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Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an IL-1-driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome pa-tients who carry NLRP3 mutations as somatic mosaicism has not been pre-cisely described because of the difficulty in separating Individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3mutant and nonmutant-induced pluripo-tent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosa-icism, and describe their differentiation into macrophages (IPS-MPs). We found that mutant cells are predominantly re-sponsible for the pathogenesis in these mosaic patients because only mutant IPS-MPs showed the disease relevant pheno-type of abnormal IL-1ß secretion. We also confirmed that the existing anti- inflammatory compounds inhibited the abnormal IL-1 p secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related Inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that A/L/?P3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related dis-orders. [ABSTRACT FROM AUTHOR]

Cryopyrin-associated periodic syndrome is an autoin-flammatory syndrome caused by mutations of the CIASl gene (currently named NLRP3), and is characterized by periodic attacks of an urticaria-like rash, fever, head-ache, conjunctivitis and arthralgia. We report here a case of a 1-year-old boy with cryopyrin-associated perio-dic syndrome, which manifested as a recurrent skin rash in the postnatal period. Genetic analysis revealed a mis-sense mutation of the CIASl gene in the mother and in-fant. [ABSTRACT FROM AUTHOR]

To cite this article: Kusunoki T, Mukaida K, Morimoto T, Sakuma M, Yasumi T, Nishikomori R, Heike T. Birth order effect on childhood food allergy. Pediatric Allergy Immunology 2012: 23: 250-254. Abstract Higher birth order is associated with a smaller risk of allergy (birth order effect). The purpose of this study was to compare the significance of the birth order effect on the prevalence of specific allergic diseases [bronchial asthma (BA), atopic dermatitis (AD), allergic rhinitis (AR), allergic conjunctivitis (AC), and food allergy (FA)] among schoolchildren. A questionnaire survey dealing with the prevalence of allergic diseases was administered to the parents of 14,669 schoolchildren aged 7-15 yr. Based on the data, the prevalence of each allergic disease was compared according to birth order (1st, 2nd, and 3rd or later). Multiple regression analysis was performed to test the significance of the differences. There was no significant difference in the prevalence of BA or AD according to birth order. The prevalence of AR, AC, and FA decreased significantly as birth order increased. The prevalence of FA among those with 1st, 2nd, and 3rd or later birth order was 4.0%, 3.4%, and 2.6%, respectively (p = 0.01). With respect to symptoms in infancy, the prevalence of wheeze increased significantly and that of FA and eczema in infancy decreased significantly as birth order increased. The present data show a significant birth order effect on FA. The effect was also observed for the prevalence of FA and eczema in infancy. These data support the concept of early, non-allergen-specific programming of IgE-mediated immunity. [ABSTRACT FROM AUTHOR]

The etiology of cryopyrin-associated periodic syndrome (CAPS) is caused by germline gene mutations in NOD-like receptor family, pryin domain containing 3 ( NLRP3)/cold-induced autoinflammatory syndrome 1 ( CIAS1). CAPS includes diseases with various severities. The aim of this study was to characterize patients according to the disease severity of CAPS. Five Japanese patients with four kinds of gene variations in NLRP3 were found and diagnosed as CAPS or juvenile idiopathic arthritis. Two mutations in NLRP3, Y563N and E688K, found in CAPS patients exhibit significant positive activities in the nuclear factor-κB reporter gene assay. Increased serum interleukin (IL)-18 levels were only observed in severe cases of CAPS. In mild cases of CAPS, the serum IL-18 levels were not increased, although lipopolysaccharide- or hypothermia-enhanced IL-1β and IL-18 production levels by their peripheral blood mononuclear cells were detectable. This series of case reports suggests that a combination of in vitro assays could be a useful tool for the diagnosis and characterization of the disease severity of CAPS. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) with macrophage activation syndrome (MAS) is well known as a complication of systemic-onset juvenile idiopathic arthritis (S-JIA). However, liver failure without overt MAS is rare in S-JIA. We encountered two Japanese children with S-JIA in whom ALF developed during the remission of clinical manifestations. ALF without MAS was improved with plasma exchange and cyclosporine A combined with pulse methylprednisolone. [ABSTRACT FROM AUTHOR]

To determine the prevalence and clinical characteristics of patients with in Japan, we conducted a nationwide survey of primary immunodeficiency disease (PID) patients for the first time in 30 years. Questionnaires were sent to 1,224 pediatric departments and 1,670 internal medicine departments of Japanese hospitals. A total of 1,240 patients were registered. The estimated number of patients with PID was 2,900 with a prevalence of 2.3 per 100,000 people and homogenous regional distribution in Japan. The male-to-female ratio was 2.3:1 with a median age of 12.8 years. Adolescents or adults constituted 42.8% of the patients. A number of 25 (2.7%) and 78 (8.5%) patients developed malignant disorders and immune-related diseases, respectively, as complications of primary immunodeficiency disease. Close monitoring and appropriate management for these complications in addition to prevention of infectious diseases is important for improving the quality of life of PID patients. [ABSTRACT FROM AUTHOR]

X-linked ectodermal dysplasia with immunodeficiency (XL-ED-ID) is caused by hypomorphic mutations in NEMO, which encodes nuclear factor-kappaB (NF-κB) essential modulator. We identified a novel mutation, 769−1 G>C, at the splicing acceptor site of exon 7 in NEMO in a Japanese patient with XL-ED-ID. Although various abnormally spliced NEMO messenger RNAs (mRNAs) were observed, a small amount of wild-type (WT) mRNA was also identified. Decreased NEMO protein expression was detected in various lineages of leukocytes. Although one abnormally spliced NEMO protein showed residual NF-κB transcription activity, it did not seem to exert a dominant-negative effect against WT-NEMO activity. CD4 T cell proliferation was impaired in response to measles and mumps, but not rubella. These results were consistent with the clinical and laboratory findings of the patient, suggesting the functional importance of NEMO against specific viral infections. The 769−1 G>C mutation is responsible for decreased WT-NEMO protein expression, resulting in the development of XL-ED-ID. [ABSTRACT FROM AUTHOR]

Background: Nuclear factor-κB essential modulator (NEMO) deficiency is a developmental and immunological disorder. The genetic and phenotypic correlation has been described. Methods: We report a unique clinical presentation and the identification of a novel missense mutation in the NEMO gene in a 3-year-old boy with bacillus Calmette-Guerin (BCG) infection. Results: The patient presented with fever, cervical lymphadenopathy, and abnormal anti-Epstein-Barr virus (EBV) antibody titers, suggestive of EBV-related diseases including chronic active EBV infection, X-linked lymphoproliferative syndrome, or nasopharyngeal carcinoma. Although the biopsy specimen from a nasopharyngeal lesion was initially diagnosed as squamous cell carcinoma, this was changed to disseminated BCG infection involving the nasopharynx, multiple systemic lymph nodes, and brain. A novel mutation (designated D311E) in the NEMO gene, located in the NEMO ubiquitin-binding (NUB) domain, was identified as the underlying cause of the immunodeficiency. Impaired immune responses which are characteristic of patients with NEMO deficiency were demonstrated. The patient underwent successful unrelated bone marrow transplantation at 4.9 years of age. Conclusion: This study suggests the importance of the NUB domain in host defense against mycobacteria. The unique presenting features in our patient indicate that a hypomorphic NEMO mutation can be associated with atypical pathological findings of the epithelial tissues in patients with BCG infection. [ABSTRACT FROM AUTHOR]

Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially lethal genetic disorder of immune dysregulation that requires prompt and accurate diagnosis to initiate life-saving immunosuppressive therapy and to prepare for hematopoietic stem cell transplantation. In the present study, 85 patients with hemophagocytic lymphohistiocytosis were screened for FHL3 by Western blotting using platelets and by natural killer cell lysosomal exocytosis assay. Six of these patients were diagnosed with FHL3. In the acute disease phase requiring platelet transfusion, it was difficult to diagnose FHL3 by Western blot analysis or by lysosomal exocytosis assay. In contrast, the newly established flow cytometric analysis of intraplatelet Munc13-4 protein expression revealed bimodal populations of normal and Munc13-4-deficient platelets. These findings indicate that flow cytometric detection of intraplatelet Munc13-4 protein is a sensitive and reliable method to rapidly screen for FHL3 with a very small amount of whole blood, even in the acute phase of the disease. [ABSTRACT FROM AUTHOR]

Background: The influence of food avoidance due to allergic symptoms in infancy on the growth of children at school age has not been well evaluated. Methods: To determine the growth of schoolchildren who avoided eggs, milk, or wheat due to immediate allergic symptoms in infancy (food avoiders in infancy) (FAI), a questionnaire on the presence of allergic diseases, as well as present height and weight, was administered to the parents of 14,669 schoolchildren. 11,473 subjects had available data. The height and weight standard deviation scores (HtSDS and WtSDS) and body mass index percentile (BMI percentile) of each subject were calculated. Results: FAI had significantly lower WtSDS than non-FAI (P = 0.01). Among those with avoidance at age 3 years, those who avoided two or more foods and those who avoided milk had significantly lower HtSDS than their counterparts (P = 0.02 and 0.04, respectively). FAI had a significantly lower prevalence of obesity (P = 0.01) and overweight (P = 0.002), while there was no difference in the prevalence of underweight (P = 0.58), resulting in a significantly higher prevalence of appropriate weight (P = 0.01) compared to non-FAI. Significantly lower prevalence of obesity and overweight was observed even among those who terminated the avoidance by age 3 years. Conclusions: FAI were less likely to be obese or overweight, resulting in a higher prevalence of appropriate weight at school age. Further investigation should contribute to better management of food allergy and obesity. [ABSTRACT FROM AUTHOR]

Urticarial rash, one of the clinical manifestations characteristic of cryopyrin-associated periodic syndrome (CAPS), is caused by a mutation in the gene encoding for NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeats containing family, pyrin domain containing 3). This intracellular pattern recognition receptor and its adaptor protein, called apoptosis associated speck-like protein containing a caspase-recruitment and activating domain (ASC), participate in the formation of a multi-protein complex termed the inflammasome. The inflammasome is responsible for activating caspase-1 in response to microbial and endogenous stimuli. From the analysis of cellular mechanisms of urticarial rash in CAPS, we have traced caspase-1 activated IL-1β in CAPS to a surprising source: mast cells. Recently, two groups have generated gene-targeted mice that harbored Nlrp3 mutations. These mice had very severe phenotypes, with delayed growth and the development of dermatitis, but not urticaria. The reason for the differences in the skin manifestations observed with CAPS and these knock-in mice relates to the findings that the inflammasome also plays a role in contact hypersensitivity, and that IL-18, another cytokine involved with inflammasome-activation of caspase-1, may be a major player in dermatitis development. [ABSTRACT FROM AUTHOR]

Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by mutations in the adenosine deaminase 2 (ADA2) gene. Loss of functional ADA2 activity results in vasculitis syndrome, immunodeficiency, and hematopoietic disorders. Early diagnosis is required for effective treatment. We developed a dried blood spot (DBS)-based ADA2 activity colorimetric assay. Heparin-affinity purification was used during sample preparation to improve the assay more efficiently. The stability of ADA2 during DBS storage and ADA2 activity of DADA2 patients and healthy controls were examined. Active ADA2 was extracted from the DBS of healthy controls. ADA2 activity in DBS, stored either frozen or refrigerated, remained stable for at least 90 days. A significant difference in ADA2 activity was observed between healthy controls and patients. No ADA2 activity was detected in DBS from patients. Our new DBS ADA2 activity assay is experimentally simple, highly adaptable, and requires no special equipment except for a microplate reader. A low background was achieved with heparin-affinity purification. The method differentiates clearly between healthy controls and patients. ADA2 activity can be reliably measured in DBS, providing an opportunity to diagnose DADA2 at an early stage. [Display omitted] • A new DBS-based ADA2 activity assay is experimentally simple and highly adaptable. • Heparin-affinity purification effectively separated active ADA2 from DBS extracts. • The DBS ADA2 activity assay identified healthy subjects and DADA2 patients. • Almost no decrease of ADA2 activity was seen during 90 days of DBS storage. [ABSTRACT FROM AUTHOR]

Eosinophilic cystitis is a rare inflammatory condition of the urinary bladder of unknown aetiology and characterized by eosinophilic infiltration of the bladder wall. We report the unique MR findings of eosinophilic cystitis in an 8-year-old girl who presented with peripheral eosinophilia. MR imaging revealed smooth and nearly circumferential thickening of the bladder wall showing distinct low signal intensity on T2-weighted images, which may histologically represent high cellularity due to massive eosinophilic infiltration. [ABSTRACT FROM AUTHOR]

A 44-day-old male infant with familial hemophagocytic lymphohistiocytosis (FHL) associated with the MUNC13-4 mutation is reported. He presented with fever and poor feeding, lymphocytosis with thrombocytopenia and CSF pleocytosis without virological explanation. On the basis of progressive hyperferritinemia (1323 ng/ml), anemia (hemoglobin: 5.2 g/dl), hypertriglyceridemia (547 mg/dl) and increased LDH (1063 IU/l) with hemophagocytosis in the bone marrow, hemophagocytic lymphohistiocytosis was diagnosed. He showed a good response to corticosteroid therapy and the disease was stable for more than 5 months. Thereafter, he suffered from central nervous system complications, and successfully underwent unrelated cord blood stem cell transplantation. A remission was observed for more than 2 years, with mild mental retardation. Genetic analysis revealed that he had a compound heterozygous mutation of MUNC13-4; namely a novel 2163G>A mutation resulting in W721X, and 754-1G>C resulting in a premature stop codon in this gene. Western blot analysis showed the complete loss of the MUNC13-4 protein, whereas other molecules associated with the SNARE systems were detected at normal levels. Conclusion. FHL may have a broad clinical spectrum, and further analysis on its phenotype-genotype association is required to establish an appropriate treatment strategy, including immunochemotherapy and stem cell transplantation in the future. [ABSTRACT FROM AUTHOR]

We investigated the antitumor effects of FR901228, a HDAC inhibitor, on human osteosarcoma cells, in vitro and in vivo to explore its possible utility in the treatment of pediatric bone cancers. FR901228 caused marked growth inhibition with a 50% inhibitory concentration of 1.2-7.3?nM and induction of apoptosis in all eight osteosarcoma cell lines tested. These effects of FR901228 were also observed in vivo xenograft models on BALB/c nude mice, and treatment with 5.6?mg/kg/day resulting in a >70% reduction in the mean final tumor volume compared with the mean initial tumor volume. TUNEL assays demonstrated extensive apoptosis in tumor sections of mice treated with FR901228. Induction of apoptosis was preceded by increased expression of Fas ligand (FasL) mRNA, resulting in expression of membrane-bound FasL, which was followed by sequential activation of caspase-8 and -3. The level of apoptosis induction was reduced using a neutralizing anti-FasL antibody and overexpression of either the dominant-negative FADD or the viral FLICE inhibitory protein. Furthermore, treatment with a suboptimal dose of FR901228 greatly sensitized osteosarcoma cells to agonistic anti-Fas antibody-mediated apoptosis. These findings suggest that FR901228 is a highly promising antitumor agent against osteosarcoma, inducing apoptosis by the activation of the Fas/FasL system.Oncogene (2003) 22, 9231-9242. doi:10.1038/sj.onc.1207184 [ABSTRACT FROM AUTHOR]

Two letters to the editor are presented in response to the article "Functional Consequences of a Germline Mutation in Theleucin-Rich Repeat domain of NLRP3 Identified in an Atypical Autoinflammatory Disorder," by I. Jeru and colleagues, published in the 2010 issue of "Arthritis and Rheumatology," including a comment on the article and the authors' reply.

The article describes the case of a Japanese girl with familial cold autoinflammatory syndrome (FCAS). The patient was referred to the hospital because of a rash, fever and arthralgia. It is noted that from four months of age, she had suffered from episodes of pruritic rash. Her physical examination revealed discrete urticarial plaques surrounded by macular erythema distributed across the cheeks and lower and upper extremities. FCAS was established in the patient, which is diagnosed clinically based on recurrent episodes of rash, polyarthralgia.

Haploinsufficiency of A20 (HA20) causes inflammatory disease resembling Behçet's disease; many cases have been reported, including some that are complicated with autoimmune diseases. This study aims to clarify the immunophenotype of patients with HA20 by analyzing lymphocyte subsets using multicolor flow cytometry. The patients with HA20 previously diagnosed in a nationwide survey were compared by their cell subpopulations. In total, 27 parameters including regulatory T cells (Tregs), double-negative T cells (DNTs), and follicular helper T cells (TFHs) were analyzed and compared with the reference values in four age groups: 0–1, 2–6, 7–19, and ≥20 years. The Tregs of patients with HA20 tended to increase in tandem with age-matched controls at all ages. In addition, patients ≥20 years had increased DNTs compared with controls, whereas TFHs significantly increased in younger patients. In HA20 patients, the increase in DNTs and TFHs may contribute to the development of autoimmune diseases. • Haploinsufficiency of A20 (HA20) is associated with an increase in regulatory T cells (Tregs). • The A20-related increase in Tregs may be a regulatory response to autoinflammation. • HA20 leads to an increase in double-negative T cells (DNTs) and follicular helper T cells (TFHs). • The observed increases in DNTs and TFHs may contribute to the development of the autoimmune disease. • Reduction in A20 expression can cause autoimmunity in the absence of Treg deficiency. [ABSTRACT FROM AUTHOR]

The article focuses on febrile attack in an infant with mevalonate kinase deficiency (MKD) which was triggered by milk allergy. It offers brief discussion of the meaning and symptoms of the disease and describes the condition of the infant who was diagnosed with MKD. It also mentions the treatments given to the infant and suggest measures on how to prevent the occurrence of the disease.

A case study of a 3-year-old Japanese boy presented with a tumor in the anterior chest wall is presented. Topics discussed include examinations revealing subcutaneous lobular cystic lesion on the precordium; a granulomatous infiltrate with central caseation necrosis indicated by histopathology; and treatment with isoniazid, rifampicin and pyrazinamide.