Masami Taniguchi

Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population

Bronchial asthma is a common inflammatory disease caused by the interaction of genetic and environmental factors. Through a genome-wide association study and a replication study consisting of a total of 7,171 individuals with adult asthma (cases) and 27,912 controls in the Japanese population, we identified five loci associated with susceptibility to adult asthma. In addition to the major histocompatibility complex and TSLP-WDR36 loci previously reported, we identified three additional loci: a USP38-GAB1 locus on chromosome 4q31 (combined P = 1.87 × 10−12), a locus on chromosome 10p14 (P = 1.79 × 10−15) and a gene-rich region on chromosome 12q13 (P = 2.33 × 10−13). We observed the most significant association with adult asthma at rs404860 in the major histocompatiblity complex region (P = 4.07 × 10−23), which is close to rs2070600, a SNP previously reported for association with FEV1/FVC in genome-wide association studies for lung function. Our findings offer a better understanding of the genetic contribution to asthma susceptibility.

Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma

BACKGROUND NLR family, pyrin domain containing 3 (NLRP3), controls the activity of inflammatory caspase-1 by forming inflammasomes, which leads to cleavage of the procytokines IL-1beta and IL-18. Recent studies have shown associations of human NLRP3 polymorphisms with susceptibility to various inflammatory diseases; however, the association with allergic diseases remains unclear. OBJECTIVE We sought to examine whether NLRP3 polymorphisms are associated with susceptibility to food allergy, food-induced anaphylaxis, and aspirin-induced asthma (AIA). METHODS We selected 15 tag single nucleotide polymorphisms (SNPs) of NLRP3 and conducted association analyses of NLRP3 using 574 and 1279 samples for food allergy and AIA, respectively. We further performed functional analyses of the susceptible SNPs. RESULTS Two NLRP3 SNPs (rs4612666 and rs10754558) were significantly associated with susceptibility to food-induced anaphylaxis (P = .00086 and P = .00068, respectively). The NLRP3 haplotype of the 2 SNPs also showed a significant association (P = .000098). We could confirm the association with susceptibility to another hypersensitivity phenotype, AIA (rs4612666, P = .0096). Functional analysis revealed that the risk alleles of rs4612666 and rs10754558 increased the enhancer activity of NLRP3 expression and NLRP3 mRNA stability, respectively. CONCLUSION Our results indicate that the NLRP3 SNPs might play an important role in the development of food-induced anaphylaxis and AIA in a gain-of-function manner. Further research on the NLRP3 inflammasome will contribute to the development of novel diagnostic and therapeutic methods for food-induced anaphylaxis and AIA.

Treatment of Churg-Strauss syndrome with high-dose intravenous immunoglobulin

BACKGROUND In some patients with Churg-Strauss syndrome (CSS), especially those with myocardial or neural involvement, conventional treatment with corticosteroids with or without cyclophosphamide is not effective. OBJECTIVE To examine the effects of intravenous high-dose immunoglobulin (IVIG) in patients with CSS who showed poor responsiveness to conventional treatment. METHODS We consecutively selected patients with CSS who showed any organ involvement despite corticosteroid treatment with or without cyclophosphamide. The diagnosis was based on the classification criteria of the American College of Rheumatology. IVIG therapy was performed with a dose of 400 mg/kg of immunoglobulin daily for 5 days. Neuropathy was evaluated with the manual muscle strength test and by the skin temperature of affected sites. Cardiac function was examined with ejection fraction by echocardiography and 2 imaging tests of myocardium (iodine 123 metaiodobenzylguanidine and thallium 201). RESULTS The manual muscle strength test results were improved, and the skin temperature of both hands and legs was increased by IVIG therapy. In 5 patients with heart failure, the mean +/- SD ejection fraction of the left ventricle increased from 35.2% +/- 13.9% to 61.0% +/- 10.1% (P < .02). The uptake of iodine 123 metaiodobenzylguanidine of the myocardium increased, indicating that the myocardial viability was improved. The thallium 201 images revealed the presence of perfusion defects, which were improved by IVIG therapy. CONCLUSIONS Patients with CSS who are resistant to corticosteroid treatment with or without cyclophosphamide may be treated effectively with IVIG therapy.

Possible involvement of mast-cell activation in aspirin provocation of aspirin-induced asthma

Background: Although there is increasing evidence of the importance of cysteinyl leukotrienes (LT) as mediators of aspirin‐induced bronchoconstriction in aspirin‐sensitive asthma, the cellular origin of the LT is not yet clear.

Intraductal oncocytic papillary neoplasm of the liver

A very rare case of intraductal oncocytic papillary carcinoma of the liver is reported. A 63‐year‐old Japanese man was admitted to our clinic because of abdominal pain and jaundice. Imaging techniques revealed a unilocular cystic neoplasm of 14 cm diameter in the medial segment of the left hepatic lobe. Combined percutaneous and endoscopic retrograde cholangiographies revealed the unilocular cystic neoplasm contained a lot of mucus and communicated with the left segmental intrahepatic bile duct, and that mucus filled the left segmental and hepatic ducts. Left lobectomy was performed. The postoperative course was good, and the patient is free of disease 30 months after operation. Pathological examination revealed that the cavity of the neoplasm was continuous with the left segmental intrahepatic bile duct, and that a lot of mucus was present in the neoplasm, as well as in the left segmental and hepatic ducts. The neoplasm consisted of papillary growth of atypical epithelial cells with oncocytic changes. Atypical goblet cells were also recognized. No invasion into the surrounding liver was noted. Non‐tumorous intrahepatic bile ducts near the lesion occasionally showed epithelial dysplasia and contained a lot of mucus. Immunohistochemically, the tumor cells were rich in mitochondria and were immunoreactive for cytokeratins 7, 18 and 19, carbohydrate antigen 19‐9, and hepatocyte‐specific antigen. Some tumor cells were immunoreactive for pancreatic alpha‐amylase and lipase. Ultrastructurally, the tumor cells showed numerous mitochondria and mucus droplets. Intraductal neoplasm communicating with the intrahepatic bile ducts has rarely been reported. The present case suggests that intraductal oncocytic papillary neoplasm, as described in the pancreas, may also occur in the intrahepatic bile ducts, and that such hepatic intraductal neoplasm may express hepatocellular and pancreatic acinar phenotypes.

Rhinoconjunctival sensitization to hydrolyzed wheat protein in facial soap can induce wheat-dependent exercise-induced anaphylaxis

Background Wheat protein is responsible for various kinds of allergic disease. Wheat-dependent exercise-induced anaphylaxis (WDEIA) is one of the most important clinical phenotypes of adult wheat allergy. Relatively homogenous clinical and immunological presentations of this phenotype have already been described. More recently, some studies have shown that sensitization to hydrolyzed wheat protein (HWP) in cosmetics can induce allergy to HWP-containing food as well as contact allergy to HWP-containing cosmetics.

Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis

Background Anaphylaxis is a life‐threatening syndrome resulting from the sudden release of mast cell‐ and basophil‐derived mediators into the circulation. However, pathological evidence of the association between inflammatory mediators and human anaphylaxis is insufficient.

Profile of eicosanoid generation in aspirin-intolerant asthma and anaphylaxis assessed by new biomarkers

BACKGROUND It has recently demonstrated that a free radical-mediated pathway generates prostaglandins (PGs) and the corresponding prostaglandin enantiomers (ent-PGs). Aspirin-intolerant asthma and anaphylaxis accompany PGD(2) overproduction, possibly associated with mast cell activation via the COX pathway. However, free radical-mediated PG generation in the pathophysiology of these diseases, which can be demonstrated by measuring urinary ent-PGF(2)alpha, has not been reported. OBJECTIVES To evaluate the characteristic profile of eicosanoid generation via the COX and/or free radical-mediated pathway underlying aspirin-intolerant asthma and anaphylaxis. METHODS A comparative group analysis consisted of asthma (n = 17) and anaphylaxis (n = 8, none with aspirin-induced anaphylaxis) cases. Urinary eicosanoid concentrations were quantified as follows: 2,3-dinor-9alpha,11beta-PGF(2) by gas chromatography-mass spectrometry; leukotriene E(4), 9alpha,11beta-PGF(2), and PGs by enzyme immunoassay. RESULTS 2,3-Dinor-9alpha,11beta-PGF(2) is a more predominant PGD(2) metabolite in urine than 9alpha,11beta-PGF(2). At baseline, the aspirin-intolerant asthma group (n = 10) had significantly higher leukotriene E(4) and lower PGE(2) concentrations in urine than the aspirin-tolerant asthma group. During the reaction, the urinary concentrations of leukotriene E(4) and PGD(2) metabolites correlatively increased, but with markedly different patterns of the mediator release, in the aspirin-intolerant asthma group and the anaphylaxis group, respectively. The urinary PGD(2) metabolites and primary PGs were significantly decreased in the aspirin-tolerant asthma group. Urinary ent-PGF(2)alpha concentrations were significantly increased in the anaphylaxis group but not the aspirin-intolerant asthma group. CONCLUSIONS When assessed by urinary 2,3-dinor-9alpha,11beta-PGF(2), PGD(2) overproduction during aspirin-intolerant bronchoconstriction was clearly identified, regardless of COX inhibition. It is evident that free radical-mediated PG generation is involved in the pathophysiology of anaphylaxis.

Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma

Asthma is a phenotypically heterogeneous disorder with many etiologic factors and clinical characteristics. T-bet, a Th1-specific transcription factor of T-box family, has been found to control interferon-γ (IFN-γ) expression in T cells. Mice lacking the T-bet gene (tbx21) demonstrate multiple physiological and inflammatory features reminiscent of human asthma. In order to examine whether polymorphisms in the candidate gene, TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the human TBX21 gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects. Among asthma phenotypes, a promoter −1993T→C SNP, which is in linkage disequilibrium with a synonymous coding 390A→G SNP in exon 1, is significantly associated with a risk of aspirin-induced asthma (AIA; P=0.004, Pc=0.016). This association has also been confirmed in additional independent samples of asthma with nasal polyposis (P=0.008), regardless of aspirin hypersensitivity. Furthermore, our data indicate that the −1993T→C substitution increases the affinity of a particular nuclear protein to the binding site of TBX21 covering the −1993 position, resulting in increased transcriptional activity of the TBX21 gene. Thus, in addition to the antigen-driven excess Th2 response, increased T-bet (and subsequent IFN-γ) production in human airways of individuals with the −1993T→C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA.

A functional polymorphism in IL-18 is associated with severity of bronchial asthma.

RATIONALE IL-18 is a unique cytokine that enhances innate immunity and both Th1- and Th2-driven immune responses. Recent murine and human genetic studies have shown its role in the pathogenesis of asthma. OBJECTIVES We conducted an association study in a Japanese population to discover variants of IL-18 that might have an effect on asthma susceptibility and/or progression and conducted functional analyses of the related variants. METHODS The IL-18 gene locus was resequenced in 48 human chromosomes. Asthma severity was determined according to the 2002 Global Initiative for Asthma Guidelines. Association and haplotype analyses were performed using 1,172 subjects. MEASUREMENTS AND MAIN RESULTS Although no polymorphisms differed significantly in frequency between the control and adult asthma groups, rs5744247 C>G was significantly associated with the severity of adult asthma (steps 1, 2 vs. steps 3, 4; P = 0.0034). We also found a positive association with a haplotype (P = 0.0026). By in vitro functional analyses, the rs5744247 variant was found to increase enhancer-reporter activity of the IL-18 gene in bronchial epithelial cells. Expression levels of IL-18 in response to LPS stimulation in monocytes were significantly greater in subjects homozygous for the susceptibility G allele at rs5744247 C>G. Furthermore, we found a significant correlation between the serum IL-18 level and the genotype of rs5744247 (P = 0.031). CONCLUSIONS Although the association results need to be replicated by other studies, IL-18 variants are significantly associated with asthma severity, and the rs5744247 variant reflects higher transcriptional activity and higher expression of IL-18 in LPS-stimulated monocytes and a higher serum IL-18 level.