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�:	Comprehensive review of rare hereditary autoinflammatory disorders


Nobuo Kanazawa

Department of Dermatology, Wakayama Medical University, Wakayama 641-0012, Japan

Tel.: +81 73 441 0661; fax: +81 73 448 1908
E-mail address: nkanazaw@wakayama-med.ac.jp
Abstract
Hereditary autoinflammatory syndromes are monogenic disorders with inborn errors of innate immunity and include a variety of diseases in some clinical categories; 1) periodic fever syndromes such as familial Mediterranean fever (FMF), hyper IgD syndrome with periodic fever (HIDS), tumor necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS), 2) pyogenic pustular diseases such as pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, deficiency for interleukin-1 receptor antagonist (DIRA) and deficiency for interleukin-36 receptor antagonist (DITRA), 3) granulomatous diseases such as Blau syndrome (BS) and early-onset sarcoidosis (EOS), and 4) newly-defined disorders categorized as autoinflammation, lipodystrophy and dermatoses (ALDD) syndrome. By identification of genetic abnormalities and subsequent analyses of molecular mechanisms underlying these disorders, critical in vivo pathways in inflammatory processes have been clarified and the disorders are recategoriged with their underlying dysregulated signaling pathways. The major and well-investigated disorders are inflammasomopathies with dysregulated NLRP3 inflammasome activation, including CAPS with NLRP3, FMF with MEFV, PAPA syndrome with PSTPIP1 and DIRA with IL1RN mutations. BS and EOS with NOD2 mutations are caused by dysregulated NOD2 signaling, corresponding to the dysregulated NLRP3 signaling in CAPS. In TRAPS with TNFRSF1 mutations, intracellular aggregation of abnormal TNFR1 protein seems to cause inflammation, similar to ALDD syndrome with PSMB8 mutations, in which ubiquitinated and oxidated proteins are accumulated intracellularly to cause inflammation. As there still remain a number of cases with predicted but undefined hereditary autoinflammatory syndromes, it is highly expected that a number of new disorders with dysregulated critical inflammatory pathways will be soon discovered by using the new next-generation sequencing technology.
Historical overview
The �autoinflammatory� diseases have recently been defined as an antonym of �autoimmune� diseases, for a spectrum of inflammatory diseases with dysregulated innate immunity demonstrating hyperactivation of neutrophil and/or macrophages [for review, 1-3]. Historically, presence of the prototypic familial Mediterranean fever (FMF; MIM#249100) has been known since the Roman era and hereditary cases with similar but different features have been reported as FMF-like syndromes. Periodic fever is the most characteristic common feature, while duration and interval of febrile attacks are variable and similar cases can be further distinguished by way of inheritance, ethnicity, other accompanying symptoms, development of amyloidosis, and effectiveness of colchicin [4]. In 1999, mutations in the tumor necrosis factor receptor superfamily 1 (TNFRSF1) gene, encoding TNFR1, have been identified to be responsible for autosomal dominant-type FMF-like syndrome or familial Hibernian fever, and the disease has been designated as TNFR-associated periodic syndrome (TRAPS; MIM#142680) [5]. As TNF is one of the key players on inflammation and innate immunity, the term �autoinflammatory syndromes� has been designated for such hereditary monogenic diseases with inborn errors of innate immunity. Actually, already in 1997, mutations in the Mediterranean fever (MEFV) gene had been identified to be responsible for FMF, but the precise role of pyrin, a new molecule encoded by this gene, was not sufficiently clarified immediately [6,7]. A pivotal role of pyrin in inflammation has been determined after identification of cryopyrin encoded by the gene cold-induced autoinflammatory syndrome 1 (CIAS1), whose mutations cause other periodic fever syndromes, familial cold-induced autoinflammatory syndrome (FCAS; MIM#120100) and Muckle-Wells syndrome (MWS; MIM#191900), and subsequently, chronic infantile neurological cutaneous and articular (CINCA) syndrome or neonatal onset multisystem inflammatory disease (NOMID; MIM#607115) [8-10]. Identification of the pyrin domain shared by pyrin and cryopyrin and definition of the inflammasome as a molecular platform to cleave pro-interleukin (IL)-1b� have led to a notion that pyrin acts as a regulator of this molecular complex [11-14]. A number of disorders with inborn or acquired dysregulation of the inflammasome, including FMF, cryopyrin-associated periodic syndromes (CAPS) with CIAS1 mutations and gout caused by uric acid crystal, are categorized as  inflammasomopathies . Because of the role of inflammasome-IL-1b� signaling and effectiveness of anti-IL-1 therapies in not a few autoinflammatory disorders, the inflammasomopathies are now considered the representative constituents of autoinflammatory disorders [1].
In 2000, NOD2 has been reported as the first non-major histocompatibility (MHC) susceptibility gene for Crohn�s disease simultaneously by two groups, a group working with linkage analysis and the other one starting with molecular cloning [15,16]. Subsequently, other gain-of-function mutations in the same gene have been identified to be responsible for systemic granulomatosis, Blau syndrome (BS; MIM#186580) and sporadic early-onset sarcoidosis (EOS; MIM#609464) [17,18]. Notably, the NOD2 mutations in these diseases were structurally and functionally homologous to the CIAS1 mutations in CAPS [19]. NOD2 (NLRC2) and cryopyrin (NLRP3) belong to the NOD-like receptor (NLR) family molecules and their dysregulation seems critical in the autoinflammatory diseases [20].
According to the expansion of the knowledge on and the concept of the autoinflammatory diseases, increasing number of cases have been proven to harbor the disease-associated mutations. However, there still remain many cases possibly with some autoinflammatory disease but without any mutation in known genes. In case of CINCA syndrome, mosaicism of a NLRP3 mutation has been identified first in a Japanese case and subsequently in global �mutation-negative� cases, however, similar situation has not been reported in other diseases [21,22]. Rather, by hunting genes responsible for rare inherited disorders concentrated in quite limited areas, several novel mutations have successfully been identified. Mutations in a distinct NLR family molecule, NLRP12, have been identified to be responsible for FCAS2 (MIM#611762), concentrated in Guadaloupe [23]. Identification of the responsible genes has defined deficiency for IL-1 receptor antagonist (DIRA; MIM#612852) and deficiency for IL-36 receptor antagonist (DITRA; MIM#614204) for distinct familial disorders with infantile pyogenic pustulosis mainly in Holland and Tunisia, respectively [24,25]. Notably, the same IL-36RN mutations have subsequently identified in sporadic cases with more common skin diseases, including generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), acrodermatitis continua of Hallopeau (ACH), and acute generalized exanthematous pustulosis (AGEP) [26,27]. Finally, mutations of PSMB8 encoding the b�5i immunoproteasome (IP) subunit have been identified in the distinctive autoinflammation, lipodystrophy and dermatoses (ALDD) syndrome (MIM#256040), including Nakajo-Nishimura syndrome (NNS) in Japan, joint contractures, muscular atrophy, microcytic anemia and panniculitis-associated lipodystrophy (JMP) syndrome in Portugal and Mexico and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome mainly in Spain and Israel [28-31]. Characteristic features of the diseases discussed in this review are summarized in Table 1.
The recently-developed next-generation sequencer is now completely changing the world of gene hunting [32]. Actually, by the whole genome/exome sequencing of each patient and his/her parents (so-called the trio), a number of novel mutations have been discovered in a short period, in contrast with the basic linkage analysis of a large family or homozygosity mapping of some small families, which need much more time. In the near future, so-called �mutation-negative� cases will be lost, even if it might be undefined which mutation is responsible.

Inflammasomopathies: CAPS, FMF, PAPA syndrome, HIDS
Familial cold urticaria (FCU), showing recurrent attacks of urticarial rash accompanied with pain, joint swelling, chills and fever after exposure to the cold, was first described in 1940 [33]. A relating hereditary disease with recurrent episodes of urticarial rash without cold exposure and late-onset sensorineural deafness and renal amyloidosis was first described in 1962 and called urticaria-deafness-amyloidosis or MWS [34]. After linking both susceptibility genes for these diseases to chromosome 1q44, a new gene has been identified to be responsible for both diseases in 2001 [8]. Since the identified gene is similar to pyrin, the MEFV gene product responsible for FMF, the molecule encoded by this gene has been designated as cryopyrin, which means �cold-induced fever� [35]. Moreover, based on the genetic and clinical similarities with FMF, the name of the disease has been changed from FCU to FCAS and its responsible gene has been designated as CIAS1. In 2002, mutations in the same gene have further been detected in another rare hereditary disorder, CINCA syndrome, characterized by a neonatal-onset triad of skin rash, chronic meningitis and joint inflammation with recurrent fever [9,10]. Then, these 3 disorders sharing the same genetic origin are defined to form a sequential spectrum of CAPS [36]. 
Cryopyrin is composed of the N-terminal pyrin domain (PYD), central nucleotide oligomerization domain (NOD) and C-terminal leucine-rich repeats (LRR) and has formally been designated as NLRP3, one of the most characterized NLR family molecules (Figure 1) [37]. When stimulated with various danger molecules such as bacterial RNA, imiquimod and uric acid crystal, NLRP3 is oligomerized to form pentamer and associates with procaspase-1 containing the caspase-recruitment domain (CARD), through an adaptor molecule apoptosis-associated speck-like protein with a CARD (ASC) consisting of both PYD and CARD. This NLRP3-ASC-procaspase-1 complex, formed through homophilic interaction of each domain (PYD-PYD and CARD-CARD), works as a cytoplasmic platform activating caspases-1-mediated IL-1b�/IL-18 secretion and has been designated as the NLRP3 inflammasome [11]. In case of CAPS, stable oligomerization of NLRP3 caused by missense mutations mainly located in the NOD is considered to result in constitutive activation of caspase-1 and subsequent IL-1b� �secretion (Figure 1). NLRP3 activation in monocytes results in elevated level of serum IL-1b�, while its activation and IL-1b� secretion by dermal mast cells are associated with vascular leakage and neutrophil recruitment in urticarial rash [38]. Actually, anti-IL-1 therapies, including IL-1 receptor antagonist (IL-1Ra) called anakinra, IL-1 Trap/rilonacept composed of extracellular IL-1R1 and accessory protein (AcP), and anti-IL-1b� antibodies such as cannakinumab, dramatically improved almost all symptoms of CAPS and these facts indicate the critical role of IL-1b� for development of CAPS [39-41]. Furthermore, the crucial role of NLRP3 for IL-1b� secretion has been revealed by analyses of its knockout mice [42]. This NLRP3-ASC-caspase-1-IL-1b� axis is considered to be the main stream of autoinflammation.
FMF is the most common periodic fever syndrome known since the Roman era. Clinical manifestations distinct from CAPS include presence of painful peritonitis and/or pleuritis and effectiveness of colchicine. Skin rash in FMF is described as erysipelas-like, but associating massive neutrophil infiltration in the dermis is similar to that observed in CAPS. Occasional development of amyloidosis is also common in both diseases. In 1997, the responsible MEFV gene on chromosome 16 has been identified and its encoding protein has been designated as pyrin, referring to the Greek word for fever, �pyrus� [6,7]. Pyrin is a multidomain molecule containing B-Box, coiled-coil and B30.2/SPRY domains, as well as PYD. In most recessively-inherited FMF cases, homozygous loss-of-function mutations of pyrin were suggested to cause impairment of its immunoregulatory function to regulate the NLRP3 inflammasome activation through its PYD or B30.2/SPRY domain [12-14]. Especially, competitive inhibition of PYD-PYD interaction between NLRP3 and ASC with PYD of pyrin is comprehensive (Figure 1). Actually, pyrin-deficient mice showed caspase-1-mediated hyperimmune phenotype, indicating the inhibitory role of pyrin on NLRP3 inflammasome signaling [43]. On the other hand, some reports demonstrated that pyrin directly activates inflammatory responses and, recently, an analysis of the dominantly-inherited FMF-causing gain-of-function pyrin mutation-knockin mice has revealed the ASC-dependent but NLRP3-independent activation of inflammasome in these mice [44,45]. Notably, anti-IL-1 therapies are reportedly effective for FMF, irrespective of its inheritance pattern [13, 46].
Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome (MIM#604416), which had previously been reported in 1975, has been defined as an autosomal dominantly-inherited pyogenic pustular disease in 1997 [47,48]. Early-onset pyogenic and corticosteroid-responsive, but recurrent and destructive arthritis is remarkable and skin manifestations of pyoderma gangrenosum and severe cystic acne are accompanied especially from adolescence. By linkage analysis on two families, distinct missense mutations in the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene on chromosome 15 has been identified in 2002 [49]. PSTPIP1 is a molecule with multiple properties, including interaction with PEST-type protein tyrosine phosphatases such as protein tyrosine phosphatase non-receptor 12 (PTPN12) and PTPN18, binding to CD2, and interaction with Wiscott-Aldrich syndrome protein (WASP) for regulating cytoskeletal actin reorganization. More importantly, PSTPIP1 can also bind to pyrin to inhibit its regulatory role and the disease-associated mutations in its CC domain diminishes its binding with PTPNs and rather strengthen its interaction with pyrin, resulting in dysregulated activation of NLRP3 inflammasome (Figure 1) [50]. Phenotypic difference between PAPA syndrome and CAPS/FMF might be due to multiple functions of PSTPIP1, but the precise explanation remains to be elucidated. Effect of IL-1Ra for PAPA syndrome has actually been reported [51]. Some alternative splice variants of the PSTPIP1 gene have specifically been detected in intractable pyoderma gangrenosum patients, their significance remains to be elucidated [52].
Hyper IgD syndrome with periodic fever (HIDS; MIM#260920) is another classical periodic fever syndrome inherited recessively [53]. Typically, early-onset (usually under 1 year of age) recurrent attacks of fever with severe abdominal pain, diarrhea, arthritis, cervical lymphadenopathy and skin rash last 3 to 7 days with 4 to 8 weeks interval [4]. This disease is mostly seen in Northern Europe, especially in Dutch and French populations. The constantly high level of serum IgD is characteristic, but is neither specific nor causative for attacks. Amyloidosis has not been reported in association with HIDS. In 1999, mevalonate kinase (MVK) gene on chromosome 12 has been identified to be responsible for this disease [54,55]. MVK phosphorylates mevalonic acid as the essential step of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase-initiated isoprenoids/cholesterol biosynthesis cascade [56]. By the complete defect of MVK activity, mevalonic aciduria occurs with much severer phenotype, including recurrent episodes seen in HIDS [57]. On the other hand, in HIDS patients, MVK activity is reduced but still remaining, and urinary mevalonate is apparent only during attacks [58]. HIDS-type homozygous loss-of-function mutations are considered to affect stability and/or maturation of MVK leading to lack of isoprenoids, especially geranylgeranyl pyruvate, followed by IL-1b�-mediated inflammation [59-61]. Actually, beneficial effect of anti-IL-1 therapies, as well as an HMG-CoA reductase inhibitor simvastatin, has been reported [62,63]. Therefore, HIDS is also categorized in inflammasomopathies, although precise underlying mechanisms are still unclear [1].

2. IL-1 family receptor antagonist deficiencies: DIRA, DITRA
Hispanic patients showing sterile lytic bone lesions and cutaneous pustulosis with fever had already been reported in 1985 and 1993, and their similarities to chronic recurrent multifocal osteomyelitis had been pointed out [64,65]. In 2009, homozygous deletion of 2 base pairs causing premature termination or nonsense mutations in the IL1RN gene encoding IL-1Ra have been identified in cases with neonatal-onset sterile multifocal osteomyelitis, periostosis and pustulosis, and DIRA has been denoted for this syndrome [24,66]. Clinically, fetal distress, pustular rash, mouth ulcers and painful joint swelling begin around birth and some patients die before 10 years of age with visceral involvement. Febrile attack is not apparent, in spite of a high serum C-reactive protein (CRP) level. Although effect of antirheumatic drugs and corticosteroid is only limited, administration of IL-1Ra gives a rapid response. As IL-1Ra works as a natural competitive inhibitor of both IL-1a� and IL-1b�,� defective IL-1Ra causes hyperactivation of IL-1a� as well as IL-1b� �signaling. Therefore, dysregulated IL-1a� signaling in keratinocytes and bone marrow should induce characteristic phenotypes of DIRA. Compared with IL-1Ra-deficient mice, which gradually develop an autoimmune disease similar to rheumatoid arthritis, a role of IL-1Ra on autoinflammation in the early stage of human development, especially in the skin and bone marrow, should be noted [67].
IL-1Ra, formally called IL-1F3, is structurally similar to other IL-1 family molecules and its gene is located on the IL-1 family locus [68,69]. Recently, IL-1 family cytokines have expanded to IL-1F11 by homology search of sequence databases. Interestingly, in two cases with DIRA, a homozygous deletion of 175 kilobases in chromosome 2, which includes IL-1F9, F6, F8, F5 and F10, as well as IL-1RN, in the order of the genomic localization, has been identified [24,66]. As a nomenclature, IL-1F6, F8 and F9 have been changed to IL-36a�, b� and g�, respectively, while IL-1F5 to IL-36 receptor antagonist (IL-36Ra), which can block the signaling with IL-36a�, b� and g�. Since such a large defect of IL-1 family members seems to have only limited effect on clinical phenotype other than that of IL-1Ra, effects of both agonistic (IL-36a�, b� and g�)� �and antagonistic (IL-36Ra) molecules might be balanced.
In 2011, homozygous mutations were identified in the IL36RN gene which encodes the IL-36Ra, by homozygosity mapping of the genome of Tunisian cases with familial GPP and by exome sequencing of the genome of sporadic European GPP cases [25,70]. IL-36Ra as well as IL-36a�, b� and g� are predominantly expressed in keratinocytes and play a role in the induction and regulation of skin inflammation [71,72]. GPP-associated IL36RN mutations cause the defective expression and/or impaired antagonistic effect of IL36Ra, leading to dysregulated skin inflammation. Recently, identification of other homozygous and compound heterozygous IL36RN mutations has been reported in Japanese sporadic GPP cases and, therefore, global and ethnicity-specific distribution of IL36RN mutations has been revealed [73,74]. As it has been reported more recently that the same mutations are detected in patients with GPP-related various pustular disorders, the phenotypes of DITRA cases have emerged to include GPP, PPP, ACH and AGEP [26,27]. Thus, defective IL-1 family receptor antagonists are crucial for development of pyogenic pustular disorders in humans.

3. NOD2-associated granulomatous diseases: BS, EOS
Sarcoidosis is a multiorganic inflammatory disease with unknown etiology, characterized by the histologic features of noncaseating epithelioid granulomas. It is already known that there is a rare but distinct type of sarcoidosis called EOS, characterized by the onset in infancy and a triad of arthritis, uveitis and skin rash, without apparent involvement of lung and hilar lymph nodes [75]. In 1985, a large family showing EOS-like systemic granulomatosis was reported by Edward B. Blau and a new entity, named BS, has been defined as a distinct disease from EOS by its autosomal dominant inheritance [76]. Histologically, it is hard to distinguish these diseases from sarcoidosis, however, the clinical features are clearly different. The skin lesion most commonly shows scaly maculopapules with tapioca-like appearance and is described as the lichenoid-type, which are rarely seen among ordinary sarcoidosis [77]. As the responsible gene for BS had been mapped close to the inflammatory bowel disease 1 (IBD1) locus on chromosome 16, mutations of the NOD2 gene, which was identified for IBD1, were searched and novel heterozygous mutations were identified in familial BS cases and, subsequently, in sporadic EOS cases, indicating the same etiology of these diseases [15-18,78]. The designation �pediatric granulomatous arthritis� was proposed to unify them for the international registry, but has not been widely accepted because of the systemic involvement of the diseases [79,80].
NOD2 is mainly expressed in the cytoplasm of monocytes and is essential for recognition of muramyl dipeptide, which is the minimum and common immunocompetent module of both gram-negative and positive bacterial cell wall peptidoglycan [19,81]. NOD2, which contains the CARD as an effector domain, instead of the PYD in NLRP3, interacts with RIP2 (receptor-interacting protein 2) through the CARD-CARD hemophilic interaction and causes nuclear factor (NF)-k�B activation, instead of IL-1b� secretion in case of NLRP3 (Figure 1). Actually, the most frequent BS/EOS-associated NOD2 mutations, R334W/Q, correspond to the CAPS-associated NLRP3 mutations, R260W/Q. Although loss-of-function mutations in the C-terminal LRR of NOD2 are reportedly associated with Crohn�s disease in Caucasians but not in Eastern Asians, BS/EOS-related gain-of-function mutations in the central NOD of the same gene are detected in both ethnic groups. By the analysis of 20 Japanese BS/EOS cases with NOD2 mutations, genotype-phenotype correlation was observed to some extent, between the mutant NOD2-induced in vitro NF-k�B activation and the disease severity, especially of the ocular complications [82]. Clinical effect of a NF-k�B inhibitor thalidomide, as well as its inhibitory effect on ex vivo giant cell formation of the patient s monocytes, further support the role of NF-k�B activation in the pathogenesis of BS/EOS [83]. Moreover, by the histological analyses of the patients  skin specimens, emperipolesis of lymphocytes within multinucleated giant cells has been pointed out as another aspect of gain-of-function NOD2 mutations [84].

3. Protein misfolding disease: TRAPS
Although TRAPS was formerly called as familial Hibernian fever (�Hibernia� is the ancient name of Ireland), its prevalence is not limited in a particular area. Clinically, this syndrome is characterized by recurrent episodes of fever, myalgia, rash, arthralgia, abdominal pain and conjunctivitis that usually last longer than 5 days [4]. AA amyloidosis leading to renal dysfunction develops in almost a half of affected families. The most common cutaneous manifestation is a centrifugal migratory and erythematous patch overlying the area with myalgia. Histologically, perivascular and interstitial infiltrate of mononuclear cells is apparent. Corticosteroid, but not colchicine, is reportedly effective for treatment of this disease. Although more than 100 mutations in the TNFRSF1 gene have been reported, some of them have been identified not only in affected cases but also in unaffected relatives [85]. This means that the penetrance of these mutations is low. However, considering that the disease reportedly onsets at the age from 2 weeks to 53 years, unaffected mutation carriers may develop symptoms in the future. In some patients, a reduced level of serum soluble TNFR1, a putative negative-feedback regulator of TNF signaling, was observed and, therefore, a defective shedding of surface TNFR1 had been postulated to cause dysregulated TNF signaling [85]. However, the serum soluble TNFR level is not constantly reduced in all patients, and therefore, another hypothesis was postulated that intracellular aggregation of misfolded TNFR1 causes hyperimmune response independent of TNF signaling [86,87]. By analyses of the disease-associated TNFRSF1 mutation-knockin mice, heterozygous, rather than homozygous, mutant mice develop inflammatory phenotype by a cooperation of intracellular aggregation of misfolded TNFR1 and surface expression of intact TNFR1 [88]. Actually, the effectiveness of IL-1Ra as well as anti-TNF drug etanercept, a recombinant soluble TNFR1 fused to human IgG1, has been reported, suggesting the involvement of both TNF-dependent and independent inflammation in the pathogenesis of TRAPS [89,90].

5. Proteasome disability syndromes: ALDD syndrome
NNS is a very rare autosomal recessive disease, originally reported in Japanese by Nakajo in 1939 and Nishimura in 1950 as �secondary hypertrophic osteoperiostosis with pernio�. The disease was soon recognized as a new entity uniquely reported from Japan and has subsequently been reported as �a syndrome with nodular erythema, elongated and thickened fingers, and emaciation  or  hereditary lipomuscular atrophy with joint contracture, skin eruptions and hyper-�-globulinemia  based on its common characteristic features [91,92]. NNS usually begins in early infancy with pernio-like rashes and develops periodic high fever, nodular erythema-like eruptions and myositis. Lipomuscular atrophy and joint contractures gradually progress, mainly in the upper body, to form the characteristic thin facial appearance and elongated clubbed fingers. Inflammatory changes are marked and include a constantly elevated CRP and hyper-g�-globulinemia, hepatosplenomegaly, basal ganglia calcification and focal mononuclear cell infiltration with vasculopathy on histopathology. Although autoantibodies are negative at the onset, their titers increase as the disease progresses in some cases. By homozygosity mapping, a G201V mutation of the PSMB8 gene encoding the b�5i IP subunit has been identified to be responsible for NNS in 2011 [28,29]. This mutation not only impairs the b�5i-responsible chymotrypsin-like activity, but inhibits proper IP assembly and all proteasome activities [28]. With accumulation of ubiquitinated and oxidated proteins, p38-mitogen-activated protein kinase (MAPK) activation and IL-6 overproduction were shown to be involved in the autoinflammatory phenotype. It has also been reported that IP contributes adipocyte differentiation and impaired b�5i activity causes lipoatrophy in vivo [29]. Although NNS has been considered to be uniquely present in Japan, similar cases have been reported from overseas in 2010, by different designations [93,94]. Portugese and Mexican familial cases were reported as JMP syndrome, who commonly showed sclerodermic skin with erythematous lesions, generalized or partial lipomuscular atrophy, joint contractures, short stature, hepatosplenomegaly, hyper-g�-globulinemia and microcytic anemia. Although no cases showed fever, elevated erythrocyte sedimentation rate, basal ganglia calcification and seizures were noted in some patients [93]. In addition, Spanish, Hispanic, Caucasian and Jewish cases were reported as CANDLE syndrome, which was characterized by onset during the first year of life, recurrent fever, purpuric skin lesions, violaceous swollen eyelids, arthralgia, progressive lipodystrophy, anemia, delayed physical develcpment, increased acute phase reactants and a characteristic histological feature with atypical infiltration of mixed mononuclear cells and neutrophils [31,94,95]. A homozygous p.T75M mutation, which only impairs the b�5i-responsible chymotrypsin-like activity, has been identified in all JMP and most CANDLE cases, while p.C135X predictably abolishing IP formation in a Jewish case [30,31]. Interestingly, marked elevation of interferon (IFN)g�-induced protein-10 (IP-10, formally called CXCL10) was observed commonly in the serum of NNS and CANDLE patients, and the IFN pathway was identified as the most dysregulated one by the whole blood microarray analysis of CANDLE patients. Furthermore, stronger phosphorylation of signal transducers and activators of transcription (STAT)-1 in the CANDLE patients� monocytes was revealed and the therapeutic application of a Janus kinase (JAK) inhibitor, tofacitinib, was proposed [31]. Thus, NNS, JMP and CANDLE syndromes, showing similar but slightly different clinical features, are caused by distinct mutations of the PSMB8 gene leading to slightly different inflammation pathways. For collection of these diseases, ALDD syndrome has recently been designated in OMIM. It should be noted that they commonly indicate significance of the ubiquitin-proteasome system in the regulation or homeostasis of inflammation and establishes a new category of autoinflammatory disorders �proteasome disability syndromes�.

Concluding remarks
Identification of the responsible genes for rare hereditary autoinflammatory syndromes has given us important clues to find novel and in vivo critical inflammatory pathways. As there should still remain a number of undefined hereditary autoinflammatory syndromes with novel mutations, further clinical and genetical approaches is necessary to clarify the underlying pathophysiology. Clinicians should distinguish the disease whether it is known or novel according to the clinical criteria, and if novel, should further define whether it can be caused by any known pathway, with profiling the serum cytokines, immunohistochemistry of the lesional tissues, flow cytometry, microarray and genomic analyses. If the results predict the presence of a novel disorder with a novel pathway, the whole exome/genome sequencing might be considered. By such a strategy, novel diseases and novel pathways would be discovered and novel therapeutics would be developed, which target the disease origin specifically and effectively with minimum side effects. 

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Figure legend
Figure 1. Signaling through NLR molecules in inflammasomopathies and NOD2-associated granulomatous diseases. In CAPS, a heterozygous missense mutation mainly located in the NOD of NLRP3/cryopyrin causes its stable oligomerization and the following formation of inflammasome with ASC and pro-caspase-1 results in constitutive caspase-1 activation and subsequent IL-1b� �secretion. In FMF, a homozygous missense mutation mainly in the PYD or B30.2 domain of pyrin causes impaired inhibitory effect on NLRP3 inflammasome activation. In PAPAS, a heterozygous missense mutation in the CC domain of PSTPIP1 causes dysregulated pyrin inhibition of NLRP3 inflammasome. In DIRA, a homozygous nonsense mutation in IL-IRa causes dysregulated IL-1 signaling. On the other hand, a heterozygous missense mutation located in the NOD of NOD2 causes its stable oligomerization in BS/EOS, and through interaction with RIP2 induces constitutive NF-*26272y2�2�2�2�2�2�2�2�2�2b3}3�3�3�3�3�3�3&4A4D4E4I4J4N4j4q4z4�4�4�4�4�4��������ܶ�������y������������nf^�nh�{cOJQJh#gZOJQJh?uh�{cOJQJh�{cCJOJQJ^JaJo(h#gZCJOJQJ^JaJh#gZCJOJQJ^JaJo( hgM�h�{cCJOJQJ^JaJ!hgM�h�{cB*OJQJaJph�h#gZOJQJaJo(h#gZOJQJaJhgM�h�{cOJQJaJhgM�h�{cOJQJaJ h#gZOJQJo(#�4�4�4�4�4�4�4�4�4�4555&5.5U5V5g5i55�5�5�5�5�5�5�5�5�5�5�5<6=6H6I6K6L6�6�6�6�6�6���������������̸���̤���q�q�q�q�q�q h�yh�{cKHOJPJQJaJ)jh�yh�{cKHOJPJQJUaJh�yh�{cOJQJaJh�yh�{cOJQJhNEOJQJo(heb�OJQJh�Lh�{cOJQJo(h�Lh�{cOJQJh?uh�{cOJQJh#gZOJQJo(h#gZOJQJh?uh�{cOJQJaJ)�6�697T7W7X7]7^7�7�7�7�7�7�788888)808J8]8^8a8b8f8h8j8p8s8�8�8�8�89999
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