disorder. Immuni- as yet unidentified autoinflammatory ciated periodic syndrome: new mutations in ty 2004; 20: 319-25. TNFRSF1A, ancestral origins, genotype-phe- 19. JANSSEN R, VERHARD E, LANKESTER A, disorders due to genetic alterations that notype studies, and evidence for further TEN CR, VAN DISSEL JT: Enhanced inter- remain to be discovered. genetic heterogeneity of periodic fevers. Am J leukin-1beta and interleukin-18 release in a Moreover, very recently it has been Hum Genet 2001; 69: 301-14. patient with chronic infantile neurologic, cut- shown that in systemic juvenile idiopa- 5. DRENTH JP, CUISSET L, GRATEAU G et al.: aneous, articular syndrome. Arthritis Rheum Mutations in the gene encoding mevalonate 2004; 50: 3329-33. thic arthritis (JIA) Anakinra may have a kinase cause hyper-IgD and periodic fever 20. HOFFMAN HM, ROSENGREN S, BOYLE DL dramatic therapeutic effect, similar to syndrome. International Hyper-IgD Study et al.: Prevention of cold-associated acute in- that observed in patients with CIAS- Group. Nat Genet 1999; 22: 178-81. flammation in familial cold autoinflammato- OBICI L, MANNO C, MUDA AO et al 1/NALP3 mutations (27,28). Systemic 6. .: First ry syndrome by interleukin-1 receptor antag- report of systemic reactive (AA) amyloidosis onist. Lancet 2004; 364: 1779-85. JIA differs substantially from the other in a patient with the hyperimmunoglobuline- 21. HOFFMAN HM, PATEL DD: Genomic-based JIA subsets (29) and is characterized by mia D with . Arthritis therapy: targeting interleukin-1 for autoin- clinical features (fever, rash, lymphad- Rheum 2004; 50: 2966-9. flammatory diseases. Arthritis Rheum 2004; 7. D'OSUALDO A, PICCO P, CAROLI F et al.: enopathy, serositis, arthritis) very simi- 50: 345-9. MVK mutations and associated clinical fea- 22. HAWKINS PN, LACHMANN HJ, AGANNA E, lar to those observed in autoinflamma- tures in Italian patients affected with autoin- MCDERMOTT MF: Spectrum of clinical fea- tory diseases. Prominent IL-6 produc- flammatory disorders and recurrent fever. Eur tures in Muckle-Wells syndrome and re- tion has been found to characterize sys- J Hum Genet 2005; 13: 314-20. sponse to anakinra. Arthritis Rheum 2004; 50: 8. HOFFMAN HM, MUELLER JL, BROIDE DH, 607-12. temic JIA with respect to other JIA sub- WANDERER AA, KOLODNER RD: Mutation 23. FRENKEL J, WULFFRAAT NM, KUIS W: An- types (30) and recently an anti-IL-6 of a new gene encoding a putative pyrin-like akinra in mutation-negative NOMID/CINCA

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syndrome: comment on the articles by Haw- tein, defining familial Mediterranean fever ties in juvenile idiopathic arthritis ? J Rheu- kins et al. and Hoffman and Patel. Arthritis and PAPA syndrome as disorders in the same matol 2003; 30: 1900-3. Rheum 2004; 50: 3738-9. pathway. Proc Natl Acad Sci USA 2003; 100: 30. DE BENEDETTI F, MARTINI A: Is systemic ju- 24. GRANEL B, SERRATRICE J, DISDIER P, 13501-6. venile rheumatoid arthritis an interleukin 6 WEILLER PJ: Dramatic improvement with an- 27. VERBSKY JW, WHITE AJ: Effective use of mediated disease ? J Rheumatol 1998; 25: akinra in a case of chronic infantile neurolog- the recombinant interleukin 1 receptor antag- 203-7. ical cutaneous and articular (CINCA) syn- onist anakinra in therapy resistant systemic 31. YOKOTA S, MIYAMAE T, IMAGAWA T et al.: drome. Rheumatology (Oxford) 2005 (E-pub onset juvenile rheumatoid arthritis. J Rheum- Therapeutic efficacy of humanized recombi- ahead of print). atol 2004; 31: 2071-5. nant anti-interleukin-6 receptor antibody in 25. CHAE JJ, KOMAROW HD, CHENG J et al.: 28. IRIGOYEN PI, OLSON J, HOM C et al.: Treat- children with systemic-onset juvenile idio- Targeted disruption of pyrin, the FMF pro- ment of systemic onset juvenile rheumatoid pathic arthritis. Arthritis Rheum 2005; 52: tein, causes heightened sensitivity to endo- arthritis with Anakinra. Arthritis Rheum 818-25. toxin and a defect in macrophage apoptosis. 2004; 50 (Suppl.): S437 32. DE BENEDETTI F, MARTINI A: Targeting the Mol Cell 2003; 11: 591-604. 29. MARTINI A: Are the number of joints involv- interleukin-6 receptor: a new treatment for 26. SHOHAM NG, CENTOLA M, MANSFIELD E ed or the presence of psoriasis still useful systemic juvenile idiopathic arthritis ? Arthri- et al.: Pyrin binds the PSTPIP1/CD2BP1 pro- tools to identify homogeneous disease enti- tis Rheum 2005; 52: 687-93.

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