Objective. Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-B activity predict the Blau syndrome/ EOS clinical phenotype.Methods. Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-B activity, which was defined as the ratio of NF-B activity without a NOD2 ligand, muramyldipeptide, to NF-B activity with muramyldipeptide.Results. All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligandindependent NF-B activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-B activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment.

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the coldinduced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutationnegative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients. (Blood. 2008;111: 2132-2141)

Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, MuckleWells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a protein that localizes to the cytosol and functions as pattern recognition receptor. Cryopyrin also participates in nuclear factor-B regulation and caspase-1-mediated maturation of interleukin 1␤. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including 7-AAD staining, the presence of cellular edema, and early membrane damage resulting in lactate dehydrogenase (LDH) release, indicated that it was more likely to be necrosis than apoptosis, and was effectively blocked with the cathepsin B-specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition, R837, a recently identified activator of cryopyrin-associated inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a cathepsin B-dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1. IntroductionChronic infantile neurologic, cutaneous, articular syndrome (CINCA; MIM #697115; Mendelian Inheritance in Man [MIM]; http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbϭOMIM), also known as neonatal-onset multisystem inflammatory disease, is characterized by recurrent fever, an urticarial rash beginning in the neonatal period, arthropathy characterized by epiphyseal patellar overgrowth, growth retardation, chronic meningitis, papilledema, and hearing loss. 1,2 The gene responsible for the syndrome is known as cold-induced autoinflammatory syndrome 1 (CIAS1), and is associated with 2 less severe but phenotypically similar syndromes, familial cold autoinflammatory syndrome (FCAS; MIM #120100) and Muckle-Wells syndrome (MWS; MIM #191900). 3-7 CIAS1, also designated as PYPAF1 and NALP3, is expressed in polymorphonuclear cells, monocytes, chondrocytes, and activated T cells. 6,8,9 Its product is cryopyrin, which contains an amino-terminal pyrin domain (PYD), a centrally located nucleotidebinding oligomerization domain (NOD), also called a NACHT domain, and several carboxy-terminal leucine-rich repeats (LRRs). Cryopyrin localizes to the cytosol and is believed to function as a patternrecognition receptor.Animals and plants have several types of so-called patternrecognition receptors that distinguish characteristic molecular structures of microorganisms and activate innate immune responses. In mammals, Toll-like receptors (TLRs) are a wellcharacterized type of pattern-recognition receptor that recognize pathogen-associated molecular patterns via their extracellular LRRs. 10 Cryopy...

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