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New findings in intra-epithelial blistering diseases
Socie1.v nreeting
SM6. InlnrlrrrodernlatoloEy
actions with cellular receptors of the integrin family and (ii) it also serves as a major structural element by establishing and maintaining biochemical connections with other components of the basement membrane such as laminin 6. collagen VII and probably collagen XVII (BP180). Recent advances and current studies are dedicated to the identification and characterization of the several interactive domains of laminin 5 at the molecular and structural levels. IIISM~ 3 Cell-cell adhesion molecules John A. McGrath. Departntertt of Ceil aad Molecular patltology, Hospital,
St. John s Iastitute London, UK
of Dermatology,
St Thomas’s
Successful adhesion between adjacent keratinocytes is of fundamental importance in the maintenance of the epidermis as a physical barrier against the environment. The main contact points between epitbelial cells are desmosomes and adherens junctions. Desmosomes. which form circular domains 0.1-0.5 pm in diameter at the plasma membrane, comprise the transmembranous desmosomal cadherins (different combinations of desmogleins 1-3 and desmocollins l-3). and the intracellular proteins plakoglobin and desmoplakins. In stratified epitheha, including epidermis, additional cytoplasmic desmosomal plaque proteins may be present including plakophilin I, desmocalmin. pinin, plectin and IFAP300. Adherens junctions are composed of classical cadherins (E-, N-, or P-cadherin) along with plakoglobin, (Y- and B-catenin, vinculin and cu-actinin. Not only do these epithelial junctions adhere cell to cell, but they also link the cell intermediate filament network to the plasma membrane. In addition, several of the integral proteins and glycoproteins have signalling functions, providing a role in cell communication as well as mechanical adhesion. Studies of patients with autoimmune blistering skin diseases, transgenie mouse models and patients with rare genodermatoses are all helping to determine the contributions of these macromolecules to the integrity and stability of the epidermis and to an improved understanding of epithelial cell biology. Such fundamental knowledge will be helpful in the refinement of diagnostic techniques and in the design of newer forms of therapy. SM6-4
New findings diseases
I’. Jdy. Groape H6pital Charles
in intra-epithelial
s121
Group
function of Dsg3, has been recently confirmed in DSG3-KO mites. In vitro, the binding of anti-DSG3 antibodies caused a phosphorylation of DSG3, leading to the dissociation of cultured keratinocytes. The role of the cellular immune response in the pathogenesis of PV is now suggested by the demonstration of DSG3-specific and HLA-DQB restricted T-cell clones. The usefulness of the first use of adjuvant therapies, especially azathioprine and cyclophosphamide in the treatment of pemphigus patients is not clearly demonstrated. The ability of low doses of methotrexate to permit withdrawal of systemic corticosteroids has been recently suggested. The depletion of anti-DSG3 antibodies using recombinant proteins and the targeting of DSG3 specific B-cells by DSG3-toxin chimeras will perhaps permit a specific immunosuppression in the future. SM6-6
Subepidermal auto-immune blistering diseases and newly identified antigens
Reza F. Ghohestani. Deparrrnent Lyon.
of Dermatology
skin
& INSERM,
France
Many components of epithelial basement membrane zone have been identified as the target antigen in sub-epidermal autoimmune blistering skin diseases (SABD). These findings lead to suggest a new classification for SABD on the basis of involved antigens. Accordingly, the inflammatory type’of epidermolysis bullosa acquisita or anti-type IV collagen bullous dermatosis could be distinguished from bullous pemphigoid (BP) by identification of the target antigens. However, in the pemphigoid group including: BP, pemphigoid gestationis (PG), cicatricial pemphigoid (CP), the same target antigen could be found in patients having different clinical entities i.e. BP180 in BP, PG and CP Alternatively distinct components of BMZ could be served as the target for the same clinical phenotype i.e. laminin-5, BP1 80 and Ml68 in CP. The class of immunoglobulinmay also play a key role in determining the clinical feature of disease as we have shown that BP antigens could be the target of IgG or IgA auto-antibodies leading to BP or linear IgA dermatosis. Collectively, these data are against the hypothesis of “a target antigen - a disease” in SABD. The classification of SABD should not be only based on the type of target antigen; the clinical feature of disease, the histopathology, and the type of auto-antibody should be also taken into account.
blistering
de Rechemhe en Ittrmtolo-Patltolo~ie-IFR Nicolles, Roaea, Frmce
SM6-7 23,
The main advances in diagnosis, pathogenesis and treatment of the different types of pemphigus will be reviewed. The relationship between PNP and PV have been clarified: 50% of PNP patients have only oral lesions at initial presentation, indistinguishable from those of PV patients. Moreover, anti-Dsg3 antibodies can be consistently detected in PNP sera, and their pathogenic properties has been clearly demonstrated. Other target antigens in PNP are desmoplakins, BPAG 1, envoplakin and Periplakin which correspond to plakins, a family of desmosomal Plaque proteins. The development of ELISA techniques using recombinant baculovirus-expressed DSG3 will allow to the routine detection of anti-DSG3 antibodies in PV. The adhesive
BP1 80 as the autoantigen in blistering diseases with different clinical phenotypes
D. Zillikens. Deparment Wiirz,burg,
Germany
of Dermatology,
University
of
L
BP180 (BPAg2, collagen XVII) is a transmembrane hemidesmosomal glycoprotein that spans the lamina lucida of the basement membrane zone (BMZ). Five autoimmune subepidermal blistering diseases are associated with an immune response to the ectodomain of BP180: bullous pempbigoid (BP), pemphigoid gestationis (PG), cicatricial pemphigoid (CP), lichen planus pemphigoides (LPP), and linear IgA disease (LAD). The BP180 ectodomain consist of 15 intapted collagen domains. The largest non-collagenous (NC) 16A domain is located right next to the cell membrane. In BP, autoantibodies are directed to a tightly clustered set of epitop& located
SM6. InlnrlrrrodernlatoloEy
actions with cellular receptors of the integrin family and (ii) it also serves as a major structural element by establishing and maintaining biochemical connections with other components of the basement membrane such as laminin 6. collagen VII and probably collagen XVII (BP180). Recent advances and current studies are dedicated to the identification and characterization of the several interactive domains of laminin 5 at the molecular and structural levels. IIISM~ 3 Cell-cell adhesion molecules John A. McGrath. Departntertt of Ceil aad Molecular patltology, Hospital,
St. John s Iastitute London, UK
of Dermatology,
St Thomas’s
Successful adhesion between adjacent keratinocytes is of fundamental importance in the maintenance of the epidermis as a physical barrier against the environment. The main contact points between epitbelial cells are desmosomes and adherens junctions. Desmosomes. which form circular domains 0.1-0.5 pm in diameter at the plasma membrane, comprise the transmembranous desmosomal cadherins (different combinations of desmogleins 1-3 and desmocollins l-3). and the intracellular proteins plakoglobin and desmoplakins. In stratified epitheha, including epidermis, additional cytoplasmic desmosomal plaque proteins may be present including plakophilin I, desmocalmin. pinin, plectin and IFAP300. Adherens junctions are composed of classical cadherins (E-, N-, or P-cadherin) along with plakoglobin, (Y- and B-catenin, vinculin and cu-actinin. Not only do these epithelial junctions adhere cell to cell, but they also link the cell intermediate filament network to the plasma membrane. In addition, several of the integral proteins and glycoproteins have signalling functions, providing a role in cell communication as well as mechanical adhesion. Studies of patients with autoimmune blistering skin diseases, transgenie mouse models and patients with rare genodermatoses are all helping to determine the contributions of these macromolecules to the integrity and stability of the epidermis and to an improved understanding of epithelial cell biology. Such fundamental knowledge will be helpful in the refinement of diagnostic techniques and in the design of newer forms of therapy. SM6-4
New findings diseases
I’. Jdy. Groape H6pital Charles
in intra-epithelial
s121
Group
function of Dsg3, has been recently confirmed in DSG3-KO mites. In vitro, the binding of anti-DSG3 antibodies caused a phosphorylation of DSG3, leading to the dissociation of cultured keratinocytes. The role of the cellular immune response in the pathogenesis of PV is now suggested by the demonstration of DSG3-specific and HLA-DQB restricted T-cell clones. The usefulness of the first use of adjuvant therapies, especially azathioprine and cyclophosphamide in the treatment of pemphigus patients is not clearly demonstrated. The ability of low doses of methotrexate to permit withdrawal of systemic corticosteroids has been recently suggested. The depletion of anti-DSG3 antibodies using recombinant proteins and the targeting of DSG3 specific B-cells by DSG3-toxin chimeras will perhaps permit a specific immunosuppression in the future. SM6-6
Subepidermal auto-immune blistering diseases and newly identified antigens
Reza F. Ghohestani. Deparrrnent Lyon.
of Dermatology
skin
& INSERM,
France
Many components of epithelial basement membrane zone have been identified as the target antigen in sub-epidermal autoimmune blistering skin diseases (SABD). These findings lead to suggest a new classification for SABD on the basis of involved antigens. Accordingly, the inflammatory type’of epidermolysis bullosa acquisita or anti-type IV collagen bullous dermatosis could be distinguished from bullous pemphigoid (BP) by identification of the target antigens. However, in the pemphigoid group including: BP, pemphigoid gestationis (PG), cicatricial pemphigoid (CP), the same target antigen could be found in patients having different clinical entities i.e. BP180 in BP, PG and CP Alternatively distinct components of BMZ could be served as the target for the same clinical phenotype i.e. laminin-5, BP1 80 and Ml68 in CP. The class of immunoglobulinmay also play a key role in determining the clinical feature of disease as we have shown that BP antigens could be the target of IgG or IgA auto-antibodies leading to BP or linear IgA dermatosis. Collectively, these data are against the hypothesis of “a target antigen - a disease” in SABD. The classification of SABD should not be only based on the type of target antigen; the clinical feature of disease, the histopathology, and the type of auto-antibody should be also taken into account.
blistering
de Rechemhe en Ittrmtolo-Patltolo~ie-IFR Nicolles, Roaea, Frmce
SM6-7 23,
The main advances in diagnosis, pathogenesis and treatment of the different types of pemphigus will be reviewed. The relationship between PNP and PV have been clarified: 50% of PNP patients have only oral lesions at initial presentation, indistinguishable from those of PV patients. Moreover, anti-Dsg3 antibodies can be consistently detected in PNP sera, and their pathogenic properties has been clearly demonstrated. Other target antigens in PNP are desmoplakins, BPAG 1, envoplakin and Periplakin which correspond to plakins, a family of desmosomal Plaque proteins. The development of ELISA techniques using recombinant baculovirus-expressed DSG3 will allow to the routine detection of anti-DSG3 antibodies in PV. The adhesive
BP1 80 as the autoantigen in blistering diseases with different clinical phenotypes
D. Zillikens. Deparment Wiirz,burg,
Germany
of Dermatology,
University
of
L
BP180 (BPAg2, collagen XVII) is a transmembrane hemidesmosomal glycoprotein that spans the lamina lucida of the basement membrane zone (BMZ). Five autoimmune subepidermal blistering diseases are associated with an immune response to the ectodomain of BP180: bullous pempbigoid (BP), pemphigoid gestationis (PG), cicatricial pemphigoid (CP), lichen planus pemphigoides (LPP), and linear IgA disease (LAD). The BP180 ectodomain consist of 15 intapted collagen domains. The largest non-collagenous (NC) 16A domain is located right next to the cell membrane. In BP, autoantibodies are directed to a tightly clustered set of epitop& located