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K Tsuzaka

Publications and source records attributed to K Tsuzaka.

At least 19 recordsLinked to original sources
PubMed2001

Role of brain-derived neurotrophic factor in wobbler mouse motor neuron disease.

Brain-derived neurotrophic factor (BDNF) is neuroprotective for motoneurons undergoing degeneration, including those in natural motor neuron disease (MND) in wobbler mice. To assess the role of BDNF in this model of MND, endogenous BDNF immunoreactivity was analyzed by semiquantitative video-image analysis. Affected cervical spinal cord motoneurons had significantly greater BDNF immunoreactivity compared to motoneurons of healthy littermates (P = 0.01) and affected lumbar spinal cord motoneurons (P = 0.008 at age 4 weeks; P = 0.005 at age 8 weeks). Neuronal nitric oxide synthase (n-NOS) immunocytochemistry revealed increased immunoreactivity in the affected cervical spinal cord motoneurons. Exogenous BDNF treatment partially inhibited the increased NOS activity, as quantitatively measured by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry. The mean number of NADPH-d(+) motoneurons in the cervical anterior horn decreased from 3.5 +/- 1.2 to 1.5 +/- 1.2 (P = 0.002). The increase in endogenous BDNF immunoreactivity in the affected spinal cord may be compensatory in diseased motoneurons, yet it appears to still be inadequate because exogenous BDNF treatment is required to suppress increased NOS activity in degenerating motoneurons. Our study indicates that BDNF is important in halting nitric oxide (NO)-mediated motor neuron degeneration, which has potential implications for the treatment of neurodegenerative disorders.

Animals↗
PubMed2001

Effects of cardiotrophin-1 (CT-1) in a mouse motor neuron disease.

Cardiotrophin-1 (CT-1) has potent survival-promoting effects on motor neurons in vitro and in vivo and may be effective in treating motor neuron diseases (MND). We investigated the effects of CT-1 treatment in wobbler mouse MND. Wobbler mice were randomly assigned to receive subcutaneously injected CT-1 (1 mg/kg, n = 18, in two experiments) or vehicle (n = 18, in two experiments) daily, 6 times/week for 4 weeks after clinical diagnosis at age 3 to 4 weeks. Cardiotrophin-1 treatment prevented deterioration in paw position and walking pattern abnormalities. Grip strength declined steadily in the vehicle group, whereas in the CT-1 group it declined at week 1 but increased thereafter to exceed baseline strength by 5% (P = 0.0002) at week 4. Running speed was faster with CT-1 (P = 0.007). Biceps muscle twitch tension, muscle weight, mean muscle fiber diameter, and intramuscular axonal sprouting were significantly greater with CT-1 treatment than with vehicle treatment. Histometry revealed a trend that indicated CT-1 modestly increased the number of immunoreactive motor neurons, as determined by both choline acetyltransferase and c-Ret antibodies, and reduced the number of phosphorylated neurofilament immunoreactive perikarya (P = 0.05). The number of large myelinated motor axons significantly increased with treatment (206 versus 113, P = 0.01). We conclude that CT-1 exerts myotrophic effects as well as neurotrophic effects in a mouse model of spontaneous MND, a finding that has potential therapeutic implications for human MND.

Animals↗
PubMed2001

Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population.

OBJECTIVE: Systemic lupus erythematosus (SLE) in a multisystem autoimmune disorder characterized by multiorgan pathology and autoantibodies against a variety of autoantigens. The CD28 and CTLA-4 genes might be candidate genes for SLE, because costimulation signals from CD80/CD86 to CD28/CTLA-4 have been suggested to play an important role in the activation or inactivation of T lymphocytes. METHODS: We investigated three polymorphic regions within the CTLA-4 gene, a C/T base exchange in the promoter region -318 (CTLA-4 -318C/T), an A/G substitution in the exon 1 position 49 (CTLA-4 49A/G), an (AT)(n) repeat polymorphism in the 3' untranslated region of exon 4 [CTLA-4 3' (AT)(n)], and a CD28 gene polymorphism, a T/C substitution in the intron 3 position +17 (CD28 IVS3+17T/C), in SLE patients and controls. RESULTS: SLE patients had significantly higher frequencies of the CTLA-4 49G allele (P=0.003) and of the CTLA-4 (AT)(n) 106 bp allele (P=0.0008) than controls. We also found a strong linkage disequilibrium between the A allele of CTLA-4 49A/G and the 86 bp allele of CTLA-4 3' (AT)(n). On the contrary, no association was found between SLE and CTLA-4 -318C/T or CD28 IVS3 +17T/C. CONCLUSION: We conclude that the CTLA-4 gene appears to play a significant role in the development of SLE in the Japanese population.

Abatacept↗
PubMed2000

Complement component 9 deficiency is not a susceptibility factor for SLE.

Almost all complement component 9 (C9) deficiency in Japan shows Arg95 Stop mutation of C9 gene. Therefore, we studied the prevalence of Arg95Stop mutation of C9 gene among 78 patients with SLE to elucidate the association of SLE and C9 deficiency. The Arg95Stop carrier frequency showed no significant difference between SLE patients and controls. Thus, C9 deficiency is not implicated in SLE susceptibility.

Complement C9↗
PubMed2000

Mikulicz's disease and Sjögren's syndrome.

PURPOSE: To characterize lacrimal gland function and lymphocyte infiltration in patients with Mikulicz's disease (MD) and Sjögren's syndrome (SS). METHODS: Four patients with MD and 5 with SS were recruited, on whom were performed Schirmer test I (Schirmer test without anesthesia), Schirmer test with nasal stimulation, and vital staining of the ocular surface. The lacrimal gland was then biopsied and the tissues stained with CD3, CD4, CD8, B220, APO2.7, Fas, and Fas ligand (Fas-L) antibodies. RESULTS: Although regular Schirmer test results in the MD group were less than 10 mm, those with nasal stimulation, 38.1 +/- 3.4 mm, were significantly greater than the SS group. There were minimal ocular surface changes in MD. Morphologic staining with hematoxylin and eosin was identical in both groups, but the acinar cells were stained with APO2.7 only in the SS group. There was strong Fas and Fas-L staining in SS patients but not in those with MD. CONCLUSIONS: Lacrimal gland acinar cells in those with MD maintained their function and were not programmed for cell death. The sicca syndrome was not observed in MD patients. Although the pathology is similar for MD and SS, the difference in acinar cell apoptosis and function can explain clinical differences.

Adult↗
PubMed1999

Preferential localization of CD8+ alpha E beta 7+ T cells around acinar epithelial cells with apoptosis in patients with Sjögren's syndrome.

The T lymphocytes that infiltrate the exocrine glands in Sjögren's syndrome (SS) play a key role in damaging glandular epithelial cells, but the mechanisms of this damage by T lymphocytes are not fully understood. To determine the cellular basis of this phenomenon, we focused our attention on the T lymphocytes around acinar epithelial cells in SS. We showed that CD8+ but not CD4+ T lymphocytes were located around the acinar epithelial cells and that a majority of these CD8+ T lymphocytes possess an unique integrin, alpha E beta 7 (CD103). The acinar epithelial cell adherent with alpha E beta 7 (CD103)+ CD8+ T lymphocytes was apoptotic. Both the perforin/granzyme B and Fas/Fas ligand pathways were implicated in the process of programmed cell death in lacrimal glands. These results suggested that alpha E beta 7 integrin, by interacting with E-cadherin, mediates the adhesion between CD8+ T lymphocytes and acinar epithelial cells in SS and participates in inducing epithelial cell apoptosis, leading to secretory dysfunction of exocrine glands, a hallmark of SS.

Adult↗
PubMed1999

Neurotrophic factors and neuro-muscular disease: II. GDNF, other neurotrophic factors, and future directions.

This is the second of two reviews in which we discuss the essential aspects of neurotrophic factor neurobiology, the characteristics of each neurotrophic factor, and their clinical relevance to neuromuscular diseases. The previous paper reviewed the neurotrophin family and neuropoietic cytokines. In the present article, we focus on the GDNF family and other neurotrophic factors and then consider future approaches that may be utilized in neurotrophic factor treatment.

Animals↗
PubMed1999

Neurotrophic factors and neuromuscular disease: I. General comments, the neurotrophin family, and neuropoietic cytokines.

Neurotrophic factors are growth factors or cytokines that are inducible polypeptides and permit intercellular communication. An explosion of information about neurotrophic factors is setting the stage for significant advances in neural disease therapy in the next century. The effects of these trophic factors are overlapping and pleiotropic, acting on many cell types and tissues to control proliferation and differentiation of developing neurons and to exert a variety of functions on mature neurons. Studies of receptors unique to several neurotrophic factor families have revealed exquisite mechanisms of signal transduction. Preclinical trials in neuromuscular disease were promising, but results from initial clinical trials have been disappointing; new and better designed clinical trials are under way. Laboratory investigators also are exploring techniques to deliver factors directly to the central nervous system by means of viral vectors or to exert neurotrophic signals on the nervous system using novel small molecules that stimulate neurotrophic factor or neuroimmunophilin receptors. Combination therapies, refined delivery techniques, and treatment timing may be the key for successful treatment with neurotrophic factors. In this two-part review, we discuss the neurobiology of neurotrophic factors, the characteristics of the major neurotrophic factors, and their therapeutic potential in neuromuscular disease.

Animals↗
PubMed1999

[Portal and pulmonary hypertension in a patient with MCTD].

A 42-year-old woman with mixed connective tissue disease (MCTD) died due to the rupture of esophageal varices. The autopsy revealed fresh thrombi in the main trunk of the portal vein. Microscopic examination disclosed wide-spread periportal fibrosis and stenosis of peripheral portal veins without remodeling of hepatic lobular architecture, which was compatible to idiopathic portal hypertension (IPH). Anti-phospholipid antibody was negative. Accordingly it is likely that portal vein thrombosis developed secondary to IPH. In the literature 6 (37.5%) of 16 collagen vascular disease patients with IPH died, and three of them were due to rupture of esophageal varices. Therefore IPH should be considered to be one of the most important complications affecting its grave prognosis in patients with collagen vascular disease. The patient also had had pulmonary hypertension (PH) when the diagnosis of portal hypertension was made. In the literature we found 5 collagen vascular disease patients with both PH and IPH like this case. The most outstanding common clinical feature among these 6 patients was Raynaud's phenomenon associated with positive anti-RNP antibody. Moreover 5 of 6 cases including this case simultaneously developed both PH and IPH. The clinical course of these patients suggests there may be a common pathogenetic factor for these two lesions. A possible candidate involved in the pathogenesis of PH and IPH may be endothelin, one of the vasoactive substances, since its receptor is said to be expressed abundantly in pulmonary and portal vasculatures. However, further investigation is necessary to elucidate the mechanism of PH and IPH in collagen vascular diseases.

Adult↗
PubMed1998

Up-regulation of alphaEbeta7, a novel integrin adhesion molecule, on T cells from systemic lupus erythematosus patients with specific epithelial involvement.

OBJECTIVE: To determine the possible role of a novel integrin, alphaEbeta7, in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: Expression of alphaEbeta7 was examined on peripheral blood lymphocytes (PBL) from normal subjects (n = 25) and patients with SLE (n = 31), primary Sjogren's syndrome (n = 7), or polymyositis/dermatomyositis (n = 8) by cytofluorometry and/or immunoprecipitation. Adhesion of alphaEbeta7+ T cells to HSG epithelial cells was investigated using a confocal image analyzer. RESULTS: After phytohemagglutinin stimulation, expression of alphaEbeta7 on PBL, especially on CD8+ T cells, was significantly higher in SLE patients than in normal subjects (P<0.01). Elevated alphaEbeta7 expression was associated with the presence of oral ulcers or serositis (P<0.05). Activated SLE T cells with enhanced alphaEbeta7 expression strongly adhered to HSG; this adhesion was partially blocked by anti-alphaEbeta7. CONCLUSION: Expression and adhesion of alphaEbeta7 on activated PBL was significantly increased in patients with SLE with epithelial involvement. This suggests a role of this novel integrin in tissue-specific retention of activated PBL, due to increased alphaEbeta7-E-cadherin interaction, which may contribute to epithelial inflammation.

Adult↗
PubMed1998

Mutations in T cell receptor zeta chain mRNA of peripheral T cells from systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown aetiology. Although it has been reported that T cells might be responsible for the pathogenesis of SLE, it remains unclear whether immune aberrations of SLE T cells are the primary event in this pathological process. We have recently reported that tyrosine phosphorylation and expression of the T cell receptor zeta chain (TCR zeta) was significantly decreased in SLE T cells and that two SLE patients exhibited a 36 bp, exon 7 deletion of the TCR zeta mRNA. To investigate further common mutations in TCR zeta mRNA among SLE patients, mRNA was isolated from the peripheral blood T cells of two normal controls, two systemic sclerosis (SSc) patients, and eight SLE patients. TCR zeta cDNA was amplified by RT-PCR. Five out of the eight SLE patients exhibited abnormal migration patterns of the TCR zeta cDNA in PCR single stranded conformational polymorphism analysis. PCR products were ligated into pUC18 and five clones obtained were sequenced. Analysis of the nucleotide sequences revealed that all of the five pUC18 clones from the normal controls and SSc patients had the normal nucleotide sequence, whereas all eight SLE patients had mutations in TCR zeta cDNA accompanied by predicted amino acid substitutions. Mutations found in six of these patients corresponded to those of the third immunoreceptor tyrosine-based activation motif (ITAM) domain or the GTP/GDP binding site in TCR zetaThus, these mutations in TCR zeta mRNA could be responsible for the decreased expression of the TCR zeta protein in SLE T cells.

Amino Acid Substitution↗
PubMed1998

TCR zeta chain lacking exon 7 in two patients with systemic lupus erythematosus.

To address the molecular mechanism underlying the functional defects of peripheral T cells in systemic lupus erythematosus (SLE), we focused on early signaling events. We demonstrated that protein expression of the TCR zeta chain was significantly decreased in peripheral T cells from patients with SLE compared to normal controls and patients with systemic sclerosis (SSc). Among those patients showing decreased TCR zeta chain expression, we found two patients with pronounced TCR zeta chain abnormalities, including an aberrant 14 kDa form in one and only trace expression in the other. RT-PCR, SSCP and subsequent cloning of the transcripts revealed that bases 468503, corresponding to exon 7, were deleted in both patients. Since exon 7 spans the GTP/GDP binding site and N-terminal tyrosine in the third ITAM domain of TCR zeta chain, the transcript lacking exon 7 may be responsible for altered signal transduction via TCR in these SLE patients.

Adult↗
PubMed1998

[A case with rheumatoid arthritis complicated with ANCA-associated vasculitis].

A 50-year-old woman with rheumatoid arthritis (RA) developed constitutive symptoms such as fever and weight loss, mononeuritis multiplex and rapidly progressive glomerulonephritis (RPGN). The renal biopsy revealed crescentic glomerulonephritis (CrGN) with few immune deposits such as IgG and C 3 and necrotizing vasculitis, which led to the pathological diagnosis of microscopic polyangiitis (MPA). Moreover the high serum level of anti-myeloperoxidase (MPO) antibody, one of the anti-neutrophil cytoplasmic antibody (ANCA), suggested that she had ANCA-associated vasculitis. The renal prognosis of the ANCA-associated vasculitis is said to be poor unless patients were treated in the early phase of the disease. As we started to treat the patient when her serum creatinine level (sCr) was 1.7 mg/dl and creatinine clearance (CCr) was 27 ml/min, her renal function returned to the almost normal level (sCr = 0.6, CCr = 91). It is well known that patients with RA may develop various kinds of extraarticular manifestations which are usually related to immune-complex mediated vasculitis, what we call malignant RA. We emphasize that ANCA-associated vasculitis is another important complication of RA. When we see a RA patient with constitutional symptom, abnormal urinary sediments and other clinical signs of vasculitis such as mononeuritis multiplex, ANCA-associated vasculitis should be considered. Since the early diagnosis and treatment of ANCA-associated vasculitis is a key to prevent renal failure, it is encouraged to measure the serum ANCA titer for not only the diagnosis of such patients but the evaluation of their clinical course.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1996

Lupus autoantibodies to double-stranded DNA cross-react with ribosomal protein S1.

One cDNA clone (G7) was isolated from a lambda gt11 human liver cDNA library by the reaction with a serum containing anti-dsDNA Abs and was ligated into pGEX-1 lambda T vector. All the 10 SLE sera with anti-dsDNA, 2 samples of human monoclonal anti-dsDNA (33.C9 and 33.H11), and 2 affinity-purified anti-dsDNA Abs recognized the glutathione S-transferase fusion protein expressed by G7 (G7-FP). Ab binding to the recombinant protein expressed by G7 (G7-RP) and to G7-FP was inhibited completely by calf thymus dsDNA. The cDNA was 1314 nucleotides in length and contained an open reading frame encoding 352 amino acids. However, it seems to be a partial length cDNA because the affinity-purified Ab from G7-FP recognized only a 104-kDa protein on Western blot using MOLT4 cell extract. The nucleotide sequence of G7 was homologous (99% identity) to a cDNA encoding human ribosomal protein (r-protein) S1 homologue mRNA. The encoded protein contains repeating residues as a feature of r-proteins S1. Cytoplasmic and nucleolar staining of 33.H11 on indirect immunofluorescence (IF) using HEP 2 cells was inhibited by both G7-RP and calf thymus dsDNA. On ELISA, 33.H11 had a higher affinity for G7-RP than for DNA while 33.C9 had a higher affinity for DNA than for G7-RP and binds nuclei on IF. We conclude that G7 encodes a portion of human r-protein S1 and anti-dsDNA Abs cross-react with this protein.

Amino Acid Sequence↗
PubMed1996

Anti-U5 small nuclear ribonucleoprotein (snRNP) antibodies: a rare anti-U snRNP specificity.

We surveyed for autoantibodies to the U small nuclear ribonucleoproteins (snRNPs) in sera from 1171 patients with various connective tissue diseases by immunoprecipitation assay. We found serum, termed LaJ, which principally recognized the U5 snRNP from one patient with systemic sclerosis-polymyositis overlap syndrome. Anti-LaJ serum immunoprecipitated predominantly U5 snRNA from a 32PO4-labeled HeLa cell extract and at least five U5-specific proteins as well as the Sm core proteins from a [35S]methionine-labeled extract. Anti-LaJ serum immunoprecipitated both U5 snRNA and these five proteins in identical fractions at 15-20S by parallel sucrose gradient, suggesting physical association of these two components. Thus, we concluded that anti-LaJ serum contained antibody specific to the U5 snRNP. Antibodies specific to U5 snRNP were found in a single serum; in contrast, the prevalence of anti-U1 snRNP and anti-Sm antibody was considerably higher. Thus, the specific proteins of the U5 snRNP are rare targets for autoantibodies in patients with connective tissue disease.

Antibodies, Antinuclear↗