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1.
Clin Exp Immunol ; 198(3): 416-429, 2019 12.
Article in English | MEDLINE | ID: mdl-31429073

ABSTRACT

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease that is caused by heterozygous mutations in the TNFRSF1A gene. Although more than 150 TNFRSF1A mutations have been reported to be associated with TRAPS phenotypes only a few, such as p.Thr79Met (T79M) and cysteine mutations, have been functionally analyzed. We identified two TRAPS patients in one family harboring a novel p.Gly87Val (G87V) mutation in addition to a p.Thr90Ile (T90I) mutation in TNFRSF1A. In this study, we examined the functional features of this novel G87V mutation. In-vitro analyses using mutant TNF receptor 1 (TNF-R1)-over-expressing cells demonstrated that this mutation alters the expression and function of TNF-R1 similar to that with the previously identified pathogenic T79M mutation. Specifically, cell surface expression of the mutant TNF-R1 in transfected cells was inhibited with both G87V and T79M mutations, whereas the T90I mutation did not affect this. Moreover, peripheral blood mononuclear cells (PBMCs) from TRAPS patients harboring the G87V and T90I mutations showed increased mitochondrial reactive oxygen species (ROS). Furthermore, the effect of various Toll-like receptor (TLR) ligands on inflammatory responses was explored, revealing that PBMCs from TRAPS patients are hyper-responsive to TLR-2 and TLR-4 ligands and that interleukin (IL)-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are likely to be involved in the pathogenesis of TRAPS. These findings suggest that the newly identified G87V mutation is one of the causative mutations of TRAPS. Our findings based on unique TRAPS-associated mutations provide novel insight for clearer understanding of inflammatory responses, which would be basic findings of developing a new therapeutic and prophylactic approach to TRAPS.


Subject(s)
Fever/genetics , Genetic Predisposition to Disease/genetics , Hereditary Autoinflammatory Diseases/genetics , Mutation, Missense , Receptors, Tumor Necrosis Factor, Type I/genetics , Adult , Aged , Amino Acid Sequence , Base Sequence , DNA Mutational Analysis/methods , Female , Fever/diagnosis , Hereditary Autoinflammatory Diseases/diagnosis , Humans , Male , Pedigree , Sequence Homology, Amino Acid
5.
Lupus ; 22(10): 1056-9, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23861027

ABSTRACT

This case report describes a Japanese girl with systemic lupus erythematosus who had recurrent fevers and erythema nodosum. She was later found to carry the complex allele E148Q/R202Q/P369S/R408Q of MEFV, the gene responsible for familial Mediterranean fever.


Subject(s)
Familial Mediterranean Fever/complications , Lupus Erythematosus, Systemic/complications , C-Reactive Protein/analysis , Child , Cytoskeletal Proteins/genetics , Familial Mediterranean Fever/genetics , Female , Humans , Lupus Erythematosus, Systemic/genetics , Pyrin
6.
Ann Rheum Dis ; 71(10): 1599-605, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22661645

ABSTRACT

Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.


Subject(s)
Genetic Testing/methods , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/genetics , Humans
8.
J Immunol ; 166(11): 6776-83, 2001 Jun 01.
Article in English | MEDLINE | ID: mdl-11359836

ABSTRACT

In BALB/c mice infected with Leishmania major, early secretion of IL-4 leads to a Th2-type response and nonhealing. We explored the role of IL-4-induced down-regulation of the IL-12Rbeta2 chain in the establishment of this Th2 response. First, we showed that the draining lymph nodes of resistant C57BL/6 mice infected with L. major were enriched in CD4+/IL-12Rbeta2 chain+ cells producing IFN-gamma. Next, we demonstrated that BALB/c background mice bearing an IL-12Rbeta2-chain transgene manifested a nonhealing phenotype similar to wild-type littermates despite the persistence of their ability to undergo STAT4 activation. Finally, we found that such transgenic mice display more severe infection than wild-type littermates when treated with IL-12 7 days after infection, and under this condition, the mice display increased Leishmania Ag-induced IL-4 secretion. These studies indicate that although CD4+/IL-12Rbeta2 chain+ T cells are important components of the Th1 response, maintenance of IL-12Rbeta2 chain expression is not sufficient to change a Th2 response to a Th1 response in vivo and thus to allow BALB/c mice to heal L. major infection.


Subject(s)
Interleukin-12/physiology , Leishmania major/immunology , Leishmaniasis, Cutaneous/genetics , Leishmaniasis, Cutaneous/immunology , Mice, Inbred BALB C/genetics , Mice, Transgenic/immunology , Receptors, Interleukin/genetics , Transgenes/immunology , Animals , Genetic Markers/immunology , Genetic Predisposition to Disease , Immunity, Innate/genetics , Immunophenotyping , Injections, Intraperitoneal , Interleukin-12/therapeutic use , Interleukin-4/biosynthesis , Interleukin-4/genetics , Leishmaniasis, Cutaneous/pathology , Leishmaniasis, Cutaneous/prevention & control , Lymph Nodes/immunology , Lymph Nodes/parasitology , Lymph Nodes/pathology , Mice , Mice, Inbred BALB C/immunology , Mice, Inbred C57BL , Receptors, Interleukin/biosynthesis , Receptors, Interleukin-12 , Severity of Illness Index , Th1 Cells/immunology , Th1 Cells/metabolism
9.
J Exp Med ; 191(5): 847-58, 2000 Mar 06.
Article in English | MEDLINE | ID: mdl-10704465

ABSTRACT

The differentiation of CD4(+) T cells into T helper type 1 (Th1) cells is driven by interleukin (IL)-12 through the IL-12 receptor beta2 (IL-12Rbeta2) chain, whereas differentiation into Th2 cells is driven by IL-4, which downregulates IL-12Rbeta2 chain. We reexamined such differentiation using IL-12Rbeta2 chain transgenic mice. We found that CD4(+) T cells from such mice were able to differentiate into Th2 cells when primed with IL-4 or IL-4 plus IL-12. In the latter case, the presence of IL-4 suppressed interferon (IFN)-gamma production 10-100-fold compared with cells cultured in IL-12 alone. Finally, in studies of the ability of IL-12 to convert Th2 cells bearing a competent IL-12R to the Th1 cells, we showed that: (a) T cells bearing the IL-12Rbeta2 chain transgene and primed under Th2 conditions could not be converted to Th1 cells by repeated restimulation under Th1 conditions; and (b) established Th2 clones transfected with the IL-12Rbeta2 chain construct continued to produce IL-4 when cultured with IL-12. These studies show that IL-4-driven Th2 differentiation can occur in the presence of persistent IL-12 signaling and that IL-4 inhibits IFN-gamma production under these circumstances. They also show that established Th2 cells cannot be converted to Th1 cells via IL-12 signaling.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , Receptors, Interleukin/metabolism , Th2 Cells/cytology , Animals , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation , DNA-Binding Proteins , Interferon-gamma/biosynthesis , Interleukin-4/biosynthesis , Lymphocyte Activation , Mice , Mice, Transgenic , Receptors, Interleukin/genetics , Receptors, Interleukin-12 , STAT4 Transcription Factor , Signal Transduction , Th1 Cells/cytology , Th1 Cells/immunology , Th2 Cells/immunology , Trans-Activators
10.
J Immunol ; 162(8): 4975-82, 1999 Apr 15.
Article in English | MEDLINE | ID: mdl-10202045

ABSTRACT

We previously demonstrated that 2,4,6-trinitrophenol (TNP)-OVA immunization leads to a transmural colitis in the IL-2-/- mouse that is caused by IL-12-driven CD4+ Th1 T cells and resembles human Crohn's disease. The integrin alpha E beta 7 is highly expressed on colonic intraepithelial lymphocytes and has been suggested to function as a homing or retention molecule for intraepithelial lymphocytes. To evaluate the role of alpha E beta 7 in colitis, we administered a mAb against alpha E beta 7 to IL-2-/- mice that were immunized at the same time with TNP-OVA in CFA. To our surprise, this treatment resulted in a significantly reduced colitis severity score, 0-2 vs 3-4, that was associated with a significant reduction in CD4+ lamina propria lymphocyte subpopulation (p < 0.01). In contrast, the total number of splenic CD4+ T cells of treated animals was significantly elevated compared with that of untreated animals (3.2 +/- 0.6 x 107 vs 1.2 +/- 0.2 x 107; p < 0.05). Similarly, functional studies revealed that IFN-gamma production by lamina propria lymphocytes isolated from IL-2-/- TNP-OVA-immunized mice treated with anti-alpha E beta 7 was significantly lower than in untreated IL-2-/- TNP-OVA-immunized mice. In contrast, IFN-gamma production by splenic cells isolated from treated IL-2-/- TNP-OVA-immunized mice was significantly higher than in untreated mice. Finally, TNP-OVA-immunized IL-2-/- mice that were treated after the colitis had been established also showed a significant decrease in mucosal inflammation after alpha E beta 7 mAb administration. Thus, the above findings demonstrate that the onset and maintenance of inflammatory bowel disease depends on the colonic localization of lamina propria CD4+ lymphocytes expressing alpha E beta 7.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Colitis/immunology , Colitis/prevention & control , Integrins/immunology , Interleukin-2/genetics , Animals , Antibodies, Monoclonal/therapeutic use , CD3 Complex/analysis , CD4 Lymphocyte Count , Cell Movement/genetics , Cell Movement/immunology , Colitis/genetics , Colitis/pathology , Female , Haptens/immunology , Immunization , Injections, Intraperitoneal , Intercellular Adhesion Molecule-1/analysis , Interferon-gamma/biosynthesis , Intestinal Mucosa/pathology , Lymphocyte Count , Lymphocytes/metabolism , Lymphocytes/pathology , Male , Mice , Mice, Knockout , Ovalbumin/immunology , Spleen/cytology , Spleen/metabolism , Trinitrobenzenes/immunology
11.
J Immunol ; 154(5): 2333-41, 1995 Mar 01.
Article in English | MEDLINE | ID: mdl-7532665

ABSTRACT

Intercellular adhesion molecule-1 (ICAM-1), the ligand of lymphocyte function-associated antigen-1, plays an important role in the interactions of a variety of hemopoietic and nonhemopoietic cells, including leukocytes, fibroblasts, and endothelial cells. ICAM-1 is known to be involved in the onset of several diseases such as inflammation, allograft rejection, and so on. In this report, we investigated the effects of dexamethasone, cyclosporin A, FK506, and pyrrolidine dithiocarbamate (PDTC) on the induction of the ICAM-1 gene by cytokines in fibroblasts. PDTC, a potent inhibitor of NF-kappa B, was shown by ELISA and FACS analysis to prevent dramatically the expression of the ICAM-1 gene stimulated by IL-1 alpha, IFN-gamma, and PMA, although the other reagents inhibited it only slightly. Ribonuclease protection assay revealed that PDTC blocked the expression of the ICAM-1 gene at the mRNA level. To elucidate the mechanism of this inhibition, we constructed a series of ICAM-1 promoter deletion mutants linked to the chloramphenicol acetyl transferase gene and analyzed the effect of PDTC on their activities. Transient transfection analysis indicated that the critical region for inhibition by PDTC is an NF-kappa B binding site-like motif (GGGAGGATTCC, ICAM-1 kappa B) that is located at position-540. Electrophoresis mobility shift assay revealed that PDTC actually inhibits the binding of NF-kappa B (or NF-kappa B-like) protein to the ICAM-1 kappa B site. These findings suggest that PDTC inhibits ICAM-1 gene expression by inhibiting the association of NF-kappa B (or NF-kappa B-like) protein with the ICAM-1 kappa B site.


Subject(s)
Cytokines/pharmacology , Intercellular Adhesion Molecule-1/biosynthesis , Pyrrolidines/pharmacology , Thiocarbamates/pharmacology , Base Sequence , Cell Line , Cyclosporine/pharmacology , DNA/genetics , Dexamethasone/pharmacology , Fibroblasts/drug effects , Fibroblasts/immunology , Fibroblasts/metabolism , Gene Expression Regulation/drug effects , Humans , Intercellular Adhesion Molecule-1/genetics , Interferon-gamma/pharmacology , Interleukin-1/pharmacology , Molecular Sequence Data , NF-kappa B/antagonists & inhibitors , Promoter Regions, Genetic , RNA, Messenger/genetics , RNA, Messenger/metabolism , Recombinant Proteins , Tacrolimus/pharmacology , Tetradecanoylphorbol Acetate/pharmacology
12.
J Immunol ; 154(2): 694-702, 1995 Jan 15.
Article in English | MEDLINE | ID: mdl-7814876

ABSTRACT

Mouse mast cells produce many kinds of cytokines in response to cross-linking of high affinity Fc epsilon receptor (Fc epsilon RI). Among these cytokines, granulocyte-macrophage CSF (GM-CSF) gene induction in mouse mast cells has been reported to be regulated at both the transcriptional level and the post-transcriptional level. We analyzed the mechanism of the transcriptional regulation of GM-CSF gene induction through Fc epsilon RI cross-linking stimulation in the mouse mast cell line MC/9. In MC/9, the GM-CSF gene was activated transcriptionally by Fc epsilon RI cross-linking stimulation. The 5' deletion analysis of GM-CSF gene promoter indicated that the 5' boundary of the responsive promoter region lay between positions -113 and -95. When the deletion was extended to positions -72 or -60, the stimulatory effect was significantly diminished. We then examined 3' deletion of pmGMCAT -113 from position -60. This analysis indicated that the 3' boundary lay between positions -84 and -72. No subfragments of the region spanning positions -113 to -72 could cover the full induction level. A site-directed mutagenesis experiment revealed that the sequence spanning positions -108 to -72 was needed for full activation. These data indicate that GM-CSF gene in mast cells is activated mainly through the sequence spanning positions -108 to -72.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Mast Cells/immunology , Promoter Regions, Genetic/immunology , Receptors, IgE/metabolism , Animals , Base Sequence , Blotting, Northern , Cell Line , Chloramphenicol O-Acetyltransferase/genetics , Gene Expression Regulation/immunology , Mice , Molecular Sequence Data , Mutagenesis, Site-Directed , RNA, Messenger/biosynthesis , Transcription, Genetic/immunology , Transcriptional Activation
13.
Biochem Pharmacol ; 48(10): 1883-9, 1994 Nov 16.
Article in English | MEDLINE | ID: mdl-7986199

ABSTRACT

We examined the effect of pyrrolidine dithiocarbamate (PDTC), which potently blocks the activation of nuclear factor kappa B (NF-kappa B), on the induction of apoptosis by a variety of agents. Treatment of a human promyelocytic leukemia cell line, HL-60, with 10 micrograms/mL etoposide or 2 microM 1-beta-D-arabinofuranosylcytosine induced NF-kappa B activation within 1 hr and subsequently caused apoptosis within 3-4 hr. The simultaneous addition of 50-500 microM PDTC with these agents blocked NF-kappa B activation and completely abrogated both morphologically apoptotic changes and internucleosomal DNA fragmentation for up to 6 hr. However, PDTC failed to inhibit the endonuclease activity contained in the whole cell lysates. The inhibitory effect of PDTC was also observed in etoposide- and dexamethasone-induced apoptosis in human thymocytes at a concentration of 1-10 microM. Since PDTC has both antioxidant and metal-ion chelating activities, we tested the effects of N-acetyl-L-cysteine (NAC) (antioxidant) or o-phenanthroline (OP) (metal-ion chelator) on the induction of apoptosis. Pretreatment of HL-60 cells or thymocytes with 100-500 microM OP for 2 hr, but not 10-60 mM NAC, suppressed subsequent occurrence of apoptosis induced by etoposide. These results suggest that the activation of NF-kappa B plays an important role in the apoptotic process of human hematopoietic cells.


Subject(s)
Apoptosis/drug effects , Leukemia, Promyelocytic, Acute/pathology , NF-kappa B/antagonists & inhibitors , Pyrrolidines/pharmacology , T-Lymphocytes/drug effects , Thiocarbamates/pharmacology , Acetylcysteine/pharmacology , Base Sequence , Cytarabine/pharmacology , Endonucleases/antagonists & inhibitors , Etoposide/pharmacology , Humans , Molecular Sequence Data , Oligodeoxyribonucleotides , Phenanthrolines/pharmacology , T-Lymphocytes/cytology , Thymus Gland/cytology , Tumor Cells, Cultured
14.
Mol Immunol ; 31(16): 1269-75, 1994 Nov.
Article in English | MEDLINE | ID: mdl-7969187

ABSTRACT

Murine embryonal carcinoma (EC) P19 cells, a tissue culture model of early embryonic development, failed to produce cytokines, such as interleukin-3 (IL-3), IL-4, granulocytemacrophage colony stimulating factor (GM-CSF) and interferon-beta (IFN-beta) at the mRNA level. Differentiation induced by retinoic acid (RA) released this repression to produce some cytokines. GM-CSF and IFN-beta genes were expressed in response to PMA/A23187, poly(I):poly(C), IL-1 alpha, forskolin, or LPS stimulation in differentiated P19 cells, whereas IL-3 and IL-4 genes were not expressed. To elucidate the mechanism of the GM-CSF gene induction after differentiation, we transfected a series of 5' deletion mutants of the mouse GM-CSF promoter fused to the bacterial CAT gene. The 740-bp fragment of the 5'-flanking region mediated the positive response. Deletion analysis revealed that the 5' boundary region of the DNA element required for activation lies between positions -95 and -84 and the region upstream of position -95 appears inhibitory. These results indicate that the maturation of the transcriptional machinery after differentiation results in the activation of the GM-CSF gene.


Subject(s)
Gene Expression Regulation, Developmental/physiology , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Animals , Base Sequence , Blotting, Northern , Cell Differentiation/genetics , Embryonal Carcinoma Stem Cells , Gene Expression Regulation, Developmental/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , Interferon-beta/genetics , Interleukin-3/genetics , Interleukin-4/genetics , Mice , Molecular Sequence Data , Neoplastic Stem Cells , Promoter Regions, Genetic , Sequence Deletion , Transcriptional Activation
15.
Biochem Biophys Res Commun ; 198(2): 473-9, 1994 Jan 28.
Article in English | MEDLINE | ID: mdl-8297357

ABSTRACT

In a previous report, we reported that the induction of GM-CSF gene in differentiated P19 cells results from the maturation of the transcriptional machinery. Here, we identified a cis-DNA element which confers the activation of GM-CSF gene in response to PMA/A23187 stimulation in differentiated state. Analysis of the 5'-flanking region between -113 and -60 revealed two elements responsible for promotion and one for inhibition, and the overall effects led to the activation of GM-CSF gene mainly through the sequence between -95 and -73. Using the oligonucleotide between -94 and -73 as a probe in gel retardation assays, we identified a DNA-binding protein, NF-GM-P19, the binding activity of which was induced after differentiation in response to PMA/A23187 stimulation. These results indicate that the induction of GM-CSF gene after differentiation results from the maturation of the transcriptional machinery which recognizes the sequence between -95 and -73.


Subject(s)
Carcinoma, Embryonal/genetics , DNA, Neoplasm/metabolism , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Regulatory Sequences, Nucleic Acid/genetics , Animals , Base Sequence , Calcimycin/pharmacology , Cell Differentiation , DNA Mutational Analysis , Gene Expression Regulation, Neoplastic/drug effects , Mice , Molecular Sequence Data , Protein Binding , Signal Transduction , Tetradecanoylphorbol Acetate/pharmacology , Transfection , Tumor Cells, Cultured
16.
Acta Paediatr Jpn ; 34(1): 72-9, 1992 Feb.
Article in English | MEDLINE | ID: mdl-1580156

ABSTRACT

We report a case of Farber disease (Farber lipogranulomatosis). The main features were a shrill voice, joint swelling, subcutaneous nodules and retarded psychomotor development. Cytological investigation revealed intracytoplasmic inclusion bodies characteristic of Farber disease. Lipid analysis of liver tissue indicated an accumulation of ceramide containing non-hydroxy fatty acids. It was found that the acid ceramidase activity in the liver was reduced to 31% of the control value. In this patient there was also persistent diarrhea, cholelithiasis, transient proteinuria and increased urinary total sialic acids. These features have not been noted in previously reported cases.


Subject(s)
Amidohydrolases/deficiency , Sphingolipidoses/diagnosis , Acid Ceramidase , Amidohydrolases/blood , Amidohydrolases/metabolism , Ceramidases , Humans , Infant , Male , Sphingolipidoses/enzymology , Sphingolipidoses/pathology
17.
J Pediatr ; 116(1): 84-7, 1990 Jan.
Article in English | MEDLINE | ID: mdl-2104930

ABSTRACT

Two infants who had clinical and radiographic findings consistent with Leigh syndrome were found to have deficiency of complex I (reduced nicotinamide-adenine dinucleotide--coenzyme Q reductase) activity. Significant abnormalities were found on computed tomographic scans and magnetic resonance images of the brain. Lactate and pyruvate concentrations in blood and cerebrospinal fluid were elevated, and muscle biopsy specimens showed abnormal mitochondria. These data indicate that Leigh syndrome, as well as MELAS syndrome (mitochondrial encephalopathy, myopathy, lactic acidosis, and stroke-like episodes) may result from complex I deficiency.


Subject(s)
Brain Diseases, Metabolic/enzymology , Leigh Disease/enzymology , Quinone Reductases/deficiency , Child, Preschool , Female , Humans , Infant , Leigh Disease/diagnosis , Magnetic Resonance Imaging , NAD(P)H Dehydrogenase (Quinone) , Tomography, X-Ray Computed
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