結核菌／非結核性抗酸菌に対する易感染性とIL-12/IFN-γ経路
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1 IL-12/IFN- BCG IFN- IL-12/IFN- IL-12/IFN- IL-121IL12RB1 - BCG -12 The Interleukin-12/Interferon- Pathway and Susceptibility to M. Tuberculosis and Nontuberculous Mycobacteria Koichi Kusuhara, Hidetoshi Takada, Toshiro Hara ABSTRACT The Interleukin (IL)-12/Interferon (IFN)- pathway plays a pivotal role in immune defense against mycobacteria through killing of intracellular bacteria. Recently, genetic analysis of severe or recurrent cases of clinical diseases caused by weakly virulent mycobacterial species, such as BCG and nontuberculous mycobacteria, have revealed the congenital deficiencies of the molecules involved in the IL-12/IFN- pathway designated as Mendelian susceptibility to mycobacterial disease (MSMD). Increased susceptibility to tuberculosis has also been observed in this type of genetic disorder. In this paper, we review the clinical manifestations, pathogenesis and genetic analysis of MSMD, with special reference to partial autosomal dominant IFN- receptor 1 deficiency, which we first identified in Japanese. We also refer to our gene-based association analysis of 21 candidate genes using marker single nucleotide polymorphisms, in which it is suggested that genetic variants of IL12RB1 confer genetic susceptibility to tuberculosis, and are associated with the progression of the disease in Japanese. keywords ; IFN-, BCG, IL-12, Susceptibility to mycobacteria, Genetic analysis TEL FAX kkusuhar@pediatr.med.kyushu-u.ac.jp Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University 9
2 BCG BCG IL -12/ IFN BCG IL-12/IFN- IL-12p40, IL-12IL-12R 1 IFN- IFN- R 1 IFN- R2STAT-1 BCG IL-12/IFN- IL-12/IFN- IL-12R 1IL12RB1 1) CD4 TCD8 T TIFN- CD4 TCD8 T 2) IL-12 NKTIL- 12R IL-12R T TIFN- IFN- R STAT-1 TNF- MHC IL-12 IL- 12/IFN- BCG IL-12/IFN- IL-12/IFN- mendelian susceptibility to mycobacterial disease MSMD MIM IFN- R1, IFN- R2 IFN- Figure 1. Host immune response to mycobacteria. Collins & Kaufmann (Immunology 2001; 103:1-9) 1) 10
3 Figure 2. IL-12/IFN- pathway. Modified from Dupuis et al. (Immunol Rev 2000; 178: ) 2) IFN- R1 IFN- R2 STAT-1IFN- IL-12p40 IL-12R 1 IL-12 IFN- IL-12/IFN- BCG, IL-12 autosomal recessive inheritance, AR IL-12 p70 p35 p40 heterodimer Th0 Th1 TNK IFN- IL12p40 Altare ) IL12B IL-12p40 homozygous 4.4 kbp IL-12p40 IL-12p70 IL-12p40 IL-12p35 in vitro BCG IL-12 IFN- BCG 4) IL- 12R IL-12 3) 4) IL-12R autosomal recessive inheritance, AR IL-12R Table 1. IL-12/IFN- pathway abnormalities and infections Clinical features Gene BCG infection Severity Granuloma NTM infection Incidence Age at onset Other infections Therapy CD AR AR AD IFN- R1 IFN- R2 STAT-1 Severe Early Severe???? Listeria # Salmonella Virus Stem Cell Transplantation PD AD AR AD IFN- R1 IFN- R2 STAT-1 Moderate Moderate Moderate / / / Over 3y Salmonella Antibiotics Anti-TB IFN- PD AR IFN- R1 Mild Salmonella Legionella M. tuberculosis Antibiotics Anti-TB CD AR IL-12p40 IL-12R 1 Mod / Salmonella M. tuberculosis Antibiotics Anti-TB # Only complete deficiency of IFN- R1, CD: complete deficiency, PD: partial deficiency, AR: autosomal recessive inheritance, AD: autosomal dominant inheritance 11
4 IL-12R 1 IL- 12R 1IL12RB1 homozygousnkt IFN- Altare ) BCG IL-12 IFN- R IFN- autosomal recessive inheritance, AR IFN- RIFNGR1 homozygous compound heterozygous heterozygous IFN- R1 IFN- in vitro IFN Newport 6) Jouanguy 7) BCG BCG BCG autosomal recessive inheritance, AR 1997 Jouanguy 8) IFNGR1 homozygous in vitroifn- IFN- BCG 1 BCG 1 9) autosomal dominace inheritance, AD Jouanguy ) IFNGR1 exon6 heterozygous truncated receptor IFNGR1818 hot spot IFN- JAK-1 STAT-1 IFN- dominant negative in vitro IFN- BCG BCG 2) IFN- R autosomal recessive inheritance, AR IFNGR2 IFN- R homozygous IFN- IFN- R2 in vitro IFN- TNF-IFN- STAT-1IFN- R Dorman Holland 10) 10) autosomal recessive inheritance, AR 2001 Doffinger 11) IFNGR2 homozygous IFN- R2in vitro IFN- BCG M. abscessus 20 12
5 11) STAT-1autosomal recessive inheritance, AR STAT-1 IFN homodimer -activating factor, GAF STAT-2/p48 trimer interferon-stimulated factor 3, ISGF3STAT-1 STAT1 STAT-1 heterozygous L706S IFN- STAT dominant negativegaf IFN Dupuis 12) BCG 11) IFN- R1IFN- R2 STAT1 GAF dominantisgf3 recessive STAT1 homozygous STAT-1 ISGF3 IFN- / 13) BCG BCGBCG BCG BCG BCG IFN- BCG IFN- R1 BCG 14) BCG BCG18 in vitro IFN-IL-12 IFN- R1 IFN- R1 IFN- R1 IFN- R1 PE IFN- R1 IFNGR1 811del4 818del4 Jouanguy 8) premature stop codon IFN- R1 IFNGR1 IFNGR2 IFN- IFNG Figure 3. Expression of IFN- receptor 1 (CD 14 gating). 13
6 Figure 4. Table 2. Case No. IL12B IL12RB1 STAT1 IFNG BCG Mutations in the IFN- receptor 1 gene identified in three of the six patients with BCG osteomyelitis. Summary of genetic analyses of IL-12/IFN- pathway on six patients with BCG osteomyelitis IFNGR1 IFNGR2 IFNG IL12B IL12RB1 STAT1 Expression of IFN- R del4 Normal ND 2 818del4 Normal ND 3 818del4 Normal ND 4 Normal Normal Normal Normal 5 Normal Normal Normal Normal 6 Normal Normal Normal Normal 7 * 818del4 Normal ND *Father of Case 2 with a history of TB lymphadenitis and Mycobacterium avium complex osteomyelitis, ND: not done Sasaki et al J Infect Dis, ) BCG IFN- RIFN-IL- 12p40ELISA IL-12p40 IL-12p70 IFN- IL-12R 1 IFN- T IL-12R 1 IFN- IFN- R IFN- R IFN- R1 IFN- R1 in vitro lipopolysaccharide LPS LPS recombinant IFN-TNF- EBtransformBEBV-B cells STAT-1 electrophoreic mobility shift assay EBV-B cellsstat-1 BCG BCG IL-12p40 IL-12R 1 IFN- R1IFN- R2 IFN-in vitro IFN g/m g/m 2 IFN- R1IFN- R2 IFN- R1 IFN- R2 14
7 Table 3. Association studies on marker SNPs of 21 candidate genes for TB susceptibility Candidate genes Number of SNPs analyzed Number of SNPs with MAF 0.1 Number of marker SNPs showing P a A1+ vs A1- b A2+ vs A2- allele 2 2 Genes with published association with TB SLC11A1 NRAMP VDR IL1B Genes associated with IL-12/IFN- axis IFNG IFNGR IFNGR IL12A p IL12B p IL12RB IL12RB STAT IL IL18R IL23A p IL23R IL27 EBI3, p IL27RA WSX Genes associated with TNF- pathway TNF TNFRSF1A TNFRSF1B Candidate gene based on linkage analysis UBE3A 15q Total MAF: Minor allele frequency, a 2 3: Comparison of genotype frequencies using 2 3 table, b A1+ vs A1-: Comparison of frequencies of genotypes with and without A1 allele using 2 2 table 10% identical twin non-identical twin ) HLA NRAMP1 D 16,17-22) locus 15q11-13 Xq26 23) SNP 24) SNP Taqman probe SNP SNP coding SNPcSNP csnp SNP IL-12/IFN- 14 TNF- 21 IL-1 IL1B IL-12R 1 IL12RB1 SNP SNPcSNP IL1BcSNP IL12RB1 IL12RB1 SNPs SNPsSNPs rs rs csnp 641A/GGG genotype Ggenotype 15
8 T/C 1132G/C csnp T G CC genotype C genotype2 3 csnp 1573G/A genotype 87 X 25) minimal moderately advanced far advanced minimaladvanced moderately faril12rb1csnp 641A/G, 1094C/G, 1132C/Ggenotype advanced 641A/GGG genotypeg, 1094T/C 1132G/CCC genotypec csnp 641A/G 1094T/C 1132C/G Table 4. Association studies of marker SNPs SNP P value (chi) Frequency A1 A2 rs Cont TB rs Cont TB rs Cont TB rs Cont TB rs Cont Figure 5. Structure of IL12RB1 gene and the location of SNPs. 24) Table 5. Genotype and allele frequencies of IL12RB1 641A/G, 1094T/C and 1132G/C SNPs in TB patients and controls 24) IL12RB1 csnps Control TB OR 95 CI P-value 641A/G Genotype frequency AA AG GG Total : P = Allele frequency A G T/C 1132G/C Genotype frequency TT GG TC GC CC CC Total : P = Allele frequency T G C C
9 1573G/A csnp csnp GCCG ATGG IL-12/IFN- IL12RB1 T NKIL-12R 1 subunit MSMD IL-12R1 TNK IFN- IL12RB1 csnp SNP Akahoshi 26) IL-12R IL12RB1 Table 6. Genotype and allele frequencies of IL12RB1 641A/G, 1094T/C and 1132G/C SNPs in TB patient subgroups classified by disease severity 24) IL12RB1 SNPs Controls TB Minimal OR 95 CI P value TB Advanced Moderately +Far OR 95 CI Pc value 641A/G Genotype frequency AA AG GG Total Allele frequency A G T/C 1132G/C Genotype frequency TT GG TC GC CC CC Total Allele frequency T G C C #International Classification of Tuberculosis Falk A et al., ) Table 7. Estimated frequencies of haplotypes constituted by 4 csnps of IL12RB1 in TB patients and controls 24) Haplotype # Frequency Controls n=249 TB n=86 chi-square P-value ATGG GCCA GCCG others * SNP, single nucleotide polymorphism; TB, tuberculosis. #Haplotypes constituted by 641A/G, 1094T/C, 1132G/C and 1573G/A *Haplotypes with frequencies
10 27) 28) IL12RB1 SNP 27) IL12RB1 /IL- 12/IFN- IL-12/IFN- Saifuddin Ahmed é é é 18
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Arts and Sciences Development and usefulness evaluation of a remote control pressured pillow for prone position 1 36057 2 45258 2 29275 3 3 4 1 2 3 4 Key words: pressured pillow prone position, stomach
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Key words : candidemia, endotoxin, D-arabinitol, Candida antigen, serological examination
Key words : candidemia, endotoxin, D-arabinitol, Candida antigen, serological examination Fig. 1 The value of fungal index and D- arabinitol/creatinine. Fungal index was mesured by Endotoxin D and Endospecy
Key words : 7432-S, Oral cephem, Urinary tract infection Fig. 1. Chemical structure of 7432-S.
Key words : 7432-S, Oral cephem, Urinary tract infection Fig. 1. Chemical structure of 7432-S. Table 1. Clinical summary of acute uncomplicated cystitis patients treated with 7432-S UTI : Criteria by the
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Table 1 Survival rates of infected mice given antibiotic doses producing peak serum a) S. aurcus Smith Challenge dose :7 ~10 (5% mucin) CFU/mouse. LD50: 1 ~103 (5% mucin) CFU/mouse. Table 2 Survival rates
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4 A study of historical transition on the producer system in Japanese film industries : A view for the redefinition of film producers 立 命 館 大 学 大 学 院 政 策 科 学 研 究 科 博 士 後 期 課 程 前 田 耕 作 MAEDA, Kosaku 立 命
Key words: bacterial meningitis, Haemophilus influenzae type b, Streptococcus pneumoniae, rapid diagnosis, childhood
Key words: bacterial meningitis, Haemophilus influenzae type b, Streptococcus pneumoniae, rapid diagnosis, childhood Fig.1 Distribution of the cases with bacterial meningitis by age and pathogens Chiba
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VOL. 40 S- 1 Table 1. Susceptibility of methicillin-resistant Staphylococcus aureus to meropenem Table 2. Coagulase typing of methicillin-resistant St
CHEMOTHERAPY VOL. 40 S- 1 Table 1. Susceptibility of methicillin-resistant Staphylococcus aureus to meropenem Table 2. Coagulase typing of methicillin-resistant Staphylococcus aureus CHEMOTHERAPY Table
CHEMOTHERAPY FEB Table 1. Activity of cefpirome and others against clinical isolates
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1 Department of Legal Medicine, Toyama University School of Medicine 2 3 4 5 6 7 8 Department of Ophthalmology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama VEGF Key words
Key words: E. coli O 157: H7, fosfomycin, verotoxin, mouse infection
Key words: E. coli O 157: H7, fosfomycin, verotoxin, mouse infection Table 1. Bacterial cell counts in feces of mice infected with Esclwrichia coli O 157: H7 NK2 before and during oral dosing with fosfomycin
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Study on Clinical Factors Affecting the Fungal Culture Test - Relevance of Dry Mouth - Yoshiko YAMAMURA, Yukihiro MOMOTA, Hideyuki TAKANO, Koichi KANI, Katsumi MOTEGI, Fumihiro MATSUMOTO, Masayuki AZUMA
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Fig.2. Sensitivity distribution of clinical isolates of S. epidermidis (24 strains, 106 CFU/ml) Staphylococcus aureus Staphylococcus epider- midis Ent
Fig.2. Sensitivity distribution of clinical isolates of S. epidermidis (24 strains, 106 CFU/ml) Staphylococcus aureus Staphylococcus epider- midis Enterococcus faecalis Klebsiella pneumoniae, Morganella
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13 The Rational Trading by Using Economic Fundamentals AOSHIMA Kentaro 14 2 26 ( ) : : : The Rational Trading by Using Economic Fundamentals AOSHIMA Kentaro abstract: Recently Artificial Markets on which
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Research and Analysis about Study Time using R MIYOSHI Yoshihiko In Saitama W. J. College, we have implemented many surveys which are the freshman questionnaire, the graduate satisfaction questionnaire,
Studies on Mild School Myopia Part II. The Amplitude of Accmmodation in Mild School Myopia By Ling Nai Kay Department of Ophthalmology Okayama University Medical School (Director: Prof. Goro Akagi) By
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Fig. 3 Flow diagram of image processing. Black rectangle in the photo indicates the processing area (128 x 32 pixels).
Fig. 1 The scheme of glottal area as a function of time Fig. 3 Flow diagram of image processing. Black rectangle in the photo indicates the processing area (128 x 32 pixels). Fig, 4 Parametric representation
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2018 (412837) 4.1 % 7.5 % Abstract Recently, various methods for improving computial performance have been proposed. One of these various methods is Multi-core. Multi-core can execute processes in parallel
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1) University Group Diabetes Program: A study of hypoglycemic agents on vascular complica- in patients with adult-onset tions diabetes. I. Design, methods and baseline results. Diabetes 19 (suppl. 2):
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CHEMOTHERAPY APR. 1994 VOL.42 S-1 CHEMOTHERAPY APR. 1994 Table 1. Criteria for evaluation of clinical efficacy by the Japanese Society of Oral and Maxillo-Facial Surgeons Grades of symptoms and numerical
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2007 18 12 2 3 30 1998 16.2 10 10 1 2008 1 44.5 41.2 39.6 6.0 2.2 1819 Bostock hay fever 4 1964 5 2008 15,673 1 1998 2008 17 300 6 10 23.4 26.5 15.4 2
30 2008 1,172 30 2008 39.6 3 1.5 2008 5 Pollen allergy due to Japanese cedar pollen and preventive measures by Tochigi Prefectural Government Abstract TAKAISHI Masaki, AOYAGI Tatsuya, MASUDA Takashi and
Fig. 1 Distribution of department stores in the Tokyo Metropolitan Area (1998) Fig. 2 Cluster structure Table 2 Average factor scores for cluster analysis Table 3 Average attributes for store clusters
Key words : R-plasmid, Urinary tract infection, E. coli Fig. 1. MIC distribution against E. coli isolated from urinary tract (366 strains) and isolation - frequencies of drug-resistant strains Table 1.