Late-onset SCA2: 33 CAG repeats are sufficient to cause disease.
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Ataxins↗
Biomedical subjects
R Matsumura
Publications and source records attributed to R Matsumura.
Glandular and extraglandular expression of costimulatory molecules in patients with Sjögren's syndrome.
OBJECTIVES: To investigate the expression and regulation of CD80, CD86, and CD28 costimulatory molecules in sialoadenitis and interstitial nephritis in patients with Sjögren's syndrome (SS). METHODS: Expression of CD80, CD86, and CD28 molecules was studied by immunohistochemical staining of lip biopsy specimens obtained from patients who had sialoadenitis associated with SS, and renal biopsy specimens obtained from patients who had interstitial nephritis associated with SS. To elucidate the mechanism of de novo expression of CD80 and CD86 antigens, their induction by cytokines in human salivary duct cell line (HSG) and renal cortical epithelial cells (HRCE) by cell enzyme linked immunosorbent assay (ELISA) was quantitatively investigated. RESULTS: In patients with severe sialoadenitis, CD80 and CD86 were strongly expressed on ductal epithelial cells. In contrast, these antigens were not found in the minor salivary glands of normal subjects or of patients with mild sialoadenitis. Some infiltrating cells expressed CD28. In patients who had interstitial nephritis associated with SS, some tubular epithelial cells expressed CD86 but not the CD80 antigen. Unstimulated HSG cells did not express CD80 or CD86. Interferon gamma (IFNgamma) consistently up regulated levels of CD80 and CD86. In contrast, tumour necrosis factor alpha (TNFalpha), interleukin 1beta (IL1beta), IL2, and IL4 had no effect on either CD80 or CD86 levels. Unstimulated HRCE did not express CD80 or CD86. IFNgamma consistently up regulated CD86 expression. No CD80 expression was found on tubular cells. TNFalpha, IL1beta, IL2, and IL4 had no discernible effects. CONCLUSIONS: Salivary ductal cells in patients with SS can express CD80 and CD86 costimulatory molecules in response to IFNgamma. Tubular epithelial cells in patients who have interstitial nephritis associated with SS express only CD86 molecules. In patients with SS, salivary ductal cells and tubular epithelial cells may activate infiltrating CD28 positive T lymphocytes by presenting antigens to T cells, potentially leading to tissue destruction.
Adult↗
[Hyperprolinemia].
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Amino Acid Metabolism, Inborn Errors↗
[Disorders of the urea cycle].
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Amino Acid Metabolism, Inborn Errors↗
[Maple syrup urine disease].
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Amino Acids, Branched-Chain↗
[Homocystinuria].
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Central Nervous System Diseases↗
[Carnosinemia].
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Amino Acid Metabolism, Inborn Errors↗
Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients.
Dentatorubral-pallidoluysian atrophy (DRPLA) is one among an increasing number of hereditary neurodegenerative diseases determined as being caused by unstable expansion of CAG repeats coding for polyglutamine stretches. To investigate the molecular mechanisms underlying CAG repeat instability, we established three transgenic lines each harboring a single copy of a full-length human mutant DRPLA gene carrying a CAG repeat expansion. These transgenic mice exhibited an age-dependent increase (+0.31 per year) in male transmission and an age-dependent contraction (-1.21 per year) in female transmission. Similar tendencies in intergenerational instabilities were also observed in human DRPLA parent-offspring pairs. The intergenerational instabilities of the CAG repeats may be interpreted as being derived from the instability occurring during continuous cell division of spermatogonia in the male, and that occurring during the period of meiotic arrest in the female. The transgenic mice also exhibited an age-dependent increase in the degree of somatic mosaicism which occurred in a cell lineage-dependent manner, with the size range of CAG repeats being smaller in the cerebellum than in other tissues including the cerebrum, consistent with observations in autopsied tissues of DRPLA patients. Thus, the transgenic mice described in this study exhibited age-dependent intergenerational as well as somatic instabilities of expanded CAG repeats comparable with those observed in human DRPLA patients, and are therefore expected to serve as good models for investigating the molecular mechanisms of instabilities of CAG repeats.
Adult↗
Eosinophil activation and in situ interleukin-5 production by mononuclear cells in skin lesions of patients with drug hypersensitivity.
In order to determine the inflammatory mechanisms of skin lesions in patients with drug hypersentivity, we examined eosinophil activation and interleukin-5 (IL-5) production in infiltrating lymphocytes. First, we showed that the number of peripheral eosinophils and the level of serum IL-5 at the eruption-active stage were both significantly higher than those in healed skin eruptions. Histological and immunohistological examination revealed that CD4+ T cells and eosinophils significantly more densely infiltrated drug eruptions than control skin lesions. The infiltrating eosinophils were also shown to be activated by immunostaining using anti-secreted formed eosinophilic cationic protein monoclonal antibody. The expression of mRNA for IL-5 in the infiltrating mononuclear cells at drug eruptions was shown by in situ hybridization. These results suggest that infiltrating CD4+ T cells might regulate both peripheral and tissue eosinophils and facilitate allergic inflammation at drug eruptions by means of IL-5 production.
Adult↗
Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice.
TGF-beta plays an important role in lung fibrosis, which is a major cause of suffering and death seen in pulmonary disease. Smad7 has been recently identified as an antagonist of TGF-beta signaling. To investigate whether this novel molecule can be exploited for therapy of lung fibrosis, we determined the effect of exogenous Smad7, introduced by a recombinant human type 5 adenovirus vector, on bleomycin-induced lung fibrosis in mice. C57BL/6 mice with bleomycin-induced lungs received an intratracheal injection of a recombinant adenovirus carrying mice Smad7 cDNA. These mice demonstrated suppression of type I precollagen mRNA, reduced hydroxyproline content, and no morphological fibrotic responses in the lungs when compared with mice administered adenovirus carrying Smad6 cDNA. In addition, we found that expression of Smad7 transgene blocked Smad2 phosphorylation induced by bleomycin in mouse lungs. These data indicated that gene transfer of Smad7 (but not Smad6) prevented bleomycin-induced lung fibrosis, suggesting that Smad7 may have applicability in the treatment of pulmonary fibrosis.
Adenoviridae↗
[Case of lupus cystitis diagnosed in the early stage].
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Adult↗
CAG repeat expansions in patients with sporadic cerebellar ataxia.
CAG repeat expansions cause spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3, SCA6 and dentatorubral-pallidoluysian atrophy (DRPLA). So far these expansions have been examined mainly in ataxia patients with a family history. However, some sporadic cases with SCA have recently been reported. To elucidate the frequency and characteristics of sporadic SCAs, we screened 85 Japanese ataxia patients without a family history for the SCA1, SCA2, SCA3, SCA6 and DRPLA mutations. As a result, 19 patients (22%) were found to have expanded CAG repeats. Among sporadic SCAs, the SCA6 mutation was most frequently observed. The sporadic SCA6 patients had smaller CAG repeats and a later age of onset than SCA6 patients with an established family history. We also identified one father-child pair in which intermediate sized CAG repeats expanded into the SCA2 disease range during transmission. These findings suggest that patients with ataxia even without a family history should be examined for a CAG repeat expansion.
Age Factors↗
Expression of cell adhesion molecules in tubulointerstitial nephritis associated with Sjögren's syndrome.
The tissue distribution of cellular adhesion molecules (ICAM-1, ELAM-1, VCAM-1) was studied in specimens from six normal human kidneys and in six biopsies from kidneys with tubulointerstitial nephritis associated with Sjögren's syndrome. In addition, the expression of cellular adhesion molecules was examined both in four renal biopsies from cases of tubulointerstitial nephritis of diverse pathogenesis and in six lip biopsies from cases of Sjögren's syndrome. ICAM-1 was expressed on vascular endothelial cells in normal kidneys, in all specimens of tubulointerstitial nephritis and in salivary glands. On tubular epithelial cells, ICAM-1 appeared slightly in normal kidneys; otherwise tubular epithelial ICAM-1 was observed in and around the foci of cellular infiltration in all cases of tubulointerstitial nephritis. ELAM-1 and VCAM-1 were observed on the newly generated vessels in massive cellular infiltrates in some cases of tubulointerstitial nephritis associated with Sjögren's syndrome; by contrast, they were not seen in normal kidneys and in cases of tubulointerstitial nephritis of diverse pathogenesis. In the lip biopsies from salivary glands, ICAM-1 was observed on ductal epithelial cells in and around the foci of cellular infiltration, and ELAM-1 and VCAM-1 occasionally appeared on the newly generated vessels in massive cellular infiltrates. Chronic and progressive inflammation may be facilitated by such ELAM-1 and VCAM-1 expression on newly generated vessels. The adhesion molecules were thought to play a role in the pathogenesis of tubulointerstitial nephritis and sialoadenitis associated with Sjögren's syndrome. It was thus concluded that the same inflammatory process that took place in the salivary glands to induce the characteristic tissue change of Sjögren's syndrome likely was operative in the renal tubulointerstitial tissue as well.
Adolescent↗
TCR in Fas-sensitive T cells from labial salivary glands of patients with Sjögren's syndrome.
Apoptosis is found in labial salivary glands of patients with Sjogren's syndrome (SS). To analyze the pathogenesis of apoptosis in labial salivary glands of SS patients, we examined the expression of Fas Ag and Fas ligand (FasL) and TCR on T cells susceptible to anti-Fas mAbs (CH-11). Fas Ag is expressed on epithelial cells and mononuclear cells in the salivary glands as observed by an immunohistochemical method. FasL is over-expressed specifically on T cells infiltrating into the labial salivary glands as seen by an reverse transcription-PCR method. These results suggest that apoptosis in SS lips is mediated by a Fas/FasL pathway. PCR single-strand conformation polymorphism (SSCP) clearly demonstrated that more than 40% of the T cells accumulated in labial salivary glands are deleted by incubation with CH-11 for 24 h in vitro, indicating that these expanded cells are Fas sensitive. junctional sequence analysis showed that the same conserved amino acid motifs (LAGG, RLA, SLG, QGPG, PGG, GGE, RGR, KPG, AGD, and MLG) in complementarity determining region 3 (CDR3) are found in Fas-sensitive T cell clones, whereas they are not detected in Fas-resistant clones, suggesting that Fas-sensitive T cells recognize restricted T cell epitopes on autoantigens. In conclusion, the findings suggest that Fas-sensitive T cells in labial salivary glands of SS patients are generated by Ag stimulation and might function as autoreactive T cells.
Amino Acid Sequence↗
IL-5 but not interferon-gamma (IFN-gamma) inhibits eosinophil apoptosis by up-regulation of bcl-2 expression.
In order to determine regulatory mechanisms of eosinophil apoptosis, we examined the effect of recombinant IL-5 and interferon-gamma (IFN-gamma) on eosinophil apoptosis and bcl-2 expression. rhIL-5 (2.5 ng/ml) significantly inhibited eosinophil apoptosis in 96 h in vitro culture compared with medium only-cultured eosinophils (89.4 +/- 3.6% versus 31.3 +/- 12.2% (mean +/- s.d.); n = 7, P < 0.05). Further, rhIL-5 significantly increased bcl-2 protein and mRNA expression on cultured eosinophils. A phosphorothioate antisense oligonucleotide targeted at the ATG translation initiation codon of bcl-2 (10(-5) M) could significantly block the supportive effect of rhIL-5 (0.25 ng/ml) for eosinophil survival compared with sense cDNA of bcl-2 on 96 h culture (inhibition rate 28.01 +/- 4.56% versus 0.07 +/- 1.73%; n = 4, P < 0.05). In contrast, rhIFN-gamma (100 U/ml) significantly inhibited eosinophil apoptosis on 96 h in vitro culture (72.7 +/- 10.5%; n = 7, P < 0.05), but did not significantly up-regulate bcl-2 protein and mRNA. These results indicate that IL-5 has inhibitory effects on eosinophil apoptosis by regulation of bcl-2 expression.
Apoptosis↗
Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion.
Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 +/- 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.
Adult↗
[A family with dentato-rubro-pallido-luysian atrophy (DRPLA): an intergenerational contraction of the CAG repeat].
We describe the relation of the CAG repeat length to the genetic anticipation in a Japanese family with dentato-rubro-pallido-luysian atrophy (DRPLA). The proband, a 21-year-old woman, developed epilepsy at age 19. Her mother has displayed cerebellar ataxia, choreoathetosis, and dementia since age 40, and the grandmother has shown cerebellar ataxia since age 52. So a genetic anticipation was observed. The CAG repeat sizes of peripheral blood lymphocytes from the proband, mother, and grandmother were found to be 61, 59, and 60, respectively. Thus, the mother showed earlier onset but a smaller CAG repeat length as compared to the grandmother. This case is thought to be rare and valuable in respect that the intergenerational contraction of the CAG repeat was shown in spite of the genetic anticipation was observed.
Adult↗