The Experts below are selected from a list of 2007 Experts worldwide ranked by ideXlab platform

Alan D Irvine - One of the best experts on this subject based on the ideXlab platform.

  • Adhesion of Staphylococcus aureus to Corneocytes from Atopic Dermatitis Patients Is Controlled by Natural Moisturizing Factor Levels.
    Mbio, 2018
    Co-Authors: Cecile Feuillie, Maeve A. Mcaleer, Alan D Irvine, Pauline Vitry, Joan A Geoghegan, Sanja Kezic, Yves F. Dufrêne
    Abstract:

    ABSTRACT The bacterial pathogen Staphylococcus aureus plays an important role in atopic dermatitis (AD), a chronic disorder that mostly affects children. Colonization of the skin of AD patients by S. aureus exacerbates the disease, but the molecular determinants of the bacterium-skin adhesive interactions are poorly understood. Specifically, reduced levels of natural moisturizing factor (NMF) in the stratum corneum have been shown to be associated with more severe AD symptoms, but whether this is directly related to S. aureus adhesion is still an open question. Here, we demonstrate a novel relationship between NMF expression in AD skin and strength of bacterial adhesion. Low-NMF Corneocytes, unlike high-NMF ones, are covered by a dense layer of nanoscale villus protrusions. S. aureus bacteria isolated from AD skin bind much more strongly to Corneocytes when the NMF level is reduced. Strong binding forces originate from a specific interaction between the bacterial adhesion clumping factor B (ClfB) and skin ligands. Remarkably, mechanical tension dramatically strengthens ClfB-mediated adhesion, as observed with catch bonds, demonstrating that physical stress plays a role in promoting colonization of AD skin by S. aureus. Collectively, our findings demonstrate that patient NMF levels regulate the strength of S. aureus-corneocyte adhesion, the first step in skin colonization, and suggest that the ClfB binding mechanism could represent a potential target for new therapeutic treatments. IMPORTANCE Bacterium-skin interactions play important roles in skin disorders, yet their molecular details are poorly understood. In this study, we decipher the molecular forces at play during adhesion of Staphylococcus aureus to skin Corneocytes in the clinically important context of atopic dermatitis (AD), also known as eczema. We identify a unique relationship between the level of natural moisturizing factor (NMF) in the skin and the strength of bacterium-corneocyte adhesion. Bacterial adhesion is primarily mediated by the surface protein clumping factor B (ClfB) and is enhanced by physical stress, highlighting the role of protein mechanobiology in skin colonization. Similar to a catch bond behavior, this mechanism represents a promising target for the development of novel antistaphylococcal agents.

  • early life regional and temporal variation in filaggrin derived natural moisturizing factor filaggrin processing enzyme activity corneocyte phenotypes and plasmin activity implications for atopic dermatitis
    British Journal of Dermatology, 2018
    Co-Authors: Maeve A. Mcaleer, Ivone Jakasa, Rainer Voegeli, C P F Odonnell, Majella E Lane, Alan D Irvine, A.v. Rawlings, Sanja Kezic
    Abstract:

    Background: Filaggrin is central to the pathogenesis of atopic dermatitis (AD). The cheeks are a common initiation site of infantile AD. Regional and temporal expression of levels of filaggrin degradation products [natural moisturizing factors (NMFs)], activities of filaggrin‐processing enzymes [bleomycin hydrolase (BH) and calpain‐1 (C‐1)] and plasmin, and corneocyte envelope (CE) maturity in early life are largely unknown. / Objectives: We conducted a cross‐sectional, observational study investigating regional and age‐dependent variations in NMF levels, activity of proteases and CE maturity in stratum corneum (SC) from infants to determine whether these factors could explain the observed predilection sites for AD in early life. / Methods: We measured NMF using a tape‐stripping method at seven sites in the SC of 129 children (aged < 12 months to 72 months) and in three sites in 56 neonates and infants (< 48 h to 3 months). In 37 of these neonates and infants, corneocyte size, maturity, BH, C‐1 and plasmin activities were determined. / Results: NMF levels are low at birth and increase with age. Cheek SC, compared with elbow flexure and nasal tip, has the lowest NMF in the first year of life and is the slowest to reach stable levels. Cheek Corneocytes remain immature. Plasmin, BH and C‐1 activities are all elevated by 1 month of age in exposed cheek skin, but not in elbow skin. / Conclusions: Regional and temporal differences in NMF levels, CE maturity and protease activities may explain the predilection for AD to affect the cheeks initially and are supportive of this site as key for allergen priming in early childhood. These observations will help design early intervention and treatment strategies for AD.

  • Adhesion of Staphylococcus aureus to Corneocytes from Atopic Dermatitis Patients Is Controlled by Natural Moisturizing Factor Levels
    American Society for Microbiology, 2018
    Co-Authors: Cecile Feuillie, Maeve A. Mcaleer, Alan D Irvine, Pauline Vitry, Joan A Geoghegan, Sanja Kezic, Yves F. Dufrêne
    Abstract:

    The bacterial pathogen Staphylococcus aureus plays an important role in atopic dermatitis (AD), a chronic disorder that mostly affects children. Colonization of the skin of AD patients by S. aureus exacerbates the disease, but the molecular determinants of the bacterium-skin adhesive interactions are poorly understood. Specifically, reduced levels of natural moisturizing factor (NMF) in the stratum corneum have been shown to be associated with more severe AD symptoms, but whether this is directly related to S. aureus adhesion is still an open question. Here, we demonstrate a novel relationship between NMF expression in AD skin and strength of bacterial adhesion. Low-NMF Corneocytes, unlike high-NMF ones, are covered by a dense layer of nanoscale villus protrusions. S. aureus bacteria isolated from AD skin bind much more strongly to Corneocytes when the NMF level is reduced. Strong binding forces originate from a specific interaction between the bacterial adhesion clumping factor B (ClfB) and skin ligands. Remarkably, mechanical tension dramatically strengthens ClfB-mediated adhesion, as observed with catch bonds, demonstrating that physical stress plays a role in promoting colonization of AD skin by S. aureus. Collectively, our findings demonstrate that patient NMF levels regulate the strength of S. aureus-corneocyte adhesion, the first step in skin colonization, and suggest that the ClfB binding mechanism could represent a potential target for new therapeutic treatments.Bacterium-skin interactions play important roles in skin disorders, yet their molecular details are poorly understood. In this study, we decipher the molecular forces at play during adhesion of Staphylococcus aureus to skin Corneocytes in the clinically important context of atopic dermatitis (AD), also known as eczema. We identify a unique relationship between the level of natural moisturizing factor (NMF) in the skin and the strength of bacterium-corneocyte adhesion. Bacterial adhesion is primarily mediated by the surface protein clumping factor B (ClfB) and is enhanced by physical stress, highlighting the role of protein mechanobiology in skin colonization. Similar to a catch bond behavior, this mechanism represents a promising target for the development of novel antistaphylococcal agents

  • filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis
    The Journal of Allergy and Clinical Immunology, 2015
    Co-Authors: Christoph Riethmuller, Jonas Franz, Sjors A Koppes, Rawad Abdayem, Stephanie F Maccallum, Linda E Campbell, W Irwin H Mclean, Maeve A. Mcaleer, Marek Haftek, Alan D Irvine
    Abstract:

    Background: Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status. Objective: We sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD. Methods: We studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anticorneodesmosin antibody and visualized with scanning electron microscopy. Results: We found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r 52 0.80 and 20.75, P < .001 and P 5 .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients. Conclusions: NMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrindeficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations. (J Allergy Clin Immunol 2015;nnn:nnn-nnn.)

Maeve A. Mcaleer - One of the best experts on this subject based on the ideXlab platform.

  • Adhesion of Staphylococcus aureus to Corneocytes from Atopic Dermatitis Patients Is Controlled by Natural Moisturizing Factor Levels.
    Mbio, 2018
    Co-Authors: Cecile Feuillie, Maeve A. Mcaleer, Alan D Irvine, Pauline Vitry, Joan A Geoghegan, Sanja Kezic, Yves F. Dufrêne
    Abstract:

    ABSTRACT The bacterial pathogen Staphylococcus aureus plays an important role in atopic dermatitis (AD), a chronic disorder that mostly affects children. Colonization of the skin of AD patients by S. aureus exacerbates the disease, but the molecular determinants of the bacterium-skin adhesive interactions are poorly understood. Specifically, reduced levels of natural moisturizing factor (NMF) in the stratum corneum have been shown to be associated with more severe AD symptoms, but whether this is directly related to S. aureus adhesion is still an open question. Here, we demonstrate a novel relationship between NMF expression in AD skin and strength of bacterial adhesion. Low-NMF Corneocytes, unlike high-NMF ones, are covered by a dense layer of nanoscale villus protrusions. S. aureus bacteria isolated from AD skin bind much more strongly to Corneocytes when the NMF level is reduced. Strong binding forces originate from a specific interaction between the bacterial adhesion clumping factor B (ClfB) and skin ligands. Remarkably, mechanical tension dramatically strengthens ClfB-mediated adhesion, as observed with catch bonds, demonstrating that physical stress plays a role in promoting colonization of AD skin by S. aureus. Collectively, our findings demonstrate that patient NMF levels regulate the strength of S. aureus-corneocyte adhesion, the first step in skin colonization, and suggest that the ClfB binding mechanism could represent a potential target for new therapeutic treatments. IMPORTANCE Bacterium-skin interactions play important roles in skin disorders, yet their molecular details are poorly understood. In this study, we decipher the molecular forces at play during adhesion of Staphylococcus aureus to skin Corneocytes in the clinically important context of atopic dermatitis (AD), also known as eczema. We identify a unique relationship between the level of natural moisturizing factor (NMF) in the skin and the strength of bacterium-corneocyte adhesion. Bacterial adhesion is primarily mediated by the surface protein clumping factor B (ClfB) and is enhanced by physical stress, highlighting the role of protein mechanobiology in skin colonization. Similar to a catch bond behavior, this mechanism represents a promising target for the development of novel antistaphylococcal agents.

  • early life regional and temporal variation in filaggrin derived natural moisturizing factor filaggrin processing enzyme activity corneocyte phenotypes and plasmin activity implications for atopic dermatitis
    British Journal of Dermatology, 2018
    Co-Authors: Maeve A. Mcaleer, Ivone Jakasa, Rainer Voegeli, C P F Odonnell, Majella E Lane, Alan D Irvine, A.v. Rawlings, Sanja Kezic
    Abstract:

    Background: Filaggrin is central to the pathogenesis of atopic dermatitis (AD). The cheeks are a common initiation site of infantile AD. Regional and temporal expression of levels of filaggrin degradation products [natural moisturizing factors (NMFs)], activities of filaggrin‐processing enzymes [bleomycin hydrolase (BH) and calpain‐1 (C‐1)] and plasmin, and corneocyte envelope (CE) maturity in early life are largely unknown. / Objectives: We conducted a cross‐sectional, observational study investigating regional and age‐dependent variations in NMF levels, activity of proteases and CE maturity in stratum corneum (SC) from infants to determine whether these factors could explain the observed predilection sites for AD in early life. / Methods: We measured NMF using a tape‐stripping method at seven sites in the SC of 129 children (aged < 12 months to 72 months) and in three sites in 56 neonates and infants (< 48 h to 3 months). In 37 of these neonates and infants, corneocyte size, maturity, BH, C‐1 and plasmin activities were determined. / Results: NMF levels are low at birth and increase with age. Cheek SC, compared with elbow flexure and nasal tip, has the lowest NMF in the first year of life and is the slowest to reach stable levels. Cheek Corneocytes remain immature. Plasmin, BH and C‐1 activities are all elevated by 1 month of age in exposed cheek skin, but not in elbow skin. / Conclusions: Regional and temporal differences in NMF levels, CE maturity and protease activities may explain the predilection for AD to affect the cheeks initially and are supportive of this site as key for allergen priming in early childhood. These observations will help design early intervention and treatment strategies for AD.

  • Adhesion of Staphylococcus aureus to Corneocytes from Atopic Dermatitis Patients Is Controlled by Natural Moisturizing Factor Levels
    American Society for Microbiology, 2018
    Co-Authors: Cecile Feuillie, Maeve A. Mcaleer, Alan D Irvine, Pauline Vitry, Joan A Geoghegan, Sanja Kezic, Yves F. Dufrêne
    Abstract:

    The bacterial pathogen Staphylococcus aureus plays an important role in atopic dermatitis (AD), a chronic disorder that mostly affects children. Colonization of the skin of AD patients by S. aureus exacerbates the disease, but the molecular determinants of the bacterium-skin adhesive interactions are poorly understood. Specifically, reduced levels of natural moisturizing factor (NMF) in the stratum corneum have been shown to be associated with more severe AD symptoms, but whether this is directly related to S. aureus adhesion is still an open question. Here, we demonstrate a novel relationship between NMF expression in AD skin and strength of bacterial adhesion. Low-NMF Corneocytes, unlike high-NMF ones, are covered by a dense layer of nanoscale villus protrusions. S. aureus bacteria isolated from AD skin bind much more strongly to Corneocytes when the NMF level is reduced. Strong binding forces originate from a specific interaction between the bacterial adhesion clumping factor B (ClfB) and skin ligands. Remarkably, mechanical tension dramatically strengthens ClfB-mediated adhesion, as observed with catch bonds, demonstrating that physical stress plays a role in promoting colonization of AD skin by S. aureus. Collectively, our findings demonstrate that patient NMF levels regulate the strength of S. aureus-corneocyte adhesion, the first step in skin colonization, and suggest that the ClfB binding mechanism could represent a potential target for new therapeutic treatments.Bacterium-skin interactions play important roles in skin disorders, yet their molecular details are poorly understood. In this study, we decipher the molecular forces at play during adhesion of Staphylococcus aureus to skin Corneocytes in the clinically important context of atopic dermatitis (AD), also known as eczema. We identify a unique relationship between the level of natural moisturizing factor (NMF) in the skin and the strength of bacterium-corneocyte adhesion. Bacterial adhesion is primarily mediated by the surface protein clumping factor B (ClfB) and is enhanced by physical stress, highlighting the role of protein mechanobiology in skin colonization. Similar to a catch bond behavior, this mechanism represents a promising target for the development of novel antistaphylococcal agents

  • clumping factor b promotes adherence of staphylococcus aureus to Corneocytes in atopic dermatitis
    Infection and Immunity, 2017
    Co-Authors: O M Fleury, W Irwin H Mclean, Maeve A. Mcaleer, Cecile Feuillie, Cecile Formosadague, Emily A Sansevere, Desiree Bennett, Aisling M Towell, Sanja Kezic
    Abstract:

    Staphylococcus aureus skin infection is a frequent and recurrent problem in children with the common inflammatory skin disease atopic dermatitis (AD). S. aureus colonizes the skin of the majority of children with AD and exacerbates the disease. The first step during colonization and infection is bacterial adhesion to the cornified envelope of Corneocytes in the outer layer, the stratum corneum. Corneocytes from AD skin are structurally different from Corneocytes from normal healthy skin. The objective of this study was to identify bacterial proteins that promote the adherence of S. aureus to AD Corneocytes. S. aureus strains from clonal complexes 1 and 8 were more frequently isolated from infected AD skin than from the nasal cavity of healthy children. AD strains had increased ClfB ligand binding activity compared to normal nasal carriage strains. Adherence of single S. aureus bacteria to Corneocytes from AD patients ex vivo was studied using atomic force microscopy. Bacteria expressing ClfB recognized ligands distributed over the entire corneocyte surface. The ability of an isogenic ClfB-deficient mutant to adhere to AD Corneocytes compared to that of its parent clonal complex 1 clinical strain was greatly reduced. ClfB from clonal complex 1 strains had a slightly higher binding affinity for its ligand than ClfB from strains from other clonal complexes. Our results provide new insights into the first step in the establishment of S. aureus colonization in AD patients. ClfB is a key adhesion molecule for the interaction of S. aureus with AD Corneocytes and represents a target for intervention.

  • filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis
    The Journal of Allergy and Clinical Immunology, 2015
    Co-Authors: Christoph Riethmuller, Jonas Franz, Sjors A Koppes, Rawad Abdayem, Stephanie F Maccallum, Linda E Campbell, W Irwin H Mclean, Maeve A. Mcaleer, Marek Haftek, Alan D Irvine
    Abstract:

    Background: Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status. Objective: We sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD. Methods: We studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anticorneodesmosin antibody and visualized with scanning electron microscopy. Results: We found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r 52 0.80 and 20.75, P < .001 and P 5 .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients. Conclusions: NMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrindeficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations. (J Allergy Clin Immunol 2015;nnn:nnn-nnn.)

Marek Haftek - One of the best experts on this subject based on the ideXlab platform.

  • filaggrin expression and processing deficiencies impair corneocyte surface texture and stiffness in mice
    Journal of Investigative Dermatology, 2020
    Co-Authors: Jacob P. Thyssen, Ivone Jakasa, Michael P Schon, Jacek Wroblewski, Andrea Braun, Padraic G Fallon, Christoph Riethmuller, Hieronim Jakubowski, Marek Haftek, Leopold Eckhart
    Abstract:

    Abundant corneocyte surface protrusions, observed in patients with atopic dermatitis with filaggrin loss-of-function mutations, are inversely associated with levels of natural moisturizing factors (NMFs) in the stratum corneum. To dissect the etiological role of NMFs and filaggrin deficiency in surface texture alterations, we examined mouse models with genetic deficiencies in the synthesis or degradation of filaggrin monomers for NMFs, cell stiffness (elastic modulus) and corneocyte surface protrusion density (dermal texture index). Five neonatal and adult mouse models carrying inactivating mutations of SASPase (Sasp−/−), filaggrin (Flgft/ft and Flg−/−), filaggrin-hornerin (FlgHrnr−/−), and bleomycin hydrolase (Blmh−/−) were investigated. Sasp−/− and Flg−/− were on the hairless mouse background. Atomic force microscopy was used to determine elastic modulus and dermal texture index. Corneocytes of each neonatal as well as hairless adult knockout mouse exhibited an increased number of protrusions and decreased elastic modulus. In these mice, NMFs were reduced except for Sasp−/−. Dermal texture index was inversely correlated with NMFs and elastic modulus. Our findings demonstrate that any filaggrin-NMF axis deficiency can affect corneocyte mechanical properties in mice and likely in humans. Differences in NMFs and corneocyte surface texture between neonatal and adult as well as hairless and hairy mice emphasize the need for carefully selecting the most appropriate animal models for studies.

  • filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis
    The Journal of Allergy and Clinical Immunology, 2015
    Co-Authors: Christoph Riethmuller, Jonas Franz, Sjors A Koppes, Rawad Abdayem, Stephanie F Maccallum, Linda E Campbell, W Irwin H Mclean, Maeve A. Mcaleer, Marek Haftek, Alan D Irvine
    Abstract:

    Background: Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status. Objective: We sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD. Methods: We studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anticorneodesmosin antibody and visualized with scanning electron microscopy. Results: We found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r 52 0.80 and 20.75, P < .001 and P 5 .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients. Conclusions: NMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrindeficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations. (J Allergy Clin Immunol 2015;nnn:nnn-nnn.)

  • development and organization of human stratum corneum after birth electron microscopy isotropy score and immunocytochemical corneocyte labelling as epidermal maturation s markers in infancy
    British Journal of Dermatology, 2014
    Co-Authors: Nadege Lachmann, Evelyne Colomb, Razvigor Darlenski, Caroline Baudouin, Philippe Msika, C De Belilovsky, Béatrice Burdin, Marek Haftek
    Abstract:

    Summary Background There is growing evidence for the ongoing structural and functional adaptation of the skin after birth. Objectives The aim of this study was the definition of scanning electron microscopy markers of skin maturation in different age groups (birth to adulthood). We propose a semiquantitative score to analyse the maturation of the skin surface and a complementary evaluation of the distribution of corneodesmosin and corneodesmosomes. Material and methods An electron microscopy isotropy (E.M.I.) score was performed in six age-groups to include fullterm neonates, babies, children and adults. The distribution of corneodesmosome remnants was analysed by corneodesmosin distribution with immunocytochemical corneocyte labelling. Results The E.M.I. score showed the highest anisotropy in neonates. The youngest groups displayed irregular and thick cell clusters composed of poorly individualized cells. In the older groups, the distribution of superficial Corneocytes was more regular. The cells evenly covered the surface and displayed easily visualized single cell outlines. The distribution of immune-labelled corneodesmosome remnants and the corneocyte projected area showed a correlation between age and structural maturation. The observed evolution indicated a poorly controlled process of corneocyte desquamation in infants and confirmed the relative immaturity of the epidermal barrier up to 1–2 years after birth under basal conditions. Conclusion Our study is the first attempt at semiquantitative evaluation of the micromorphology maturation of the epidermal surface at the ultrastructural level. The E.M.I. score and the associated pattern of corneodesmosome breakdown may be used as markers of the stratum corneum maturation.

  • Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation.
    The Journal of biological chemistry, 2001
    Co-Authors: Michel Simon, Nathalie Jonca, Marina Guerrin, Cécile Caubet, Marek Haftek, Rainer Schmidt, Dominique Bernard, Torbjörn Egelrud, Guy Serre
    Abstract:

    Corneodesmosin is a putative adhesion glycoprotein located in the extracellular part of the desmosomes in the upper layers of the epidermis. Synthesized by granular keratinocytes as a 52-56-kDa protein, corneodesmosin is progressively proteolysed during corneocyte maturation. This processing is a prerequisite for desquamation. Two glycine- and serine-rich domains of the protein might take on the conformation of adhesive secondary structures similar to glycine loops. Corneodesmosin proteolysis was further characterized. Deglycosylation experiments and reactivity with lectins demonstrated that the corneodesmosin carbohydrate moiety does not prevent the proteolysis. Immunoblotting, immunohistochemistry, and immunoelectron microscopy experiments using affinity-purified anti-peptide antibodies raised to four of the five structural domains of corneodesmosin and a monoclonal antibody against its fifth central domain showed that the first step in corneodesmosin processing is the cleavage of its extremities and probably occurs before its incorporation into desmosomes. Then the glycine loop-related domains are cleaved, first the N-terminal and then part of the C-terminal domain. At the epidermis surface, the multistep proteolytic cleavage leaves intact only the central domain, which was detected on exfoliated Corneocytes and probably lacks adhesive properties. Importantly, corneodesmosin was demonstrated to be a preferred substrate of two serine proteases involved in desquamation, the stratum corneum tryptic and chymotryptic enzymes.

  • identification of late differentiation antigens of human cornified epithelia expressed in re organized desmosomes and bound to cross linked envelope
    Journal of Investigative Dermatology, 1991
    Co-Authors: Guy Serre, Marek Haftek, Valerie Mils, Christian Vincent, Francoise Croute, A Reano, J P Ouhayoun, Stephane Bettinger, Jeanpierre Soleilhavoup
    Abstract:

    Little is known about the process leading to desquamation in cornified epithelia. We describe late differentiation antigens (Ag) specific for human cornified squamous epithelia, defined by two murine monoclonal antibodies (MoAb), G36-19 and B17-21, produced after immunization with plantar stratum corneum (SC). Histologically, in epidermis both Ag are cytoplasmic in the lower stratum granulosum (SG), become pericellular in the upper SG, and progressively disappear in the lower SC. In contrast, they persist up to the desquamating Corneocytes in the palmoplantar epidermis and hard palate epithelium as well as in the three cornified epithelial components of the inner root sheath (IRS) of the hair follicle (HF). Cytologically, both Ag are expressed as surface spots only on rough Corneocytes. They are largely preserved on cross-linked envelopes (CLE) of the fragile type. Ultrastructurally, both Ag appear in keratinosome-like cytoplasmic vesicles in the upper stratum spinosum (SS) and the SG keratinocytes, then are found in both the regular and reorganizing desmosomes of the SG keratinocytes, and lastly in the corneocyte- specific reorganized desmosome were propose to name corneodesmosomes. On CLE, the Ag are located on fibrils gathered over the external side of the envelope. Immunochemically, the G36-19–defined epitope is sequential and shared by five non-cytokeratin protein antigens of molecular weight 33.5, 36.5, 40, 49 and 52 kD, the higher molecular weight polypeptides being possibly precursors of the 33.5-kD protein. In contrast, the B17-21 epitope, unaccessible by immunoblotting, is probably conformational. In long-term cultured keratinocytes, the Ag are only expressed when epidermal sheets are morphologically differentiated. The expression is enhanced in the absence of fetal calf serum (FCS) and of epidermal growth factor (EGF). G36-19 and B17-21 Ag participate in a corneodesmosome-CLE superstructure that is probably involved in corneocyte cohesiveness and partly responsible for the mechanical resistance of the SC. These Ag are relevant markers for studying desmosomal maturation during epidermal differentiation and desquamation.

Majella E Lane - One of the best experts on this subject based on the ideXlab platform.

  • 12r lipoxygenase activity is reduced in photodamaged facial stratum corneum a novel activity assay indicates a key function in corneocyte maturation
    International Journal of Cosmetic Science, 2019
    Co-Authors: D Guneri, Rainer Voegeli, Majella E Lane, Madeleine R Munday, A.v. Rawlings
    Abstract:

    BACKGROUND: During the late stage of keratinocyte differentiation Corneocytes gain a strong protein-lipid structure: the corneocyte envelopes (CE), composed of the inner corneocyte protein envelope (CPE) and the outer corneocyte lipid envelope (CLE). The hydrophobicity of CEs depends on the covalent attachment of linoleoyl-acyl-ceramides by transglutaminases (TG). These ceramides are processed by a range of other enzymes, including 12R-lipoxygenase (12R-LOX), before the covalent attachment of the free ω-hydroxyceramides to the CPE surface to form the CLE. The mechanical strength of CE is obtained with the formation of isodipeptide bonds by transglutaminase. The increase in hydrophobicity and rigidity leads to CE maturation which supports the integrity and mechanical resistance of the stratum corneum (SC). OBJECTIVES: The aim of this work was to develop and validate a novel enzyme activity assay for 12R-LOX in tape strippings of photo-exposed (PE) cheek and photo-protected (PP) post auricular SC of healthy Chinese volunteers (n=12; age 25 ± 3 years). RESULTS: A fluorescence based assay was developed with ethyl linoleic acid as the substrate and a polyclonal antibody against 12R-LOX as an inhibitor. The specificity was shown by the lack of effect by a LOX inhibitor (ML351) and an epidermal-type lipoxygenase 3 (eLOX3) antibody on the acquired 12R-LOX activity. Reduced 12R-LOX activity was observed in the outer compared to the inner SC layers. Moreover, dramatically lower activity was shown in the PE vs PP samples. Furthermore, the enzyme activity has a positive correlation (r= 0.94 ± 0.03) with CE maturity, in particular hydrophobicity, and a negative correlation (r= -0.96 ± 0.01) with transepidermal water loss (TEWL). CONCLUSION: This novel enzyme assay revealed a lower 12R-LOX activity in tape strippings from PE cheek for the first time. This finding is in line with less mature CEs and higher TEWL compared to PP post auricular samples. This study indicates a strong link between 12R-LOX activity and CE maturation and SC integrity.

  • early life regional and temporal variation in filaggrin derived natural moisturizing factor filaggrin processing enzyme activity corneocyte phenotypes and plasmin activity implications for atopic dermatitis
    British Journal of Dermatology, 2018
    Co-Authors: Maeve A. Mcaleer, Ivone Jakasa, Rainer Voegeli, C P F Odonnell, Majella E Lane, Alan D Irvine, A.v. Rawlings, Sanja Kezic
    Abstract:

    Background: Filaggrin is central to the pathogenesis of atopic dermatitis (AD). The cheeks are a common initiation site of infantile AD. Regional and temporal expression of levels of filaggrin degradation products [natural moisturizing factors (NMFs)], activities of filaggrin‐processing enzymes [bleomycin hydrolase (BH) and calpain‐1 (C‐1)] and plasmin, and corneocyte envelope (CE) maturity in early life are largely unknown. / Objectives: We conducted a cross‐sectional, observational study investigating regional and age‐dependent variations in NMF levels, activity of proteases and CE maturity in stratum corneum (SC) from infants to determine whether these factors could explain the observed predilection sites for AD in early life. / Methods: We measured NMF using a tape‐stripping method at seven sites in the SC of 129 children (aged < 12 months to 72 months) and in three sites in 56 neonates and infants (< 48 h to 3 months). In 37 of these neonates and infants, corneocyte size, maturity, BH, C‐1 and plasmin activities were determined. / Results: NMF levels are low at birth and increase with age. Cheek SC, compared with elbow flexure and nasal tip, has the lowest NMF in the first year of life and is the slowest to reach stable levels. Cheek Corneocytes remain immature. Plasmin, BH and C‐1 activities are all elevated by 1 month of age in exposed cheek skin, but not in elbow skin. / Conclusions: Regional and temporal differences in NMF levels, CE maturity and protease activities may explain the predilection for AD to affect the cheeks initially and are supportive of this site as key for allergen priming in early childhood. These observations will help design early intervention and treatment strategies for AD.

  • a fundamental investigation into aspects of the physiology and biochemistry of the stratum corneum in subjects with sensitive skin
    International Journal of Cosmetic Science, 2017
    Co-Authors: N Raj, A.v. Rawlings, R Voegeli, S Dopple, Dominik Imfeld, M R Munday, Majella E Lane
    Abstract:

    BACKGROUND: Sensitive skin is a poorly understood skin condition. Defects in stratum corneum (SC) barrier function and/or extrasensory neuronal networks in the epidermis are believed to be involved in the problem. OBJECTIVES: This study aimed to unravel the relationships between bleomycin hydrolase (BH) and calpain-1 (C-1), pyrrolidone carboxylic acid (PCA) levels, corneocyte maturation, transglutaminase (TG) and plasmin activities on the cheeks of subjects with sensitive skin. METHODS: Forty-eight female Caucasian subjects, Fitzpatrick skin phototypes II-III, with self - perceived sensitive facial skin were assessed and underwent a capsaicin reactivity test. Expert grading of skin condition was conducted as well as measurement of transepidermal water loss (TEWL), skin capacitance, SC cohesion and SC integrity. BH, C-1 and plasmin activities were measured as well as PCA levels, plasmin and TG activity. Differential Nile red and involucrin immunostaining was performed to assess corneocyte maturation and size. RESULTS: 52% of the subjects reacted to capsaicin. There were no significant differences between the capsaicin-sensitive and non-capsaicin-sensitive subjects with reference to skin grading, TEWL, skin capacitance and SC cohesion. PCA levels and BH activity were lowest in the capsaicin-sensitive panel (p<0.05) and were correlated in non-capsaicin-sensitive subjects (r = 0.72). The activity of TG was significantly lower (48%) in the capsaicin-sensitive subjects (p<0.001) and their Corneocytes were less mature and smaller (p ≤ 0.03). SC was estimated to be thinner (6.87 ± 0.28 vs. 8.68 ± 0.26 μm; p=0.001) in the capsaicin-sensitive subjects with a corresponding shorter SC path length (83.2± 4.4 μm and. 113.1 ± 4.5 μm; p=0.001). CONCLUSIONS: Despite the physiological similarities between the two groups of sensitive skin subjects, differences in their biochemistry were clearly evident. Lower levels of PCA, BH and TG activities together with a greater number of smaller and immature Corneocytes indicate inferior SC maturation in the capsaicin-sensitive subjects. The reduced maturation of Corneocytes and thinner SC likely contributes to a greater penetration of capsaicin and the associated increased skin sensitivity.

  • variation in the activities of late stage filaggrin processing enzymes calpain 1 and bleomycin hydrolase together with pyrrolidone carboxylic acid levels corneocyte phenotypes and plasmin activities in non sun exposed and sun exposed facial stratum c
    International Journal of Cosmetic Science, 2016
    Co-Authors: Rainer Voegeli, B Summers, Madeleine R Munday, A.v. Rawlings, Majella E Lane
    Abstract:

    BACKGROUND: Knowledge of the ethnic differences and effects of photodamage on the relative amounts of natural moisturizing factor (NMF) together with filaggrin processing enzymes in facial stratum corneum is limited. Our aim was to characterize the activities of calpain-1 (C-1), bleomycin hydrolase (BH) and the levels of pyrrolidone carboxylic acid (PCA) as a marker for total NMF levels and to relate them to plasmin activities and corneocyte maturation. METHODS: Enzyme activities, PCA levels and corneocyte maturation were determined from facial tape strippings of photoexposed cheek and photoprotected post-auricular areas (PA) of healthy Caucasian (C), Black African (BA) and albino African (AA) female subjects living in South Africa. RESULTS: PCA concentration levels were of the order AA > BA > C subjects, and the highest activities of BH were present in the AA subjects. BH activities were greater on the photoexposed sites for the BA and C subjects, but they were only numerically elevated in the AA subjects. Photoprotected sites had an increase in C-1 activity in pigmented groups (C and BA), whereas in the AA subjects, the opposite was measured. Plasmin activities were greater on the cheek compared with the PA site for the AA and C subjects, but the activity was low in the BA subjects. In both test sites, the AA, but not the BA and C subjects, had smaller, parakeratotic and less mature Corneocytes. CONCLUSION: Variation in PCA levels has been found for different ethnic groups in this study (AA > BA > C subjects). The values in the AA subjects are surprising as one might expect that the lack of pigmentation, and thereby increased photodamage, might lead to lower levels. Increased BH, but not C-1 activity, was observed in the AA subjects indicating that BH is associated with PCA production to a greater extent. Surprisingly, corneocyte maturation is still impaired with elevated PCA levels in AA subjects. The higher levels of plasmin and BH activities on the cheeks, especially for AA and C subjects, suggest that they can be used as markers for epidermal photodamage.

  • the relationship between transepidermal water loss and skin permeability
    International Journal of Pharmaceutics, 2010
    Co-Authors: Marta Machado, Teresa M. Salgado, Majella E Lane
    Abstract:

    Transepidermal water loss (TEWL) is a measure of the steady-state water vapour flux crossing the skin to the external environment and it has been used extensively to characterise skin barrier function. We have previously hypothesised that in vivo TEWL is directly related to the reciprocal of the diffusional permeation pathlength through the stratum corneum (SC). The aim of the present paper is to validate experimentally this hypothesis. Ninety volunteers were recruited and TEWL and corneocyte surface areas were measured for six anatomic sites. The number of cell layers in the SC was calculated for each anatomic site in order to estimate the geometric pathlength for water efflux. Significant anatomic site variability was found for both TEWL and corneocyte surface area which were inversely correlated. A direct reciprocal relationship between TEWL and pathlength was determined, with TEWL values tending to zero when Corneocytes are infinitely large. In general, skin sites with smaller Corneocytes have fewer cell layers, with shorter permeation pathlengths and higher TEWL values. The results confirm our previous hypothesis and suggest that TEWL may be used to characterise the permeation routes for different anatomic sites.

Sanja Kezic - One of the best experts on this subject based on the ideXlab platform.

  • Adhesion of Staphylococcus aureus to Corneocytes from Atopic Dermatitis Patients Is Controlled by Natural Moisturizing Factor Levels.
    Mbio, 2018
    Co-Authors: Cecile Feuillie, Maeve A. Mcaleer, Alan D Irvine, Pauline Vitry, Joan A Geoghegan, Sanja Kezic, Yves F. Dufrêne
    Abstract:

    ABSTRACT The bacterial pathogen Staphylococcus aureus plays an important role in atopic dermatitis (AD), a chronic disorder that mostly affects children. Colonization of the skin of AD patients by S. aureus exacerbates the disease, but the molecular determinants of the bacterium-skin adhesive interactions are poorly understood. Specifically, reduced levels of natural moisturizing factor (NMF) in the stratum corneum have been shown to be associated with more severe AD symptoms, but whether this is directly related to S. aureus adhesion is still an open question. Here, we demonstrate a novel relationship between NMF expression in AD skin and strength of bacterial adhesion. Low-NMF Corneocytes, unlike high-NMF ones, are covered by a dense layer of nanoscale villus protrusions. S. aureus bacteria isolated from AD skin bind much more strongly to Corneocytes when the NMF level is reduced. Strong binding forces originate from a specific interaction between the bacterial adhesion clumping factor B (ClfB) and skin ligands. Remarkably, mechanical tension dramatically strengthens ClfB-mediated adhesion, as observed with catch bonds, demonstrating that physical stress plays a role in promoting colonization of AD skin by S. aureus. Collectively, our findings demonstrate that patient NMF levels regulate the strength of S. aureus-corneocyte adhesion, the first step in skin colonization, and suggest that the ClfB binding mechanism could represent a potential target for new therapeutic treatments. IMPORTANCE Bacterium-skin interactions play important roles in skin disorders, yet their molecular details are poorly understood. In this study, we decipher the molecular forces at play during adhesion of Staphylococcus aureus to skin Corneocytes in the clinically important context of atopic dermatitis (AD), also known as eczema. We identify a unique relationship between the level of natural moisturizing factor (NMF) in the skin and the strength of bacterium-corneocyte adhesion. Bacterial adhesion is primarily mediated by the surface protein clumping factor B (ClfB) and is enhanced by physical stress, highlighting the role of protein mechanobiology in skin colonization. Similar to a catch bond behavior, this mechanism represents a promising target for the development of novel antistaphylococcal agents.

  • early life regional and temporal variation in filaggrin derived natural moisturizing factor filaggrin processing enzyme activity corneocyte phenotypes and plasmin activity implications for atopic dermatitis
    British Journal of Dermatology, 2018
    Co-Authors: Maeve A. Mcaleer, Ivone Jakasa, Rainer Voegeli, C P F Odonnell, Majella E Lane, Alan D Irvine, A.v. Rawlings, Sanja Kezic
    Abstract:

    Background: Filaggrin is central to the pathogenesis of atopic dermatitis (AD). The cheeks are a common initiation site of infantile AD. Regional and temporal expression of levels of filaggrin degradation products [natural moisturizing factors (NMFs)], activities of filaggrin‐processing enzymes [bleomycin hydrolase (BH) and calpain‐1 (C‐1)] and plasmin, and corneocyte envelope (CE) maturity in early life are largely unknown. / Objectives: We conducted a cross‐sectional, observational study investigating regional and age‐dependent variations in NMF levels, activity of proteases and CE maturity in stratum corneum (SC) from infants to determine whether these factors could explain the observed predilection sites for AD in early life. / Methods: We measured NMF using a tape‐stripping method at seven sites in the SC of 129 children (aged < 12 months to 72 months) and in three sites in 56 neonates and infants (< 48 h to 3 months). In 37 of these neonates and infants, corneocyte size, maturity, BH, C‐1 and plasmin activities were determined. / Results: NMF levels are low at birth and increase with age. Cheek SC, compared with elbow flexure and nasal tip, has the lowest NMF in the first year of life and is the slowest to reach stable levels. Cheek Corneocytes remain immature. Plasmin, BH and C‐1 activities are all elevated by 1 month of age in exposed cheek skin, but not in elbow skin. / Conclusions: Regional and temporal differences in NMF levels, CE maturity and protease activities may explain the predilection for AD to affect the cheeks initially and are supportive of this site as key for allergen priming in early childhood. These observations will help design early intervention and treatment strategies for AD.

  • Adhesion of Staphylococcus aureus to Corneocytes from Atopic Dermatitis Patients Is Controlled by Natural Moisturizing Factor Levels
    American Society for Microbiology, 2018
    Co-Authors: Cecile Feuillie, Maeve A. Mcaleer, Alan D Irvine, Pauline Vitry, Joan A Geoghegan, Sanja Kezic, Yves F. Dufrêne
    Abstract:

    The bacterial pathogen Staphylococcus aureus plays an important role in atopic dermatitis (AD), a chronic disorder that mostly affects children. Colonization of the skin of AD patients by S. aureus exacerbates the disease, but the molecular determinants of the bacterium-skin adhesive interactions are poorly understood. Specifically, reduced levels of natural moisturizing factor (NMF) in the stratum corneum have been shown to be associated with more severe AD symptoms, but whether this is directly related to S. aureus adhesion is still an open question. Here, we demonstrate a novel relationship between NMF expression in AD skin and strength of bacterial adhesion. Low-NMF Corneocytes, unlike high-NMF ones, are covered by a dense layer of nanoscale villus protrusions. S. aureus bacteria isolated from AD skin bind much more strongly to Corneocytes when the NMF level is reduced. Strong binding forces originate from a specific interaction between the bacterial adhesion clumping factor B (ClfB) and skin ligands. Remarkably, mechanical tension dramatically strengthens ClfB-mediated adhesion, as observed with catch bonds, demonstrating that physical stress plays a role in promoting colonization of AD skin by S. aureus. Collectively, our findings demonstrate that patient NMF levels regulate the strength of S. aureus-corneocyte adhesion, the first step in skin colonization, and suggest that the ClfB binding mechanism could represent a potential target for new therapeutic treatments.Bacterium-skin interactions play important roles in skin disorders, yet their molecular details are poorly understood. In this study, we decipher the molecular forces at play during adhesion of Staphylococcus aureus to skin Corneocytes in the clinically important context of atopic dermatitis (AD), also known as eczema. We identify a unique relationship between the level of natural moisturizing factor (NMF) in the skin and the strength of bacterium-corneocyte adhesion. Bacterial adhesion is primarily mediated by the surface protein clumping factor B (ClfB) and is enhanced by physical stress, highlighting the role of protein mechanobiology in skin colonization. Similar to a catch bond behavior, this mechanism represents a promising target for the development of novel antistaphylococcal agents

  • clumping factor b promotes adherence of staphylococcus aureus to Corneocytes in atopic dermatitis
    Infection and Immunity, 2017
    Co-Authors: O M Fleury, W Irwin H Mclean, Maeve A. Mcaleer, Cecile Feuillie, Cecile Formosadague, Emily A Sansevere, Desiree Bennett, Aisling M Towell, Sanja Kezic
    Abstract:

    Staphylococcus aureus skin infection is a frequent and recurrent problem in children with the common inflammatory skin disease atopic dermatitis (AD). S. aureus colonizes the skin of the majority of children with AD and exacerbates the disease. The first step during colonization and infection is bacterial adhesion to the cornified envelope of Corneocytes in the outer layer, the stratum corneum. Corneocytes from AD skin are structurally different from Corneocytes from normal healthy skin. The objective of this study was to identify bacterial proteins that promote the adherence of S. aureus to AD Corneocytes. S. aureus strains from clonal complexes 1 and 8 were more frequently isolated from infected AD skin than from the nasal cavity of healthy children. AD strains had increased ClfB ligand binding activity compared to normal nasal carriage strains. Adherence of single S. aureus bacteria to Corneocytes from AD patients ex vivo was studied using atomic force microscopy. Bacteria expressing ClfB recognized ligands distributed over the entire corneocyte surface. The ability of an isogenic ClfB-deficient mutant to adhere to AD Corneocytes compared to that of its parent clonal complex 1 clinical strain was greatly reduced. ClfB from clonal complex 1 strains had a slightly higher binding affinity for its ligand than ClfB from strains from other clonal complexes. Our results provide new insights into the first step in the establishment of S. aureus colonization in AD patients. ClfB is a key adhesion molecule for the interaction of S. aureus with AD Corneocytes and represents a target for intervention.

  • Nanoscale alterations of Corneocytes indicate skin disease.
    Skin Research and Technology, 2015
    Co-Authors: Jonas Franz, K. Gevers, A. Krämer, Markus Beutel, Jacob P. Thyssen, Sanja Kezic, Christoph Riethmuller
    Abstract:

    Background The skin barrier protects the organism against exogenous stressors and simultaneously prevents excessive water loss. While the delicate regulation of skin barrier is not completely understood, morphological and histological evaluation remain key features of clinical investigations. Here, we extended the phenotypic perspective down to the nanoscale. Methods Corneocyte samples were obtained non-invasively by a standard tape stripping procedure from 21 indviduals. Scanning electron (SEM) and atomic force microcopy (AFM) were used to record nanoscale topography. Circular nano-objects were identified and these were quantitated through computer vision. Results Typical dimensions of 273 nm height and 305 nm width. We showed that their density does not correlate to age or pigmentation in healthy subjects, but that they were clearly elevated in Corneocytes from patients with atopic dermatitis, a common inflammatory skin condition. Conclusion The presence of these corneocyte-nanostructures might be used as a diagnostic parameter for skin disorders - even in cases below a clinical threshold.