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At least 343 records · Page 19Linked to original sources
PubMed2005

Role of curvature and phase transition in lipid sorting and fission of membrane tubules.

We have recently developed a minimal system for generating long tubular nanostructures that resemble tubes observed in vivo with biological membranes. Here, we studied membrane tube pulling in ternary mixtures of sphingomyelin, phosphatidylcholine and cholesterol. Two salient results emerged: the lipid composition is significantly different in the tubes and in the vesicles; tube fission is observed when phase separation is generated in the tubes. This shows that lipid sorting may depend critically on both membrane curvature and phase separation. Phase separation also appears to be important for membrane fission in tubes pulled out of giant liposomes or purified Golgi membranes.

Brain Chemistry↗
PubMed2001

A polymorphic variant of the gene coding desmoglein 1, the target autoantigen of pemphigus foliaceus, is associated with the disease.

Two polymorphic markers were identified on the desmoglein 1 gene which encodes the autoantigen targeted by pathogenic antibodies in pemphigus foliaceus (PF), a cutaneous autoimmune blistering disease. The first marker, made of a variant haplotype of five mis-sense mutations located on the part of the gene encoding the fourth and fifth extracellular domains of the protein, is not associated with the disease. The second marker consists of a single silent T to C transition at position 809 and was found to be significantly more frequent (P = 0.015) in Caucasian PF patients (n = 36) than in controls (n = 98). Thus, pemphigus foliaceus constitutes another example of autoimmune disease in which the autoantigen polymorphism contributes to disease susceptibility.

Amino Acid Sequence↗
PubMed2002

Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus.

Pemphigus foliaceus (PF) is a rare and severe cutaneous autoimmune disease caused by autoantibodies directed against desmoglein 1 (DSG1), a desmosomal adhesion glycoprotein. We previously showed that the DSG1 gene is polymorphic and that a coding synonymous T/C single nucleotide polymorphism at position 809 is associated with PF. To determine whether the disease occurred as a consequence of complex genetic interactions, we simultaneously examined the contribution of major histocompatibility complex (MHC) class II and DSG1 polymorphisms to PF susceptibility. Our analysis performed in 31 PF patients and 84 healthy controls first confirmed the previously reported common DRB1*04 and DRB1*14 genetic background in PF and individualized DRB1*0102, DRB1*0402 and DRB1*0406, and DRB1*1404 as susceptibility MHC class II alleles in French Caucasian PF patients. It also showed that the C/C(809) genotype was associated with PF. Combined analysis of HLA class II and DSG1 polymorphisms with several distinct statistical methods including logistic regression, showed that the DRB1*04 allele and the C/C(809) genotype interact to confer a higher susceptibility to PF. These data demonstrate the role of epistasis between individual genes in PF susceptibility and illustrate the genetic complexity of organ-specific autoimmune diseases.

Autoantigens↗
PubMed2006

N-3 fatty acids modulate antioxidant status in diabetic rats and their macrosomic offspring.

OBJECTIVE: We investigated the role of dietary n-3 polyunsaturated fatty acids (n-3 PUFA) in the modulation of total antioxidant status in streptozotocin (STZ)-induced diabetic rats and their macrosomic offspring. DESIGN: Female wistar rats, fed on control diet or n-3 PUFA diet, were rendered diabetic by administration of five mild doses of STZ on day 5 and were killed on days 12 and 21 of gestation. The macrosomic (MAC) pups were killed at the age of 60 and 90 days. MEASUREMENTS: Lipid peroxidation was measured as the concentrations of plasma thiobarbituric acid reactive substances (TBARS), and the total antioxidant status was determined by measuring (i) plasma oxygen radical absorbance capacity (ORAC), (ii) plasma vitamin A, E and C concentrations, and (iii) antioxidant enzymes activities in erythrocytes. The plasma lipid concentrations and fatty acid composition were also determined. RESULTS: Diabetes increased plasma triglyceride and cholesterol concentrations, whereas macrosomia was associated with enhanced plasma cholesterol and triglyceride levels, which diminished by feeding n-3 PUFA diet. N-3 PUFA diet also reduced increased plasma TBARS and corrected the decreased ORAC values in diabetic rats and their macrosomic offspring. EPAX diet increased the diminished vitamin A levels in diabetic mothers and vitamin C concentrations in macrosomic pups. Also, this diet improved the decreased erythrocyte superoxide dismutase and glutathione peroxidase activities in diabetic and macrosomic animals. CONCLUSION: Diabetes and macrosomia were associated with altered lipid metabolism, antioxidant enzyme activities and vitamin concentrations. N-3 PUFA diet improved hyperlipidemia and restored antioxidant status in diabetic dams and MAC offspring.

Animals↗
PubMed2006

Presence of chimeric maternally derived keratinocytes in cutaneous inflammatory diseases of children: the example of pityriasis lichenoides.

During pregnancy, maternal cells may enter the fetal circulation and persist until adulthood. The fate of these cells remains unknown. As unexplained T-cell-mediated conditions such as pityriasis lichenoides (PL) may occur in children, we aimed at identifying maternal cells in lesional skin of PL and controls. Archived skin biopsy specimens from young males with PL, atopic dermatitis, or normal skin were scanned for the presence of female (presumably maternal) cells using fluorescence in situ hybridization (FISH) with X and Y chromosome-specific probes. Phenotyping of maternal cells relied on FISH combined with anti-CD45, anti-CD1a, or anti-cytokeratin labelling, identifying leukocytes, Langerhans cells, and keratinocytes, respectively. Maternal cells were found in PL (11/12) and controls (4/7), but their average frequency was higher in PL: 99 per million cells as compared to 5 per million cells in controls (P = 0.005). In the epidermis, the maternal microchimeric cells were labelled by anti-cytokeratin in all cases. We identified maternally derived keratinocytes in the skin of male children with inflammatory skin disorders. These cells may either help repair the damaged skin or home initially in the skin and trigger a host (child) versus graft (mother) disease.

Antigens, CD1↗
PubMed2006

Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome.

SPINK5 (serine protease inhibitor Kazal-type 5), encoding the protease inhibitor LEKTI (lympho-epithelial Kazal-type related inhibitor), is the defective gene in Netherton syndrome (NS), a severe inherited keratinizing disorder. We have recently demonstrated epidermal protease hyperactivity in Spink5(-/-) mice resulting in desmosomal protein degradation. Herein, we investigated the molecular mechanism underlying the epidermal defect in 15 patients with NS. We demonstrated that, in a majority of patients, desmoglein 1 (Dsg1) and desmocollin 1 (Dsc1) were dramatically reduced in the upper most living layers of the epidermis. These defects were associated with premature degradation of corneodesmosomes. Stratum corneum tryptic enzyme (SCTE)-like and stratum corneum chymotryptic enzyme (SCCE)-like activities were increased, suggesting that these proteases participate in the premature degradation of corneodesmosomal cadherins. SCTE and SCCE expression was extended to the cell layers where Dsg1 and Dsc1 immunostaining was reduced. In contrast, a subset of six patients with normal epidermal protease activity or residual LEKTI expression displayed apparently normal cadherin expression and less severe disease manifestations. This suggests a degree of correlation between cadherin degradation and clinical severity. This work further supports the implication of premature corneodesmosomal cadherin degradation in the pathogenesis of NS and provides evidence for additional factors playing a role in disease expression.

Abnormalities, Multiple↗
PubMed2006

Epigallocatechin gallate's protective effect against MMP7 in recessive dystrophic epidermolysis bullosa patients.

The analysis of phenotype-genotype correlations of patients suffering from recessive dystrophic epidermolysis bullosa (RDEB) evidenced intrafamilial and interfamilial phenotype variability occurring for the same mutation of COL7A1; this underscores the role of other genetics environmental factors in the expressivity of the disease. In this work, we checked whether matrilysin 1 (matrix metalloproteinase (MMP)7) could take part in the epidermal detachment in RDEB. Furthermore, we investigated epigallocatechin 3 gallate (EGCG) to determine whether it could inhibit matrilysin activities on collagen type VII and fibrillin 1 known to be associated with the dermo-epidermal junction. In this work, matrilysin 1 was detected in affected and unaffected skins of the three RDEB patients; furthermore, MMP7 was shown to degrade ex vivo on healthy normal skin collagen VII and fibrillin 1. Thus, we suspect that MMP7 could take an active part in the epidermal detachment occurring during RDEB. We evidenced that EGCG in in vitro as well as in ex vivo experiments was a good inhibitor of MMP7 and developed a good protection of collagen type VII and fibrillin 1 susceptible of being degraded by MMP7. We therefore propose that EGCG could be used beneficially in patients suffering from RDEB.

Adult↗
PubMed2004

Additive effect of p53, p21 and Rb deletion in triple knockout primary hepatocytes.

Using Cre-Lox technology to inducibly delete Rb from wild-type, p21- and/or p53-deficient primary hepatocytes, we investigated the role of p53, p21 and pRb in the regulation of liver cell proliferation, polyploidization and death. These cellular decisions are critical to maintaining liver cell replacement in disease, and in determining the likelihood of carcinogenesis in chronic liver injury. Clearly, the present study shows a complex interplay between p53, p21 and pRb, which regulates the likelihood of hepatocytes stimulated from quiescence, to proliferate, undergo polyploidy or die. It reveals that these proteins act both in concert and independently, demonstrating that a small set of key cellular players is common to diverse cell decisions of fundamental importance to disease.

Animals↗
PubMed2006

E2F regulates DDB2: consequences for DNA repair in Rb-deficient cells.

DDB2, a gene mutated in XPE patients, is involved in global genomic repair especially the repair of cyclobutane pyrimidine dimers (CPDs), and is regulated by p53 in human cells. We show that DDB2 is expressed in mouse tissues and demonstrate, using primary mouse epithelial cells, that mouse DDB2 is regulated by E2F transcription factors. Retinoblastoma (Rb), a tumor suppressor critical for the control of cell cycle progression, regulates E2F activity. Using Cre-Lox technology to delete Rb in primary mouse hepatocytes, we show that DDB2 gene expression increases, leading to elevated DDB2 protein levels. Furthermore, we show that endogenous E2F1 and E2F3 bind to DDB2 promoter and that treatment with E2F1-antisense or E2F1-small interfering RNA (siRNA) decreases DDB2 transcription, demonstrating that E2F1 is a transcriptional regulator for DDB2. This has consequences for global genomic repair: in Rb-null cells, where E2F activity is elevated, global DNA repair is increased and removal of CPDs is more efficient than in wild-type cells. Treatment with DDB2-siRNA decreases DDB2 expression and abolishes the repair phenotype of Rb-null cells. In summary, these results identify a new regulatory pathway for DDB2 by E2F, which does not require but is potentiated by p53, and demonstrate that DDB2 is involved in global repair in mouse epithelial cells.

Animals↗
PubMed2000

Time course of changes in serum glucose, insulin, lipids and tissue lipase activities in macrosomic offspring of rats with streptozotocin-induced diabetes.

The aim of this investigation was to determine the time course of changes in serum glucose, insulin and lipid levels, as well as lipid and protein content and lipolytic activities in insulin target organs (liver, adipose tissue and muscle), in macrosomic offspring of streptozotocin-induced mildly hyperglycaemic rats. Food intake and nutritional efficiency were also evaluated. Mild hyperglycaemia in pregnant rats was induced by intraperitoneal injection of streptozotocin (40 mg/kg body weight) on day 5 of gestation. Control pregnant rats were injected with citrate buffer. At birth, macrosomic pups (birth weight >1.7 S.D. greater than the mean value for the control pups) had higher serum insulin, glucose and lipid levels than control pups. These macrosomic rats maintained accelerated postnatal growth combined with high adipose tissue weight up to 12 weeks of age. These rats were not hyperphagic; however, they had higher food efficiency and fat storage capacity with higher adipocyte lipoprotein lipase activity, which contributed to persisting obesity. Hepatic lipase activity was increased in macrosomic rats at all ages. Moreover, macrosomia was associated with metabolic disturbances that varied according to age and sex. After 1 month, several alterations observed at birth had disappeared. Serum glucose, insulin and lipid levels in male and female macrosomic rats became similar to those of their respective controls. At 2 months of age, hepatic and serum triacylglycerol levels were higher in macrosomic females than in controls. By 3 months, macrosomic rats (both males and females) had developed insulin resistance with hyperinsulinaemia, hyperglycaemia, and higher serum and hepatic lipids. In conclusion, macrosomia was associated with alterations in glucose and lipid metabolism through to adulthood. It should be considered as an important potential risk factor for obesity and its metabolic complications.

Adipose Tissue↗
PubMed1997

IgA-epidermolysis bullosa acquisita in a child resulting in blindness.

Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal bullous disease characterized by IgG autoantibodies directed against type VII collagen, the major component of anchoring fibrils. The classical phenotype of EBA is a non-inflammatory, mechanobullous disease resembling the dystrophic forms of inherited epidermolysis bullosa. Mucous membrane involvement is frequent but usually mild. We report a 1-year-old girl suffering from IgA-EBA, who presented with an initial eruption of disseminated urticarial lesions and tense blisters of the skin but subsequently developed severe oral and ocular lesions reminiscent of cicatricial pemphigoid. Direct immunofluorescence of the skin and buccal mucosa revealed linear IgA and C3 at the basement membrane zone (BMZ). IgA anti-BMZ autoantibodies stained the dermal side of salt-split skin by indirect immunofluorescence and recognized a dermal protein of 290 kDa co-migrating with type VII collagen by immunoblotting. Direct and indirect immunoelectron microscopy revealed IgA deposits overlying the anchoring fibrils. The ocular involvement led to total blindness in spite of intense treatment. This case of childhood IgA-EBA is particularly striking because of the cicatricial pemphigoid phenotype with severe ocular involvement which resulted in blindness. It reinforces the necessity to use modern immunological methods to classify autoimmune bullous diseases in order to allow early and appropriate treatment.

Autoantibodies↗
PubMed1998

Acquired junctional epidermolysis bullosa associated with IgG autoantibodies to the beta subunit of laminin-5.

We report the case of a 72-year-old man with clinical features resembling those of non-lethal junctional epidermolysis bullosa associated with IgG autoantibodies to the beta chain of laminin-5. The patient presented with a sudden onset of blistering and severe fragility of the skin and mucous membranes resulting in atrophic scars. Electron microscopy showed that the blistering arose in the lamina lucida. Indirect immunofluorescence indicated that the autoantibodies bound to the dermal side of 1 mol/L NaCl-split skin, and both direct and indirect immunoelectron microscopy demonstrated antibody binding to the lamina densa. Postembedding immunogold electron microscopy also revealed labelling in the lamina lucida beneath the hemidesmosomes. On immunoblotting, we found the autoantibodies to comigrate with the beta chain of laminin-5. Following the nomenclature of inherited junctional epidermolysis bullosa with mutations of the laminin-5 gene, we propose the name acquired junctional epidermolysis bullosa for this newly recognized disease.

Aged↗
PubMed1998

Lichen planus pemphigoides is a heterogeneous disease: a report of five cases studied by immunoelectron microscopy.

Lichen planus pemphigoides (LPP) is a rare and controversial disease. It is characterized by bullae arising on lichen planus papules and on uninvolved skin, subepidermal bullae in histology, and linear deposits of IgG and C3 along the basal membrane zone on immunofluorescence of peribullous skin. Our goal was to identify the localization of the target antigen in cases of LPP. Five patients diagnosed with LPP on clinical, histological and immunofluorescence criteria were explored by immunoelectron microscopy and immunoblot. Our results show that the target antigen in LPP is not unique. The localization of the immune deposits was consistent with a diagnosis of bullous pemphigoid in two cases, of cicatricial pemphigoid in two cases and of epidermolysis bullosa acquisita in one case. Our study supports the view that LPP is a heterogeneous condition in which lichen planus may induce different subepidermal acquired bullous dermatoses.

Adolescent↗
PubMed2003

High frequency of detection of human papillomaviruses associated with epidermodysplasia verruciformis in children with psoriasis.

BACKGROUND: Psoriasis is a T-cell-mediated immunological disease characterized by epidermal proliferation. The nature of the antigen(s) responsible for T-cell activation is still unknown. It has been suggested that the human papillomaviruses (HPVs) associated with epidermodysplasia verruciformis (EV), including the oncogenic HPV5, may contribute to the pathogenesis of psoriasis. OBJECTIVES: To determine whether EV-HPVs may play a role early in the disease, we searched for these viruses in children with psoriasis. The influence of clinical data on EV-HPV infection was investigated. METHODS: We studied scrapings of involved skin from 26 children aged 1.5-13 years with psoriasis. As controls, we analysed scrapings from 28 adults with psoriasis and 15 children with atopic dermatitis, as well as scrapings from normal skin of 28 adults with no known history of HPV infection. We searched for EV-HPV DNA sequences with a nested polymerase chain reaction method using degenerate primers specific for EV-HPVs and primers specific for HPV5 and HPV36, two EV-HPVs frequently detected in adults with psoriasis. RESULTS: Similar high prevalences were observed in children and adults with psoriasis for EV-HPVs (38.5% vs. 35.7%), HPV5 (46.2% vs. 46.4%) and HPV36 (15.4% vs. 25.0%). As in adults, we found several EV-HPV genotypes and HPV5 and HPV36 variants. A novel HPV36 subtype, HPV36b, was identified. Lower prevalences were observed in children with atopic dermatitis and in adults from the general population (6.7-10.1%). No correlation was observed between frequency of detection of HPVs and clinical data. It is noteworthy that HPV5 was identified in an 18-month-old girl and in a boy with psoriasis developing for only 1 week. CONCLUSIONS: The early detection of several EV-HPV genotypes in children further supports the link between psoriasis and EV-HPVs and suggests a putative role for these viruses in the pathogenesis of psoriasis.

Adolescent↗
PubMed1999

Spatial and temporal mapping of c-kit and its ligand, stem cell factor expression during human embryonic haemopoiesis.

Receptor tyrosine kinases (RTKs) mediate cellular responses to the extracellular signals involved in the regulation of cell differentiation and proliferation. Ligand binding initiates a cascade of events, such as receptor dimerization and tyrosine phosphorylation. The c-kit gene encodes an RTK for stem cell factor (SCF), (c-kit ligand, KL), both of which play a critical role in the differentiation and growth of haemopoietic stem cells (HSCs). We investigated the expression of the c-kit and SCF genes and the presence of the corresponding proteins in haemopoietic tissues during human embryogenesis. We have examined c-kit and SCF transcripts levels in human embryonic yolk sac, the AGM region, and liver at different stages of gestation (days 25 to 63), using RT-PCR amplification combined with PhosphorImager quantitative analysis and RNase Protection Assay (RPA). Weak levels of SCF gene expression were observed in the AGM region (days 25 to 34) and high levels were found in the early-stage liver (day 34). The expression of c-kit transcript was observed in all studied tissues, but at various levels. The restricted presence of SCF protein following mRNA expression was demonstrated in embryonic liver CD38+ haemopoietic cells by immunocytochemistry. These observations suggest that the biological function of the c-kit receptor plays an important role in the early stages of human haemopoiesis, and that c-kit/SCF signalling is particularly involved in early human definitive haemopoiesis.

Embryo, Mammalian↗
PubMed1998

Inactivation of isocitrate dehydrogenase kinase/phosphatase by 5'-[p-(fluorosulfonyl)benzoyl]adenosine is not due to the labeling of the invariant lysine residue found in the protein kinase family.

The ATPase activity of Escherichia coli isocitrate dehydrogenase kinase/phosphatase was rapidly lost after prior incubation with the ATP analogue 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSBA). This inactivation was prevented by the presence of either 5 mM ATP or 5 mM ADP plus Mg2+, while it could be fully reversed by subsequent addition of dithiothreitol, thereby indicating the involvement of cysteine residue(s) in this process. About 2 mol [3H]FSBA/mol IDHK/P were bound during the time course of the inactivation. However, this binding was not significantly modified by either prior incubation with ATP or subsequent addition of dithiothreitol. This suggested that FSBA-mediated inactivation of isocitrate dehydrogenase kinase/phosphatase occurred via the formation of a disulfide bond. Accordingly, mass spectral analysis revealed that on addition of FSBA, a disulfide bond was formed between residues Cys356 and Cys523. The mutation Cys356Ser renders the enzyme insensitive to FSBA treatment indicating that Cys356 is the primary target for this analogue. However, the Cys523Ser mutant was still inactivated by FSBA and mass spectral analysis showed that this was due to the formation of a new disulfide bond between Cys356 and Cys480.

Adenosine↗
PubMed1999

Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP180.

Lichen planus pemphigoides is an autoimmune subepidermal blistering disease. The finding of immunoglobulin G antibodies directed against the basement membrane zone differentiates it from bullous lichen planus. The aim of this study was to identify the target antigen of lichen planus pemphigoides autoantibodies. Sera from lichen planus pemphigoides patients (n = 4) stained the epidermal side of NaCl-split human skin in a pattern indistinguishable from that produced by bullous pemphigoid sera. In bullous pemphigoid, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. We previously demonstrated that bullous pemphigoid sera predominantly react with a set of four epitopes (MCW-0 through MCW-3) clustered within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, lichen planus pemphigoides sera were also strongly reactive with recombinant bullous pemphigoid 180 NC16A. The lichen planus pemphigoides epitopes were further mapped using a series of overlapping recombinant segments of the NC16A domain. All lichen planus pemphigoides sera reacted with amino acids 46-59 of domain NC16A, a protein segment that was previously shown to be unreactive with bullous pemphigoid sera. Two lichen planus pemphigoides sera, in addition, reacted with the immunodominant antigenic region associated with bullous pemphigoid. In conclusion, there are now five bullous diseases that are associated with an autoimmune response to BP180: bullous pemphigoid; pemphigoid/herpes gestationis; cicatricial pemphigoid; linear immunoglobulin A disease; and lichen planus pemphigoides. In addition, we have identified a novel epitope within the BP180 NC16A domain, designated MCW-4, that appears to be uniquely recognized by sera from patients with lichen planus pemphigoides.

Adult↗