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T Nishikawa

Publications and source records attributed to T Nishikawa.

At least 289 records · Page 16Linked to original sources
PubMed1998

Novel non-radioisotope immunoprecipitation studies indicate involvement of pemphigus vulgaris antigen in paraneoplastic pemphigus.

We have developed two different novel immunoprecipitation assays in which radioisotopes are not used, and have examined antigens for four cases of paraneoplastic pemphigus (PNP) including three new patients. The PNP sera showed a clear reactivity with transitional epithelia of rat urinary bladder by immunofluorescence, and reacted with a characteristic doublet of the 210 and 190 kD proteins by immunoblotting of normal human epidermal extract, confirming the diagnosis of PNP. In addition, by immunoprecipitation using silver-stain to detect immunoprecipitated proteins, the PNP sera detected the 250, 210 and 190 kD proteins, while control bullous pemphigoid sera detected only the 230 kD bullous pemphigoid antigen. Furthermore, with another immunoprecipitation using cell surface biotinylation, three of the four PNP sera specifically reacted with the 130 kD pemphigus vulgaris antigen (Dsg3), indicating that pemphigus vulgaris antigen may be involved in PNP. This reactivity was further suggested by the immunoblot analysis using recombinant pemphigus vulgaris antigen. In future, these non-radioisotope immunoprecipitation assays should become a useful tool not only to unravel the complex situation for the PNP antigens, but also to study antigens in other autoimmune bullous skin diseases.

Animals↗
PubMed1998

Characterization of the phencyclidine-induced increase in prefrontal cortical dopamine metabolism in the rat.

1. We have investigated the effects of a schizophrenomimetic drug phencyclidine (PCP) and N-methyl-D-aspartate (NMDA)-related agents alone or in combination on dopamine metabolism in the medial prefrontal cortex and striatum of the rats by measuring the tissue concentrations of dopamine and its metabolite, 3,4-dihyroxyphenylacetic acid (DOPAC), and the rate of dopamine disappearance (dopamine utilization) after its synthesis inhibition. 2. Systemic injection of PCP and selective, non-competitive, NMDA antagonists caused an increase of both tissue concentrations of DOPAC and dopamine utilization in the prefrontal cortex but not in the striatum. The PCP-induced augmentation of cortical dopamine metabolism was not influenced by selective lesion of ascending noradrenergic neurones. 3. Intra-prefrontal cortical infusion of PCP or selective competitive or non-competitive antagonists of the NMDA receptor mimicked the ability of systemic PCP injection to enhance DOPAC levels and dopamine utilization in the prefrontal cortex. However, an NMDA antagonist injected into the cell body area of the mesocortical dopaminergic neurones failed to affect dopamine metabolism in the prefrontal cortex. 4. The increasing effects of PCP and selective NMDA antagonists on cortical dopamine utilization were not additive, although a dopamine receptor antagonist, haloperidol, still accelerated the disappearance of dopamine, even in the presence of PCP. 5. Intra-cortical or intra-ventricular infusion of NMDA or D-alanine but not L-alanine, attenuated the ability of systemic PCP administration to facilitate prefrontal dopamine utilization. 6. These data suggest that PCP might activate prefrontal cortical dopaminergic neurones, at least in part, by blocking the NMDA receptor in the prefrontal cortex which participates in a tonic inhibitory control of the mesoprefrontal dopaminergic projections.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Precise ultrastructural localization of in vivo deposited IgG antibodies in fresh perilesional skin of patients with bullous pemphigoid.

Bullous pemphigoid (BP) is a blistering skin disease in which the patient develops autoantibodies to the epidermal basement membrane zone. Using postembedding immunogold electron microscopy, we previously demonstrated that autoantibodies against the 230-kDa BP antigen (BPAG1) bind to the intracellular hemidesmosomal component of normal skin, whereas those against the 180-kDa BP antigen (BPAG2) bind only along the plasma membrane of hemidesmosomes. The purpose of the present study was to elucidate the precise localization of the in vivo deposited IgG antibodies in fresh perilesional skin of patients with BP. Samples of fresh perilesional skin were obtained from three patients with BP whose sera reacted only with BPAG1, only with BPAG2, and with both BPAG1 and BPAG2 upon immunoblotting using epidermal extracts. Cryofixed and cryosubstituted skin samples were used as a substrate for on-surface immunolabelling. In all three cases, most of the gold particles were observed close to the plasma membrane of the basal keratinocytes. A quantitative analysis revealed that most (> 80%) of the in vivo deposited IgG antibodies in the three cases were localized within 10 nm inside to 50 nm outside of the cell membrane, with a single peak observed 0-10 nm outside of the cells (> 50%). This distribution corresponded to the location of BPAG2, but not to that of BPAG1. These findings suggest that most, if not all, of the in vivo deposited IgG antibodies in the perilesional skin of BP are directed against BPAG2, rather than against BPAG1, thus further supporting the crucial role of anti-BPAG2 autoantibody in the initial stage of blister formation in BP.

Autoantigens↗
PubMed1998

Recurrent annular erythema in juvenile chronic myelogenous leukaemia.

Juvenile chronic myelogenous leukaemia (JCML) is a rare haematological malignancy of myelomonocytic lineage that affects patients less than 4 years of age and is known as an entity different from adult-type chronic myelogenous leukaemia. In JCML, skin manifestations are relatively common but most of them have been reported as a non-specific eruption, which histologically may show changes resembling neurofibromatosis or xanthogranuloma. We present a 2-year-old boy with JCML who developed a recurrent annular erythema in which leukaemic infiltrates were confirmed histologically, even though his bone marrow examination suggested that be remained in haematological remission.

Child, Preschool↗
PubMed1998

Significance of local recurrence of rectal cancer as a local or disseminated disease.

BACKGROUND: The nature of 'local recurrence' of rectal cancer remains unclear. METHODS: Fifty-nine patients with locally recurrent rectal cancer who underwent extended repeat resections including total pelvic exenteration (39) and sacrectomy (43) were reviewed. Twelve patients had distant metastases before or at the time of repeat resection. RESULTS: The 5-year survival rate was 25 per cent. A second recurrence occurred in 45 patients including five of the eight 5-year survivors. Thirty-six of these recurrences had locoregional manifestations and 29 had distant metastases. Of 18 prognostic factors examined, the most significant determinant was the postoperative carcinoembryonic antigen doubling time (CEADT), followed by the preoperative CEADT, carcinoembryonic antigen (CEA) level and occurrence of distant metastases, in decreasing order. Late onset of first recurrence was also a favourable indicator. Thus, the growth rate of the tumour had a more profound impact on survival than the current extent of tumour progression. After operation the CEADT was reduced in patients with second recurrence (P = 0.05). CONCLUSION: Locally recurrent rectal cancer is a manifestation of disseminated disease spreading locoregionally and often to distant organs with a low probability of long-term cure. However, survival varies widely depending on the tumour growth rate, which is biologically predetermined and is also influenced by surgery.

Adult↗
PubMed1998

Successful prenatal exclusion of an unspecified subtype of severe epidermolysis bullosa.

BACKGROUND: In most cases of prenatal diagnosis of epidermolysis bullosa (EB), the subtype of severe EB from which the fetus is at risk is identified by studying the specimens of the proband. In this study, the parents of a child with an unspecified subtype of severe EB sought prenatal diagnosis for their second and third pregnancies. METHODS: The firstborn of a couple (the proband) suffered generalized blistering and erosions of the skin present from delivery, and died on the 11th postnatal day of severe EB of an unspecified type. The only diagnostic specimen available from the first infant was a conventionally stained skin section for light microscopy that showed the dermo-epidermal separation. For prenatal diagnosis in the second and third pregnancies, fetal skin biopsies were performed at 19 weeks of gestation. RESULTS: In both cases, fetal skin showed no ultrastructural abnormalities and no evidence of dermo-epidermal separation. Indirect immunofluorescence was positive for monoclonal antibodies against type VII collagen, laminin 5, uncein, alpha6 and beta4 integrins, BPAG2, and HD1/plectin, which are known to be reduced or absent in specific subsets of severe EB. The pregnancies were therefore continued, and normal healthy second and third children were delivered. CONCLUSIONS: Fetal skin biopsy, together with a panel of newly developed monoclonal antibodies, provided reliable prenatal diagnosis in the present family in which preliminary information of the EB proband was limited.

Biopsy↗
PubMed1998

Psychotomimetic-induction of tissue plasminogen activator mRNA in corticostriatal neurons in rat brain.

We have studied in the rat the effects of acute subcutaneous injection of psychotomimetics including methamphetamine (MAP), cocaine and phencyclidine (PCP) on the expression of a brain plasticity-related molecule, tissue plasminogen activator (tPA) mRNA, using non-radioactive in situ hybridization histochemistry. In addition to the constitutive expression of tPA mRNA in cerebellar Purkinje cells, ventricular ependymal cells and meningeal blood vessel-associated cells, MAP (1-4 mg/kg), cocaine (30 mg/kg) and PCP (1.25-5 mg/kg) caused a transient and dose-dependent induction of the transcript with its peak at 3 h postinjection in a group of neurons of the medial and insular prefrontal cortices, and the piriform cortex. Another indirect dopamine agonist nomifensine (20-40 mg/kg) mimicked the tPA mRNA induction in the prefrontal cortical areas. Moreover, MAP induction of tPA mRNA was markedly inhibited by pretreatment with a D1 (R(+)-SCH23390: R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-be nza zepine hydrochloride) or a D2 (haloperidol) dopamine receptor-preferring antagonist. Intramedial striatum, but not intrathalamic, application of a fluorescent tracer, fluorogold, retrogradely labelled the cortical cells expressing tPA mRNA. The present results suggest that acute injections of the above psychotomimetic drugs may induce tPA mRNA in a group of the prefrontal cortical neurons that project to the medial striatum. This tPA mRNA expression may be due to the activation of the dopamine neurotransmission. Because it is well documented that single or repeated administration of methamphetamine, cocaine and PCP produces enduring changes in responses to these drugs in humans and experimental animals (e.g. behavioural sensitization), the psychotomimetic-induction of tPA mRNA could be implicated in an initial step in the plastic rearrangements in the neuronal circuits underlying long-lasting changes in behavioural expression.

Animals↗
PubMed1998

Lack of mucosal involvement in pemphigus foliaceus may be due to low expression of desmoglein 1.

Oral mucosal lesions are seen in most cases of pemphigus vulgaris, whereas they are only rarely seen in pemphigus foliaceus; however, both pemphigus vulgaris and pemphigus foliaceus sera show positive immunofluorescence staining on oral mucosa. To explain this apparent paradox, we examined the expression level of desmoglein (Dsg)3, pemphigus vulgaris antigen, and Dsg1, pemphigus foliaceus antigen, in human squamous mucosal epithelia and epidermis by immunofluorescence staining and immunoblotting. For immunofluorescence staining, Dsg isotype-specific antibodies were produced by immunoadsorbing pemphigus vulgaris sera with either recombinant Dsg1 or Dsg3 baculoprotein. In oral mucosa and esophagus both Dsg were immunoreactive on cell surfaces throughout the entire epithelia, but staining intensity was weaker for Dsg1 than for Dsg3. Immunoblotting was performed to compare Dsg1 and Dsg3 expression levels in extracts from epidermis and oral mucosa. The total amount of desmosomal proteins applied was adjusted to give the same degree of staining intensity for desmoplakin, a cytoplasmic plaque protein of desmosomes. In the mucosal extract, the Dsg1 band was much weaker than Dsg3, whereas in the epidermal extract the Dsg1 band was stronger than Dsg3. These data suggest that although Dsg1 and Dsg3 are expressed in a similar distribution throughout squamous mucosal epithelia, Dsg1 is expressed at a much lower level than Dsg3. This finding provides a good explanation for the paradox: even though anti-Dsg1 autoantibodies block the function of Dsg1 in the mucosal epithelia, Dsg3 may be sufficient for cell-cell adhesion, with consequently no apparent oral involvement in pemphigus foliaceus patients.

Autoantigens↗
PubMed1998

Novel mutations in the LAMB3 gene shared by two Japanese unrelated families with Herlitz junctional epidermolysis bullosa, and their application for prenatal testing.

The LAMB3 gene encoding the beta3 chain of laminin 5 is a candidate gene for mutations in the autosomal recessive blistering skin disorder, junctional epidermolysis bullosa. In this study, we performed genetic analyses in two unrelated Japanese families with Herlitz junctional epidermolysis bullosa and identified two novel nonsense mutations in the LAMB3 gene. One of them, Q166X (CAG --> TAG), was found in the maternal allele of family 1 and the paternal allele of family 2. Conversely, the other mutation, W610X (TGG --> TGA), was found in the paternal allele of family 1 and the maternal allele of family 2. Thus, probands of both families were compound heterozygotes for these nonsense mutations. Haplotype analyses with intragenic LAMB3 polymorphisms suggested that both mutations had arisen independently in these two families. Both mutations create a premature translation termination codon predicting truncated beta3 chains that lead to absent expression of laminin 5 in the epidermal basement membrane zone. Based on these results, DNA-based prenatal diagnosis was performed by chorionic villus sampling for subsequent pregnancies in both families. Both fetuses were found to be heterozygous carriers of the W610X mutation together with a normal LAMB3 allele, indicating that they were phenotypically unaffected. These findings expand the repertoire of LAMB3 mutations in junctional epidermolysis bullosa, and emphasize the notion that premature termination codons in both alleles of the laminin 5 genes result in Herlitz junctional epidermolysis bullosa.

Base Sequence↗
PubMed1998

Epitope spreading: lessons from autoimmune skin diseases.

Autoimmune diseases are initiated when patients develop aberrant T and/or B cell responses against self proteins. These responses presumably are directed to single immunogenic epitopes on these proteins. Recent data in animal models of autoimmune diseases suggest that the targets of immune responses in autoimmunity do not remain fixed, but can be extended to include other epitopes on the same protein or other proteins in the same tissue, a phenomenon termed "epitope spreading." The "epitope spreading" phenomenon also applies to situations in which tissue damage from a primary inflammatory process causes the release and exposure of a previously "sequestered" antigen, leading to a secondary autoimmune response against the newly released antigen. In experimental autoimmune animal diseases, "epitope spreading" seems to have significant physiologic importance in determining the course and duration of disease. In this paper, we review the current concepts in animal models of autoimmune diseases in order to define the "epitope spreading" phenomenon, and we then propose how this phenomenon might play a significant role in the development and the course of autoimmune skin diseases. Hopefully, an understanding of "epitope spreading" will help the dermatology community to better understand the pathogenesis of autoimmune skin diseases and to rationally fashion disease-specific immune therapy in the future.

Animals↗
PubMed1998

Maternal uniparental meroisodisomy in the LAMB3 region of chromosome 1 results in lethal junctional epidermolysis bullosa.

Herlitz junctional epidermolysis bullosa (OMIM#226700) is a lethal, autosomal recessive blistering disorder caused by mutations in one of the three genes LAMA3, LAMB3, or LAMC2, encoding the constitutive polypeptide subunits of laminin 5. In this study, we describe a patient homozygous for a novel nonsense mutation Q936X in exon 19 of LAMB3, which has been mapped to chromosome 1q32. The patient was born with extensive blistering and demonstrated negative immunofluorescence staining for laminin 5, and transmission electron microscopy revealed tissue separation within lamina lucida of the dermal-epidermal junction, diagnostic of Herlitz junctional epidermolysis bullosa. The mother of the proband was found to be a heterozygous carrier for this mutation, whereas the father demonstrated the wild-type LAMB3 allele only. Nonpaternity was excluded by 13 microsatellite markers in six different chromosomes. Genotype analysis using 28 microsatellite markers spanning chromosome 1 revealed that the patient had maternal primary heterodisomy, as well as meroisodisomy within two regions of chromosome 1, one on 1p and the other one on 1q, the latter region containing the maternal LAMB3 mutation. These results suggest that Herlitz junctional epidermolysis bullosa in this patient developed as a result of reduction to homozygosity of the maternal LAMB3 mutation on chromosome 1q32.

Cell Adhesion Molecules↗
PubMed1998

97 kDa linear IgA bullous dermatosis antigen localizes in the lamina lucida between the NC16A and carboxyl terminal domains of the 180 kDa bullous pemphigoid antigen.

Linear IgA bullous dermatosis is an autoimmune blistering disease characterized by circulating IgA anti-basement membrane autoantibodies. A 97 kDa protein (97-LAD), which localizes at the basement membrane zone of normal human skin, is one of the major autoantigens associated with this disease and possesses multiple regions of amino acid identity with the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAG2. To investigate further the relationship between 97-LAD and BPAG2, immunogold electron microscopy was performed on cryo-ultrathin sections of normal human skin using a series of polyclonal and monoclonal antibodies. Gold particles immunolabeling two newly developed monoclonal antibodies against 97-LAD were localized to the lamina lucida. This immunolabeling pattern was associated with hemidesmosomes and localized at a mean distance of 28 nm beneath the plasma membrane of basal keratinocytes. In contrast, polyclonal antibodies against a fusion protein containing the NC16A domain of BPAG2 immunolabeled the plasma membrane of the hemidesmosomal complex, whereas polyclonal antibodies against the carboxyl terminus mainly immunolabeled the lower lamina lucida with a mean distance of 42 nm beneath the plasma membrane. By double immunolabeling, 97-LAD was localized as if being sandwiched between the NC16A and the carboxyl terminal domains of BPAG2. These results clearly demonstrated the co-localization of 97-LAD and the extracellular portion of BPAG2 in the lamina lucida, and suggested that 97-LAD is closely related to, and/or forms a complex with, the extracellular domain of BPAG2.

Autoantibodies↗
PubMed1998

The 97 kDa linear IgA bullous dermatosis antigen is not expressed in a patient with generalized atrophic benign epidermolysis bullosa with a novel homozygous G258X mutation in COL17A1.

The nature and expression pattern of the 97 kDa linear IgA bullous dermatosis antigen (LAD-1) and its role in epidermolysis bullosa have not been fully elucidated. In this study, we examined the expression of LAD-1 in the skin specimens of 70 patients with the various subtypes of epidermolysis bullosa, including simplex (n = 23), junctional (n = 15), and dystrophic variants (n = 32). For immunolabeling, we used two recently developed monoclonal antibodies to LAD-1 whose epitopes were ultrastructurally localized in the lamina lucida between NC16A and carboxyterminal domains of BPAG2, as well as autoantibodies against LAD-1 from the sera of two patients with linear IgA dermatosis. Among the 70 patients, only one patient with generalized atrophic benign epidermolysis bullosa failed to demonstrate LAD-1 expression. Although other major basement membrane components, including laminin 5, BPAG1, plectin, alpha6 and beta4 integrins, as well as type IV and type VII collagens were normally expressed, BPAG2/type XVII collagen was absent from the skin of this patient. Mutation analysis on COL17A1 using polymerase chain reaction amplification, heteroduplex scanning, and direct nucleotide sequencing revealed that this patient was homozygous for a novel nonsense mutation G258X in exon 11, and her parents were heterozygous carriers for this mutation. This is the first mutation located in the intracellular domain of BPAG2, and resides 817 bp upstream from the N-terminal amino acid sequence of LAD-1. These findings indicate that the absent expression of LAD-1 is observed in a BPAG2-deficient generalized atrophic benign epidermolysis bullosa patient with mutations in both alleles of COL17A1, and not in other epidermolysis bullosa subtypes. These findings also support the notion that LAD-1 is a degradation product of BPAG2.

Antigens↗