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Dermo epidermal junction

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  • 1. D ermo – E pidermal J unction Presented by Adel A. Al-Ghamdi Dermatology Department King Fahd Hospital of university
  • 2.
    • Introduction
      • Origin of basement membrane
      • Function of basement membrane
    • Ultrastructure of DEJ
    • Ubiquitous components of basement membrane
    • epithelial-specific basement membrane components
    • Scope in some diseases affecting DEJ
  • 3. Introduction
  • 4.
    • It is a highly complex form of basement membrane which underlie epithelial & endothelial cells which separate them from each other or from the adjacent connective tissue stroma.
    • It is considered as one of the largest epithelial-mesenchymal junction on the body.
    • It forms an extensive interface between the dermis & epidermis.
    • It is continuous with the junction between dermis & epidermal appendages.
  • 5.
    • As all basement membranes, it stains strongly for carbohydrates & anionic sites
            • Periodic acid shifft stain (PAS)
    • The complexity & heterogeneity of DEJ can be appreciated only at electron microscopic level
  • 6. Origin of Basement Membrane
    • Serial studies strongly suggest that all types of basement membranes are not produced by a single cell type, but rather it is contributed to by both epithelial & mesenchymal cells.
      • Laminine 5 & 6 epidermal compartment
      • Nidogen mesenchymal compartment
      • Type IV collagen & other laminines produced by both compartment
  • 7. Functions of basement membrane
    • Substrates for the attachment of differentiated cells
    • Templates for repair and restoration of tissue functions.
    • Sites of attachment for different cell layers or for cells to their underlying matrix.
    • Substrates for the programmed migration and selective interactions of germ layers in development.
    • Barriers to cell passage in normal tissues.
    • Protection of attached cell types from apoptosis.
    • The anchoring complex within the epithelial basement membrane is responsible for the stability of epithelial-stromal attachment.
  • 8. Ultrastructure of DEJ
  • 9. WWW.SMSO.NET
  • 10. Ultrastructure of DEJ
    • Each of these zones contains structures that are distinctive by ultrastructure, biochemical & immunological criteria.
    • Size of these regions varies in different tissue types, at different ages & as consequence of several disease states.
    DEJ 1 ST ZONE 2 ND ZONE 3 RD ZONE Sub basal lamina Lamina densa Tonofilement, Hemidesmosomes Anchoring filement complexs
  • 11. First zone
    • Tonofilament – Hemidesmosome- Anchoring filaments Complex.
    • It is the site of attachment of the epithelium to the basement membrane.
    • Tonofilaments
      • Also called keratin intermediate filaments, it is comprising keratin 5&14.
      • It is a fine filamentous structures maintain the intracellular architecture & organization of basal cells.
      • They course through the basal cells & inserted into the desmosome & hemidesmosome.
  • 12.
    • Hemidesmosome
      • Numerous electron- dense plated located in the region of the plasma membrane of the basal cells.
    • Lamina Lucida
      • External to the plasma membrane
      • 25- 50 nm in width.
      • Contains the anchoring filaments
  • 13. Second zone
    • Lamina densa
      • Appears as an electron- dense amorphous structure.
      • 20-50 nm in width below it the dermal epidermal basal lamina.
      • At high magnification, it has a granular fibrous appearance.
      • Account for 40 -65% of total basement membrane proteins.
      • Major proteins component is type IV collagen where it appears as a filament of variable thickness which is morphologically distinct from the collagen fibers in the subjacent dermis.
  • 14.
      • The basement membrane heparin sulfate proteoglycan appears as sets of two parallel lines of the surface of the collage cords.
      • Laminin also associated with the cords, appearing as a fine wavy lines.
  • 15. Third zone ( the sub basal lamina)
    • It contains several microfibrillar structures in which 3 of them can be distinguished.
    • Anchoring fibrils
      • It appears as condensed fibrous aggregates 20 - 75 nm in diameter ( not found in the basement membrane of blood vessels ,smooth muscles).
      • At high resolution, these structures appear to have a nonperiodic cross-striated banding pattern (positively stained of collagen).
  • 16.
      • The anchoring fibrils are primarily aggregates of type VII collagen.
      • The proximal end inserts into the basal lamina, & the distal end is integrated into the fibrous network of the dermis.
      • Many of the anchoring fibrils inserted their distal ends into electron-dense amorphous-appearing structures completely independent of lamina densa, known anchoring plaques . ( type IV collagen primarily )
  • 17.
    • The other 2 types of tubular microfibrils where on the bases of classic histochemical staining procedures, these have been identified as elastic – related fibrils .
      • The microfibrillar component in the absence of amorphous component known as Oxytalan fibers.
      • The microfibrillar component in the presence of small amounts of amorphous component known as Elaunin fibers, and in the presence of abundant amorphous component known as Elastic fibers.
  • 18.
      • In the papillary dermis, oxytalan fibers insert into the basal lamina perpendicular to the basement membrane & extend into the dermis, where they merge with elaunin fibers to form a plexus parallel to the axis of DEJ, where they appear to be continuous with elastic fibers present deep within the reticular dermis.
      • From this distribution of this structure, we can appreciate that DEJ provides a continuous series of attachment among the major connecting tissue component of the reticular dermis & internal cytoskeletons of the basal cells.
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  • 20. Ubiquitous Components of Basement Membrane Type IV collage Laminin Nidogen/Entactin Heparan sulfate proteoglycan
  • 21. Type IV Collagen
    • Immunolocalized mainly to L.D. & also found in anchoring plaque.
    • It has a structure closely related to the intracellular or procollagen form, typical of all members of the collagen protein family.
    • All procollagens contain 3 subunit peptides, termed alpha chains.
    • Several collagens are homopolymers of 3 identical chains ( i.e. type II, III,VII) , although some are hetropolymers containing 2 identical chains & one dissimilar alpha chain. ( i.e. type I, IV,V)
  • 22.
    • The largest portion of all procollagen molecules is composed of a characteristic triple-helical domain.
    • The stability of this structural domain depend upon:-
    • The presence of the amino acid glycine in every 3 rd position of the amino acid sequence of each chain.
    • A high content of the amino acid proline.
    • Post translational hydroxylation of specific proline residues to hydroxyproline.
  • 23.
    • In the content that these criteria are met, the resulting triple-helix structural domain are:-
      • Resistant to non-collagen-specific protease digestion.
      • Has extended, semirigid conformation.
    • Type IV collagen contain both triple-helical & globular domain.
    • The amino terminus of type IV procollagen (NC-I) is globular, similar to the analogous structure of other procollagens.
  • 24.
    • The carboxyl-terminal domain appears to contain a short globular region ( NC-2) preceded by a relatively large second triple helical domain.
    • The triple helical nature of the amino terminus of type IV collagen is unique & has been designated as the 7-S domain.
    • Covalent interactions among 7-S domain of the type IV collagen are the basis for the specialized fiber form characteristic of basement membrane.
    • The major triple helix of type IV collagen measures 330 nm, which is longer than other types of collagens ( types I,II,III,V = 300nm).
  • 25.
    • It is not helical throughout its length but contains several specific sites at which glycin is not present in every 3 rd position.
    • These minor discontinuities in the triple-helical structure result in increased flexibility in the type IV collagen helix & increased its resistance to a variety of proteases.
  • 26.  
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  • 29. Laminin
    • Immunolocalized to L.D.
    • It is a member of glycoprotein family with semirigid & extended structures.
    • It is hetrotrimetric molecule, where each laminin isoform consisting of
      • alpha chain.
      • Beta chain.
      • Gamma chain.
  • 30.
    • At least 7 different laminin isoforms identified but laminins 1, 5, 6,& 7 are known to occur in DEJ which immunolocalized mainly to L.D.
    • By using rotary shadowing technique to allow the electron microscope to visualize the laminin molecule which appear to have an asymmetric cross-like structure ( 1 long arm & 3 short arms).
    • The long arm is approximately 125 nm in length & the short arms are variable, but the largest measures approximately 80 nm.
  • 31.
    • The laminin molecule is divided into:-
      • Globular
      • Rodlike section
    • The 4 extremities of the crosslike structure contain globular domains,& the 3 short arms contain extra domain, approximately 20 nm from their free end.
    • The globular & rodlike domains of laminin have been individually implicated in various functions including
      • Cell attachment & spreading.
      • Aggregation with itself & with other component of the L.D. specially type IV collagen.
      • Neurite outgrowth.
      • Cellular differentiation.
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  • 33. Nidogen / Entactin
    • It is a glycoprotein with dumbbell configuration.
    • It is attached to one of the short arms of laminin at the gamma 1 chain forming a stable complex.
    • Nidogen alone as well as laminin- nidogen complex specifically bind to type IV collagen.
    • Nidogen is localized to the L.D. of basement membrane & along the adjacent cell surface of epithelial cell.
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  • 35. Heparan sulfate proteoglycan
    • HSPG molecules accumulate at cell-matrix interfaces.
    • It consists of a core protein of various length with different numbers of covalently associated heparan sulfate chains.
    • High sulfate content makes this molecule with highly negative charge & hydrophilic.
    • It swell with hydration & have a major role in determining which proteins or ions can transverse the lamina lucida & access the epidermal intracellular spaces .
  • 36. Epithelial-Specific Basement membrane Components Hemidesmosome Anchoring filaments Epithelial lamina densa Anchoring fibrils & anchoring plaques
  • 37. Hemidesmosome (HD)
    • It is closely resembles ½ of the desmosome seen in cell – cell junction but based on chemical criteria, these 2 structures appear to be immunologically distinctive.
    • Characteristics of HD proteins has been aided by the use of auto-antibodies presented in serum samples of patients with bullous pemphigoid.
    • As result of this, the antigens recognized by these sera identified proteins ranging in mass from 165- 240 kDa.
  • 38.
    • However, there is fair agreement that;-
      • 230/240-kDa protein the major antigens recognized
      • 180-kDa protein by these antibodies
      • 16-kDa protein
    • These proteins are immunologically & structurally distinct.
    • Monoclonal antibodies have been constructed to both intracellular & extracellular regions of HD.
  • 39.
    • These monoclonal antibodies identified 3 distinctive proteins
      • 240-kDa protein
      • 180-kDa protein
      • 125-kDa protein
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  • 41. Major Hemidesmosomal Antigens 240-kDa protein BPAG1 180-kDA protein BPAG2 Plectin Integrin alpha6 beta4
  • 42. BPAG1
    • It is a homodimer with homology to desmosomal desmoplakin.
    • It is generally believed that it is the major component of the HD inner dense plaque.
    • Mutation in BPAG1 EBS
  • 43. BPAG2
    • It is an unusual trans-membrane collagen domain.
    • It is also called type XVII collagen.
    • Its collagenous domain is extra-cellular & its function still unknown.
    • Mutation in BPAG2 GABEB
  • 44. Plectin
    • Previously called HD-1 antigen.
    • It is another dimeric desoplakin homologue.
    • Its tissue distribution is not limited to DEJ.
    • Mutation causing loss of plectin EBS like blisters
    • +PMD
  • 45. Integrin alpha6 beta4
    • They are large class of trans-membrane extra-cellular matrix binding proteins that provide cell attachment & subsequent signal transduction.
    • It has a selective high affinity for laminin 5 & therefore is essential to integration of HD with underlying basement membrane & stroma.
    • Mutation in either alpha6 or beta4 chains
    • less sever JEB
  • 46. Anchoring filaments
    • Series of filaments transversing the lamina lucida from the epidermal basal cells &insert into the lamina densa.
    • Several antigens now appear to be anchoring filament proteins.
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  • 48. Major Anchoring filament Antigens Laminin 5 125-kDa 19-DEJ-1 105-kDa Ladinin LAD-1
  • 49. Laminin 5 (alpha3 beta3 gamma 2)
    • Its general structure as laminin family ( glycoproteins, semirigid & extended structure has an asymmetric cross-like).
    • It has short arms comparing to other laminins.
    • Its shape is consistent with its potential to be the anchoring filament protein.
    • It has a high affinity for integrin alph6 beta4.
    • it also bind to the NC-1 domain of type VII collagen ( the anchoring fibril protein).
  • 50.
    • Mutation in any of its components will lead to loss of its ability to bridge HD & anchoring fibrils resulting in separation within the lamina lucida
    • Herlitz JEB
  • 51. 125-kDa protein
    • It is located at the region where intermediate filaments of basal keratinocyte intersect the HD plaque & at the extra-cellular region.
  • 52. 19-DEJ-1 antigen
    • It is localized to the region of the lamina lucida beneath the HD.
    • ? Sulfated ? Proteoglycan.
    • Its role in adhesion not fully studied, but supported by if absent JEB
  • 53. 105-kDa Antigen
    • It is localized in extra-cellular region but closely associated with the cell surface.
    • If absent immune-mediated bullous
    • dermatoses
  • 54. Ladinin & LAD-1
    • Their function unknown.
    • Their implication in epithelial adhesion by their identification as ligands for auto-antibodies present in patients with linear IgA bullous dermatosis.
  • 55. Epithelial Lamina Densa
    • The basement membrane beneath & between HD contains at least alpha1-&alpha2- containing collagen IV molecules.
    • It contains laminins, but the exact composition remains in doubt.
    • Laminin alpha3- containing molecules are present between HD as well as beneath them.
    • However, alpha3 is also contained in two additional epithelial specific namely :-
      • Laminin 6 (alpha3,beta1,gamma1)
      • Laminin 7 (alpha3,beta2,gamma1)
  • 56.
    • At DEJ laminin 6 appears to be the major alpha3-containing laminin other than laminin 5.
    • Laminin 6 & 7 have the unique property of forming disulfate bounded dimers with laminin 5.
    • This laminin 5-6 complex is the major alph3- containing laminin in the lamina densa between HD.
    • This complex is a ligand for integrin alpha3 beta1 present between HD, which mediates the binding to the intra-cellular actin cytoskeleton.
  • 57.
    • If integrin alpha3 beta1 knockout , this will lead to loss of the basement membrane between HDs but not beneath them.
    • Laminin 5-6 complex contains gamma 1 chain & can therefore bind to nidogen & type IV collagen network.
    • Additional laminins within DEJ found but of minor role including laminin 1.
    • Much work remains in LD area which is not fully understood at the molecular level.
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  • 59. Anchoring fibrils & Anchoring plaques
    • The major component of the anchoring fibril is type VII collagen.
    • Type VII collagen appears to have a major triple-helical domain is approximately 450 nm in length.
    • Non-triple-helical globular domains exist at the terminal ends of this triple helix,& the N- terminal domain NC-1 is very large & trident-like.
    • Type VII collagen is synthesized & secreted as monomeric protein but rapidly dimerizes through disulfate cross-like at the amino terminals.
    • These structures are proteolytically cleaved after formation of the centrosymmetric dimer.
  • 60.
    • The dimers then aggregates laterally to form the anchoring fibrils.
    • The complex NC-1 domain binds to laminin 5 & also to components of the lamina densa.
    • The helical domain extends perpendicular from the lamina densa & insert into structures termed anchoring plaques.
    • The anchoring plaques are electron-dense structure composed of type IV collagen & laminin & possible other components.
  • 61.
    • They are independent of lamina densa , & distributed randomly in the papillary dermis below lamina densa & are inter-related by additional anchoring filaments.
    • Mutation in the gene encoding type VII collagen
    • Sever generalized recessive DEB
    • To date, all mutation known to underlie both recessive & dominants forms of DEB are due to COL7A1 mutation
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  • 63. EBS EBS MD EBS GABEB JEB Herlitz JEB Dystrophic EB WWW.SMSO.NET
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  • 65.
    • Thank You
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