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K Agematsu

Publications and source records attributed to K Agematsu.

At least 19 recordsLinked to original sources
PubMed2001

Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein--epsilon.

Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder. The neutrophils of individuals with SGD display atypical bi-lobed nuclei, lack expression of all secondary and tertiary granule proteins, and possess defects in chemotaxis, disaggregation, receptor up-regulation, and bactericidal activity, resulting in frequent and severe bacterial infections. Previously, a homozygous mutation in the CCAAT/enhancer binding protein-epsilon (C/EBPepsilon) gene was reported for one case of SGD. To substantiate the role of C/EBPepsilon in the development of SGD and elucidate its mechanism of inheritance, the mutational status of the gene was determined in a second individual. An A-nucleotide insertion in the coding region of the C/EBPepsilon gene was detected. This mutation completely abolished the predicted translation of all C/EBPepsilon isoforms. Microsatellite and nucleotide sequence analyses of the C/EBPepsilon locus in the parents of the proband indicated that the disorder may have resulted from homozygous recessive inheritance of the mutant allele from an ancestor shared by both parents. The mutant C/EBPepsilon(32) protein localized in the cytoplasm rather than the nucleus and was unable to activate transcription. Consistent with this, a significant decrease in the levels of the messenger RNAs (mRNAs) encoding the secondary granule protein human 18-kd cationic antimicrobial protein (hCAP-18)/LL-37 and the primary granule protein bactericidal/permeability-increasing protein were observed in the patient. The hCAP-18 mRNA was induced by overexpression of C/EBPepsilon(32) in the human myeloid leukemia cell line, U937, supporting the hypothesis that C/EBPepsilon is a key regulator of granule gene synthesis. This study strongly implicates mutation of the C/EBPepsilon gene as the primary genetic defect involved in the development of neutrophil SGD and defines its mechanism of inheritance.

Adult↗
PubMed2001

Inhibition of methicillin-resistant Staphylococcus aureus colonization of oral cavities in newborns by viridans group streptococci.

We investigated the role of viridans group streptococci in the prevention of colonization with methicillin-resistant Staphylococcus aureus (MRSA) in neonatal intensive care units. During a 26-month period at a children's hospital, 207 (49.9%) of 415 newborns were colonized with MRSA by the time of discharge. Two groups of newborns with matching durations of hospitalization were compared with regard to the prevalence of future colonization with MRSA: group 1 (103 patients) did not acquire colonization with viridans group streptococci and group 2 (63 patients) did acquire colonization with viridans group streptococci at birth or by 1 to 2 weeks (age, < or =11 days). The rate of colonization among patients in group 2 (9.5%) was significantly lower than that among patients in group 1 (44.7%; P<.001). No significant difference in patient characteristics (e.g., birth weight, diseases) was observed. These results indicate that viridans group streptococci, as bacteria that formerly occupied the oral cavities in newborns, may inhibit later colonization with MRSA.

Antibiosis↗
PubMed2001

H(2)O(2) produced by viridans group streptococci may contribute to inhibition of methicillin-resistant Staphylococcus aureus colonization of oral cavities in newborns.

In an accompanying report, we showed that viridans group streptococci may prevent methicillin-resistant Staphylococcus aureus (MRSA) colonization of the oral cavities of newborns. In the present study, we investigated the mechanism of prevention in vitro. Most viridans group streptococci had bacteriocin-like activity and killed MRSA, Burkholderia cepacia, Enterobacter aerogenes, and Pseudomonas aeruginosa; however, Escherichia coli, Enterobacter cloacae, and Candida albicans were resistant. The activity was induced only by H(2)O(2)-secreting strains and was inhibited by horseradish peroxidase or catalase in a dose-dependent manner. The mean concentration of H(2)O(2) produced by 18 strains of viridans group streptococci (1 x 10(8) cfu in 200 microL of culture medium+/-standard deviation was 1.24+/-0.60 mmol. Viridans group streptococci inhibited MRSA growth in saliva as well as in culture media. These results indicate that H(2)O(2) produced by viridans group streptococci may inhibit MRSA colonization of oral cavities in newborns.

Antibiosis↗
PubMed2000

Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway.

Surrogate light chains (lambda 5/VpreB) are selectively expressed in early precursors of B cells. B-cell defects in X-linked agammaglobulinemia (XLA) are caused by mutations in the gene for Bruton's tyrosine kinase. To elucidate the nature of early B-lineage cells in bone marrow (BM), samples from 13 XLA patients and 24 healthy controls of different ages were comparatively analyzed using an antihuman VpreB monoclonal antibody. Expression of surrogate light (SL) and mu-heavy chains were examined after cell membrane permeabilization because they are mainly expressed in the cytoplasm of early B-lineage cells. A flow cytometric analysis of normal BM identified 5 discrete cell types of B cells: mu(-)SL(++) (pro-B [B-cell progenitor]), mu(low)SL(++) (pre-B1a), mu(low)SL(+) (pre-B1b), mu(low)SL(- )(pre-B2), and mu(high)SL(- )(B). The large cells, presumably in cycling states, were enriched in pre-B1a cells. The frequencies of B-lineage cells in BM were higher in young children, and declined with advancing age. In contrast, XLA showed a profound reduction in BM B-lineage cells. In XLA BM, an expansion of pro-B cells with some small pre-B1a cells was marked, but other cells were negligible. These observations illustrate a B-cell maturation defect in XLA as well as a normal human B-cell differentiation pathway. The results suggest that the genetic defect in XLA may impede the evolution of pro-B cells beyond the earlier pre-B stage into the later stage of pre-B cells in B-cell development. (Blood. 2000;96:610-617)

Adolescent↗
PubMed2000

Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism.

This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism. A selective adenosine A2 receptor agonist (CGS-21680, 1 microM) exhibited the most efficient potency for decreasing neutrophil apoptosis for 16 h from 63+/-5 to 19+/-4% (P < 0.001); it exerted poor and adverse effects on eosinophil survival. A selective protein kinase A inhibitor KT-5720 (10 microM) reversed the capacity of dibutyryl cAMP but not CGS-21680 to induce an inhibitory effect on neutrophil apoptosis, suggesting that occupancy of adenosine A2 receptors inhibit neutrophil apoptosis by a cAMP-independent mechanism. Theophylline derivatives show the following pattern of potency for inducing neutrophil apoptosis competing with CGS-21680: 8-phenyltheophylline = 8-p-sulfophenyltheophylline > theophylline >> enprofylline. This pattern is consistent with the affinity established for A2A receptors. Theophylline demonstrated an additive effect to that of anti-Fas antibody (CH11, 1 microg/mL) in inducing neutrophil apoptosis, but not to that of adenosine deaminase or KF-17837 (a selective A2 receptor antagonist; 1 microM), suggesting conflicting effects on the receptor antagonism. These findings suggest that theophylline has an immunomodulatory action on neutrophil apoptosis via a mechanism of A2A antagonism.

Adenosine↗
PubMed2000

Spontaneous B-cell IgE production in a patient with remarkable eosinophilia and hyper IgE.

BACKGROUND: The pathophysiology of eosinophilia and hyper-IgE is not fully elucidated yet. OBJECTIVE: To clarify the pathophysiology of a patient with remarkable eosinophilia and hyper IgE, we examined cytokine levels in serum, surface antigens of peripheral blood eosinophils and IgE production in vitro. RESULTS: Concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), and granulocyte/macrophage-colony stimulating factor (GM-CSF) in the serum were 21 pg/mL, <15 pg/mL, <15 pg/mL, 8 pg/mL, and <5 pg/mL pg/mL, respectively. Newly expressed surface antigens CD4, CD25, CD69, and HLA-DR, but not CD54, were observed on peripheral blood eosinophils. Extremely high levels of IgE secretion was found in the patient's mononuclear cells without stimuli; this was not enhanced by IL-4 or IL-4 plus anti-CD40 monoclonal antibody stimulation. Furthermore, highly purified B cells spontaneously produced large amounts of IgE and the production was not enhanced in addition of his T cells. CONCLUSION: The eosinophils were activated, and the B cells spontaneously produced IgE independently of T cells or cytokines, suggesting that intrinsic abnormality of B cells leading to dysregulated production of IgE in this disease.

Aged↗
PubMed2000

Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry.

CVID is frequently diagnosed in male and female individuals with hypogammaglobulinaemia of unknown aetiology. To examine the possibility that sporadic male cases with X-linked agammaglobulinaemia (XLA), which is caused by mutations in the Bruton's tyrosine kinase (Btk) gene, might be misregistered as having CVID, we employed a flow cytometric test to identify XLA in hypogammaglobulinaemic males registered as CVID in the Japanese Immunodeficiency Registry. From 30 male cases registered as having CVID between 1992 and 1998, we selected 21 males with low or unreported peripheral B cell counts. Blood samples could be obtained from 11 patients and their mothers. Using flow cytometric analysis, the Btk-deficient status in monocytes was demonstrated in seven out of nine cases with decreased numbers of peripheral B cells. The diagnosis of XLA was confirmed in each of the seven patients by demonstration of Btk gene mutations in the patients or cellular mosaicism in the mother. This study demonstrates misregistration of XLA as CVID.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2000

Bacterial interference among nasal inhabitants: eradication of Staphylococcus aureus from nasal cavities by artificial implantation of Corynebacterium sp.

To evaluate the role of normal flora in the nares in preventing Staphylococcus aureus colonization, we conducted a replacement study in vivo. Staphylococcus epidermidis (rate of colonization: 100%), various species of corynebacteria (52.5%) and S. aureus (25.%) were the major bacterial inhabitants in the nares of 156 healthy volunteers. The low incidence of S. aureus colonization in the carriers with corynebacteria (8.5%), compared to non-carriers (44. 5%) indicated the possibility of competition for survival between S. aureus and corynebacteria. To confirm this hypothesis, we artificially implanted a strain of Corynebacterium sp (API Coryne bioprofile; 5100304), denoted as Co304 into the nares of 17 S. aureus carriers. S. aureus was completely eradicated in 71% of carriers by up to 15 inoculations of Co304. However, similar doses of 0.9% NaCl or S. epidermidis into the nares of 10 volunteers did not eradicate S. aureus. No bacteriocin-like activity against S. aureus was detectable, even after mitomycin C stimulation of Co304. Thus Co304 interfered with S. aureus by a different mechanism to a bacteriocin-like activity.

Adult↗
PubMed2000

Memory B cells and CD27.

Following antigen activation in germinal centers, B cells develop into memory B cells or plasma cells. Triggering via B-cell immunoglobulin receptors by antigens, cytokines and direct cell-to-cell contact by B and T cells plays an important role in the B cell differentiation into memory or plasma cells. Adult human peripheral blood B cells are separated into three subtypes by the expression of IgD and CD27, which belong to the tumor necrosis factor receptor (TNFR) family: IgD+ CD27- naive B cells, IgD+ CD27+ and IgD- CD27+ B cells. CD27+ B cells are larger cells with abundant cytoplasm carrying somatic hypermutation, and have an ability to produce immunoglobulin, indicating that CD27 is a memory marker of B cells. The ligation of CD27 yields crucial signals that positively control the entry of B cells into the pathway to plasma cells. We review observations on subpopulations and differentiation of mature B-cells by T/B cell interaction via CD27/CD70 as compared with CD40/CD154 interaction, and discuss about memory B cells.

Adult↗
PubMed2000

Effects of theophylline on human eosinophil functions: comparative study with neutrophil functions.

The understanding of theophylline as a bronchodilator has been reconsidered in recent years. We undertook to determine its immunomodulatory actions in granulocytes and elucidate their mechanism. Preincubation of neutrophils with theophylline (10(-5) to 5 x 10(-3) M) had a biphasic effect on O2(-) production stimulated with N-formyl-methionyl-leucyl-phenylalanine or C5a. Theophylline potentiates O2(-) production via adenosine A(2A) receptor antagonism induced by receptor-linked agonists from neutrophils, but not from eosinophils. The addition of theophylline caused a significant decline in neutrophil chemotaxis at lower concentrations than those for eosinophil motility. Theophylline reduces neutrophil chemotaxis via adenosine A1 receptor antagonism. At high concentrations, with an intracellular cAMP accumulation as a result of phosphodiesterase (PDE) inhibition, theophylline also exerts an inhibitory effect on the O2(-) production and chemotaxis of both types of cells. The difference in theophylline's effect on neutrophils and eosinophils appears to depend on the existence of specific adenosine receptors. Theophylline thus modulates granulocyte functions in association with specific adenosine receptor antagonism and cAMP-PDE inhibition.

Bronchodilator Agents↗
PubMed2000

B cell development and primary immunodeficiencies with hypogammaglobulinemia.

The differentiation of B cells along the pathway of B cell development has been well characterized. In the bone marrow, the differentiation from pro-B cells to immature B cells can be defined by several surface antigens, such as a surrogate light chain. Immature B cells become mature B cells and then circulate in the peripheral blood as naive B cells. In the peripheral lymphoid tissues, naive B cells differentiate into memory B cells, which express the CD27 molecule, or plasma cells. Primary immunodeficiencies with hypogammaglobulinemia are caused by defects of the specific molecules which are needed for the B cell differentiation. Recent studies of the genes responsible for such immunodeficiencies have clarified B cell development as well as their pathogenesis. We discuss here the molecules affecting the B cell development and primary immunodeficiencies with hypogammaglobulinemia.

Agammaglobulinemia↗
PubMed1999

Presenility of granulocytes in Down syndrome individuals.

Neutrophil function defects occur in individuals with Down syndrome (DS). We examined apoptosis of granulocytes (neutrophils and eosinophils) in DS individuals and control healthy subjects. Granulocyte survival was shortened in DS individuals, and the percentage of apoptotic granulocytes from DS during incubation was significantly higher than that from healthy subjects. The difference was time-dependent, and that between DS and healthy subjects was nearly 30% after longer periods of incubation. In control granulocytes, both granulocyte-macrophage colony-stimulating factor (10 ng/ml) and interleukin-5 (5 ng/ml) counteracted the programmed cell death and delayed the apoptosis caused by anti-Fas antibodies, whereas those inflammatory cytokines were not able to completely prevent cellular apoptosis in DS patients. Apoptosis and functional impairment of granulocytes may contribute to the risk of infections underlying pathological conditions of DS, and accelerated apoptosis of granulocytes may be a factor to prevent chronic airway inflammation and bronchial asthma in DS individuals.

Adult↗
PubMed1999

Cytolytic mechanisms involved in non-MHC-restricted cytotoxicity in Chediak-Higashi syndrome.

To determine the mechanisms responsible for the impaired lymphocyte-mediated cytotoxicity in Chediak-Higashi syndrome (CHS), we investigated the killing ability of peripheral blood lymphocytes (PBL) from three patients with CHS using several kinds of target cells that were sensitive to perforin, Fas ligand (FasL), and/or tumour necrosis factor-alpha (TNF-alpha). Freshly isolated CHS PBL did not kill K562 target cells, killing of which by normal PBL was perforin-dependent, as demonstrated by complete inhibition by concanamycin A (CMA), an inhibitor of perforin-based cytotoxicity. In contrast, the CHS PBL exhibited substantial cytotoxicity against Jurkat cells, which was only partially inhibited by CMA treatment but not by the addition of neutralizing anti-FasL or anti-TNF-alpha antibodies. IL-2-activated CHS PBL exhibited substantial levels of cytotoxicity against K562 and Jurkat cells, the levels being 74% and 83% of the respective normal control values, respectively. CMA treatment showed that while the cytotoxicity of IL-2-activated CHS PBL against K562 was largely dependent on perforin, that against Jurkat was largely not. IL-2-activated CHS PBL expressed FasL mRNA, and killed Fas transfectants. These findings indicate that CHS PBL have an ability to kill some target cells via a perforin-mediated pathway, especially when they are activated by IL-2. It was also demonstrated that CHS PBL can exert cytotoxicity against certain target cells by utilizing FasL and an undefined effector molecule other than perforin, FasL, or TNF-alpha.

Adult↗
PubMed1999

[A case of SLE with positive antiphospholipid antibody and various coagulopathy].

We described an 11 year-old boy with systemic lupus erythematosus (SLE) and various coagulopathy. He had purpura on the legs, pancytopenia, positive anti-DNA antibodies and hypocomplementia. Hematological examination also showed that platelet counts were 80 x 10(3)/microliter, lupus anticoagulant and anticardiolipin antibodies were positive. The aPTT was remarkably prolonged. Those laboratory findings fulfilled the criteria of antiphospholipid syndrome. Following treatment with predonisolone and heparin, thrombocytopenia improved. When heparin discontinued and renal biopsy was performed, severe thrombocytopenia recureded. FDP and FDP-DD became high, but the aPTT was not prolonged. Thrombocytopenia didn't improved by the therapy with heparin, high dose of methylpredonisolone, FOY and gamma-globulin. However by the therapy with both warfarin and cyclophosphamide, remarkable improvement of coagulopathy was absorbed. Probably anticardiolipin antibodies and disseminated intravascular coagulation (DIC) participate in the various coagulopathy in this case.

Antibodies, Antiphospholipid↗