Objective. To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS.Methods. Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescenceactivated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes.Results. Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (⌬D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants.Conclusion. The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without

BackgroundThis study assessed the psychometric profile of 10 questionnaires (every 6 months, from 6 to 60 months) from the Japanese translation of the Ages and Stages Questionnaires, third edition (J‐ASQ‐3).MethodsData from 439 children in a birth cohort were used to identify the J‐ASQ‐3 score distribution, establish cut‐off scores, and calculate the instrument's internal consistency. Data were also collected from 491 outpatients to examine J‐ASQ‐3 test–retest reliability and concurrent validity, which was examined using the Kyoto Scale of Psychological Development (KSPD) and the Japanese version of the Denver Developmental Screening Test II (J‐Denver II). Both the original and the alternative screening criteria of the ASQ‐3 were used (failure in at least one and at least two domains, respectively).ResultsCronbach's alpha for each J‐ASQ‐3 subscale on each questionnaire ranged from 0.45 to 0.89. Test–retest reliability was >0.75 for the subscales on almost all questionnaires. Concurrent validity was also adequate. In comparison with the screening results of the KSPD, the overall sensitivity and specificity were 96.0% and 48.8%, respectively, when the ASQ‐3 original criterion was used, and 92.1% and 74.9%, respectively, when the alternative criterion was used. In comparison with the screening results of the J‐Denver II, the overall sensitivity and specificity were 75.6% and 74.7%, respectively, when the ASQ‐3 original criterion was used, and 56.3% and 93.0%, respectively, when the alternative criterion was used.ConclusionsThis study quantified the psychometric profiles of the Japanese translations of 10 ASQ‐3 questionnaires. We demonstrated the validity of the J‐ASQ‐3 and determined new cut‐off scores. Further studies with larger samples from a greater range of locations are required to clarify the suitability of this tool for all Japanese children.

Objective-The goal of this study was to investigate the effects of stimulants for a nucleotide-binding domain, leucine-rich repeat-containing (NLR) protein family on human artery endothelial cells and murine arteries. Methods and Results-Human coronary artery endothelial cells were challenged in vitro with microbial components that stimulate NLRs or Toll-like receptors. We found stimulatory effects of NLR and Toll-like receptor ligands on the adhesion molecule expression and cytokine secretion by human coronary artery endothelial cells. On the basis of these results, we examined the in vivo effects of these ligands in mice. Among them, FK565, 1 of the nucleotide-binding oligomerization domain (Nod)-1 ligands induced strong site-specific inflammation in the aortic root. Furthermore, coronary arteritis/valvulitis developed after direct oral administration or ad libitum drinking of FK565. The degree of the respective vascular inflammation was associated with persistent high expression of proinflammatory chemokine/ cytokine and matrix metallopeptidase (Mmp) genes in each tissue in vivo by microarray analysis. Conclusion-This is the first coronary arteritis animal model induced by oral administration of a pure synthetic Nod1ligand. The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis. These findings might lead to the clarification of the pathogenesis and pathophysiology of coronary artery disease in humans. Key Words: coronary artery disease Ⅲ immune system Ⅲ Kawasaki disease Ⅲ pathology Ⅲ coronary arteritis Ⅲ inflammation G erm-line encoded pattern-recognition receptors of the innate immune system sense exogenous microbial components and endogenous danger signals to protect the host. [1][2][3][4] The pattern-recognition receptors include Toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-I-like receptors, the leucine-rich repeat-containing (NLR) protein family, and as-yet-unidentified pattern-recognition receptors that recognize double-stranded DNA. 1,3 The TLR, RIG-I-like receptor, and NLR families consist of 10 (human), 3, and more than 20 members, respectively. 1,3,4 In the cardiovascular system, endothelial cells are usually the first among the structural cells to sense microbial components through pattern-recognition receptors. Human endothelial cells express functional innate immune receptors, such as TLRs and NLRs. 5,6 There is a line of evidence that activation of TLRs, especially TLR4 and TLR2, contributes to the development and progression of cardiovascular diseases, including atherosclerosis, cardiac dysfunction in sepsis, and congestive heart failure. 7 With respect to NLRs, only a limited number of studies have shown that human endothelial cells express functional NLRs, nucleotide-binding oligomerization domain 1 (NOD1) and NOD2. Chlamydophila pneumoniae and Listeria monocytogenes elicited NOD1-dependent interleukin (IL)-8 production in endothelial cells. 8,9 A selective NOD1 ligand, FK565, ...

Ab repertoires exhibit marked restrictions during fetal life characterized by biases of variable gene usage and lack of junctional diversity. We tested the hypothesis that Ab repertoire restriction contributes to the observed poor quality of specific Ab responses made by infants to viral infections. We analyzed the molecular determinants of B cell responses in humans to two Ags of rotavirus (RV), a common and clinically important infection of human infants. We sequenced Ab H and L chain V region genes (VH and VL) of clones expanded from single B cells responding to RV virus protein 6 or virus protein 7. We found that adults exhibited a distinct bias in use of gene segments in the VH1 and VH4 families, for example, VH1–46, VH4–31, and VH4–61. This gene segment bias differed markedly from the VH3 dominant bias seen in randomly selected adult B cells. Recombinant Abs incorporating any of those three immunodominant VH segments bound to RV-infected cells and also to purified RV particles. The RV-specific B cell repertoires of infants aged 2–11 mo and those of adults were highly related when compared by VH, D, JH, VL, and JL segment selection, extent of junctional diversity, and mean H chain complementarity determining region 3 length. These data suggest that residual fetal bias of the B cell repertoire is not a limiting determinant of the quality of Ab responses to viruses of infants beyond the neonatal period.

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We analyzed the genetic polymorphisms of vascular endothelial growth factor (VEGF) and its receptors [Fms-related tyrosine kinase-1, kinase insert domain receptor (KDR)] in Japanese patients with Kawasaki disease (KD) and normal control subjects to examine whether these genes would contribute to the KD occurrence and/or the development of coronary artery lesion (CAL) in KD. We found that the frequency of G allele of VEGF g.Ϫ634 GϾC single-nucleotide polymorphism in the promoter region was significantly higher in KD patients with CAL than in those without CAL (p ϭ 0.012) or control subjects (p ϭ 0.021) because of a significantly higher frequency of the GG genotype in KD patients with CAL. In addition, the frequency of the A1 allele with 11 AC repeats of KDR g.ϩ4422(AC)11-14 dinucleotide repeat polymorphism in intron 2 was significantly higher in KD patients with CAL than in those without CAL (p ϭ 0.013) or control subjects (p ϭ 0.040) as a result of a significantly higher frequency of the A1A1 genotype in KD with CAL patients. The multivariate analysis of clinical features and genotypes of the two polymorphisms showed that the A1A1 genotype of KDR g.ϩ4422(AC)11-14 polymorphism was an independent risk factor for the development of CAL with the highest odds ratio among several clinical parameters (odds ratio 6.76; 95% confidence interval 1. 05-43.48). Dual luciferase assay demonstrated that the A1 allele with KDR g.ϩ4422(AC)11 repeats showed a weaker silencer function than the A2 allele with 12 AC repeats. These findings suggested that VEGF and its receptor, KDR, genes contributed to the development of CAL in KD patients. Kawasaki disease (KD) is an acute febrile vasculitis of infants and children and is accompanied by the coronary artery lesions (CALs) that occur in~5-16% of patients (1,2). Even after the introduction of high-dose i.v. immunoglobulin (IVIG) therapy, CAL occurs in a small proportion of KD patients and leads to life-threatening complications, including myocardial infarction, as well as acquired heart diseases such as myocardial dysfunction, valvular diseases, and arrhythmias (3,4). Therefore, it is important to identify as early as possible KD patients who are at risk for the development of CAL.During the acute stage of KD, activation of the immune system with increased serum cytokines such as tumor necrosis factor-␣, interferon-␥, IL-1, IL-2, IL-6, and IL-8 may play important roles in the occurrence of endothelial cell injury (5-7). The pathologic findings of vascular tissues in KD patients include subendothelial edema, vascular damage, gap formation, and fenestration of endothelial cells (8,9

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