Dermo-epidermal junction and Desmogleins

he dermo-epidermal junction is a complex structure, composed of semidesmosomes (attachment plaque, cell membrane and junction plate) anchoring filaments, basal lamina, anchoring fibrils and elastic fibrils. A similar structure is seen in other epithelial and endothelial tissues, muscles and nerves. Among them, mucous epithelium is very like the epithelium of skin.

As observed under the light microscope, the PAS-positive basement membrane includes the basal lamina and anchoring fibrils. Elastic fibrils seem to be identical with oxytalan fibers and elastofibrils. Histochemical studies suggest that the junction consists of neutral mucopolysaccharides, collagenous protein, SO4-groups and lipids. However, no chemical analyses have been done.

The normal junction can be separated by physical, chemical or enzymatic methods. Suction is a unique technique for dermo-epidermal separation. Its formation is studied in embryonic skin, cultivated skin and wound healing. The junction is initiated by an increased density of basal cell membrane and is laid down on the surface of the dermis.

The junction binds the epidermis firmly to the corium and controls the passage of material from the dermis to the epidermis or vice versa.

1. DERMOEPIDERMAL JUNCTION AND DESMOGLEINS DR. MOHNISH SEKAR

2. INTRODUCTION The dermo -epidermal junction (BMZ) is the interface between the lower part of the epidermis and the top layer of the dermis P lays a key role in epidermal–dermal interactions. DEJ mediates adhesion between the basal keratinocytes and the dermis and provides resistance against shearing forces on the skin.

3. DEVELOPMENT DEJ develops from a simple, generic basement membrane in the embryo  highly complex, multilayered structure in the 2 nd trimester of fetus . The embryonic DEJ  lamina densa and lamina lucida . C omposed of molecules common to all basement membrane zones (e.g. type IV collagen, laminin , heparan sulfate, proteoglycans) .

4. 8 weeks  Skin - specific components of the DEJ start to appear after the embryonic–fetal coincident with the onset of epidermal stratification . 12 weeks  almost all of the structures characteristic of the mature DEJ. Hemidesmosomes , anchoring filaments and anchoring fibrils  synthesized by basal keratinocytes.

5. Type VII collagen-containing anchoring fibrils localizing to the sub-lamina densa . Laminin 5 and the bullous pemphigoid antigens also expressed . As development progresses, the flat embryonic DEJ acquires the rete ridges and dermal papillae  the adult DEJ.

6. STRUCTURE AND ULTRASTRUCTURE BMZ  not visible on H and E stained sections. Is seen on staining with Periodic Acid-Schiff (PAS) staining as a 0.5 to 1.0 mm thick homogeneous band. Electron microscopy is an essential technique to reveal the ultrastructure morphology of the BMZ.

7. LAYERS OF BMZ A specialized portion in the basal-most part of the basal cell layer  hemidesmosome . A n electron lucent sub-basal zone  lamina lucida (approx. 40 nm thick ). A n electron- dense zone  lamina densa (approx. 50 nm thick) or basal lamina. Lamina fibroreticularis .

8. HEMIDESMOSOMES Focal thickenings of plasma membrane. Adhesion between epidermis and dermis. Cytoplasmic portion  inner plaque, to which tonofilaments (keratin 14, 5) are attached. Portion near basal plasma membrane  outer plaque. Sub basal dense plaque

9. Sub-basal dense plaque (extracellular component)  parallel and beneath the outer plaque, approx. 10 nm away from outer surface of plasma membrane . No. of hemidesmosomes  constant in each individual .

10. Components Of Hemidesmosomes HD1 PLECTIN HD2230-kDa BULLOUS PEMPHIGOID ANTIGEN HD3 β 4 INTEGRIN SUBUNIT POLYPEPTIDE HD4 180-kDa BULLOUS PEMPHIGOID ANTIGEN HD5 α 6 INTEGRIN PEMPHIGOID ANTIGEN

11. Lamina Lucida Less electron dense on transmission electron microscopy COMPONENTS Anchoring filaments  span lamina lucida and connecting hemidesmosomes with lamina densa . Laminin 5, α6β4 integrin, ectodomain of the 180 kDa BPAg2/BP180  major constituents of the lamina lucida . The endodomain of BP180  in the outer plaque of the hemidesmosome .

12. Anchoring Filaments Fine thread like structures,3-4nm in diameter Major antigen LAMININ322Binds to α 6 β 4 INTEGRIN in HD and to TYPEVII COLLAGEN in anchoring fibrils OTHER ANTIGENS 125-kDa,19-DEJ-1,105kDa,LAD-1.

13. Laminin Major Laminins In Skin TYPE COMPOSITION OLD DESIGNATION DISTRIBUTION 111 α 1 β 1 γ 1 1 BLOOD VESSELS,LD 332 α 3 β 3 γ 2 5 LL/LD 311 α 3 β 1 γ 1 6 LL/LD 511 α 5 β 1 γ 1 10 LL/LD

14. Functions Provides integrity to BMZ Cellular Differentiation Interaction with extracellular molecules(HD and TYPE VII COLLAGEN)

15. Lamina Densa The lamina densa lies just below the lamina lucida . Electron dense layer Interacts with mesenchymal matrix with upper dermis Major biochemical component  Type IV collagen Other Components Laminin 5,6,10 Nidogen Perlecan Heparan sulphate,proteoglycans .

16. COLLAGEN Collagen is a protein made up of amino acids built of carbon di oxide and hydrogen. Specific Amino Acids: Glycine,  Proline ,  Hydroxyproline and Arginine.

17. Types Of Collagen COLLAGEN I & III COLLAGEN IV COLLAGEN V COLLAGEN VI COLLAGEN VII COLLAGEN XVII MAIN INTERSTITIAL DERMAL COLLAGEN MAJOR COMPONENT OF BASEMENTMEMBRANE ZONE MOST IN CONNECTIVE TISSUES MINOR COLLAGEN MAJOR COMPONENT OF ANCHORING FIBRILS BPAG2 TRANSMEMBRANE COMPONENT EHLERS DANLOS SYNDROME ALPORT SYNDROME GOOD PASTURE SYNDROME EHLERS DANLOS SYNDROME MUSCULAR DYSTROPHY DYSTROPHIC EPIDERMOLYSIS BULLOSA JUNCTIONAL EPIDERMOLYSIS BULLOSA

18. Type IV Collagen Collagen IV  primary collagen found in the extracellular basement membrane. Major component of the dermal–epidermal junction  lamina densa . Collagen IV is a heterotrimeric molecule containing two α 1 -like and one α 2 -like genes .

19. Lamina Fibroreticularis Anchoring fibrils  major component of the lamina fibroreticularis . Short, curved, central portion  irregularly spaced cross banding . I nsert into the lamina densa , project into papillary dermis . Main constituent  type VII collagen .

20. Elastic fibers (consist of microfibril bundles)  another component of the lamina fibroreticularis . Attached to the undersurface of the lamina densa . E xtend into the dermis  enmesh with the microfibrillar system surrounding dermal elastin.

21. MOLECULAR COMPONENTS Intermediate filament (IF) components • Keratin 5 • Keratin 14 Hemidesmosomal plaque components • 230 kDa bullous pemphigoid antigen (BP230/BPAG1) • Plectin Transmembrane components • α6β4 integrin • Type XVII collagen (180 kDa bullous pemphigoid antigen/BPAG2) • α3β1 integrin • Type XIII collagen • Syndecans 1 and 4

22. Lamina lucida/lamina densa components • Laminin 332 ( laminin 5) • Laminin 311 ( laminin 6) • Laminin 511 ( laminin 10) Lamina densa components • Type IV collagen • Laminin 111 ( laminin 1) • Nidogen • BM‐40/SPARC • Perlecan Anchoring fibril components • Type VII collagen • GDA‐J/F3 antigen

23. DISTURBANCES OF DERMO-EPIDERMAL COHESION JUNCTIONAL(at the lamina lucida ) DERMOLYTIC(below basal lamina) Junctional epidermolysis bullosa Epidermolysis bullosa dystrophicans Bullous pemphigoid Epidermolysis bullosa acquisita Porphyria cutanea tarda Dermatitis herpetiformis

24. DESMOGLEINS Desmosomal cadherins major role in stabilizing cell-cell adhesion in the living layers of the epidermis Desmosomal cadherins are transmembrane proteins whose extracellular amino-terminal domains interact to form the trans-adhesive interface between the cells.

25. Electron microscopy of desmoglein R epresented by the electron-dense midline of the desmoglea

26. Within Normal Epidermis Dsg1&4  expressed predominantly in the differentiated cells of the superficial epidermis. Dsg2&3  expressed more strongly in the basal &/or suprabasal layers.

27. Among different epithelial tissues Dsg1&3 expression  largely limited to stratified squamous epithelia of skin &oropharynx , as well as thymic epithelial cells. Dsg3  also strongly expressed in SCCs , other H&N cancers , where it has been proposed as a potential molecular target for therapy. Dsg2  major desmoglein isoform in the most simple and transitional epithelia, as well as cardiac myocytes . Dsg4  prominent in desmosomes of hair follicle, testis, and prostate.

28. Desmoglein 1 T arget of pathologic proteolytic cleavage in the infectious disorders bullous impetigo and SSSS& inherited ichthyosis associated with Netherton syndrome Pathogenic autoAbs to desmoglein 1 found in Pemphigus foliaceus M ucocutaneous pemphigus vulgaris Paraneoplastic pemphigus

29. Autosomal dominant mutations causing haploinsufficiency of desmoglein 1 result in palmoplantar keratoderma(striate)

30. Desmoglein 2 Dsg2  implicated as a cause of autosomal dominant arrhythmogenic right ventricular cardiomyopathy ( ARVC ) The lack of skin phenotypes in affected patients indicates  desmoglein 2 not required for epidermal adhesion, likely due to compensatory adhesion from other more highly expressed epidermal desmosomal cadherin isoforms .

31. Desmoglein 3 Target of pathogenic autoantibodies in Mucosal & M ucocutaneous pemphigus vulgaris. P araneoplastic pemphigus. Most pathogenic autoantibodies in pemphigus vulgaris target the amino-terminal extracellular (EC1–2 ) domains of desmoglein .

32. Desmoglein 4 Desmoglein 4 mutations  rare autosomal recessive forms of hypotrichosis & monilethrix . Desmoglein 4 immunoreactivity  observed in pemphigus vulgaris and pemphigus foliaceus sera,but subsequent studies have attributed this to cross-reactivity from Dsg1 autoantibodies.

33. References McGrath A, Uitto J. Structure and Function of the Skin. In: Griffiths E. M, editor. Rook’s Textbook of Dermatology 9 th ed. Blackwell Publishing, Ltd 2010. p. 2.20-2.29. Elenitsas R, Chu Y. Pathology of Skin Lesions. In: Kang S, editor. Fitzpatrick’s Dermatology 9 th ed. Mc-Graw Hill Education 2019. p. 23-5 Vandergriff W, Bergstresser R. Anatomy and Physiology. In: Bolognia L. Bolognia Dermatology 3 rd Ed. Elsevier Limited 2012. p. 43-4 Thappa D. M, Konda D. Structure and Functions of the Skin. In: Sacchidanand S, editor. IADVL Textbook of Dermatology 4 th ed. Bhalani Publishing House 2018. p.27-30

34. James W, Elston M, Treat R et al. Skin: Basic Structure and Function. In: James D, editor. Andrew’s Diseases of the Skin 13 th ed. Elsevier Inc. 2020. p. 4 Ortonne JP. The dermo -epidermal junction and its acquired and hereditary pathology- A few recent advances. Pathol Biol (Paris). 1992; 40(2 ):121-32.  Campbell ID, Humphries MJ. Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol. 2011;3(3 ): a004994. Amagai M, Stanley JR. Desmoglein as a target in skin disease and beyond. J Invest Dermatol . 2012;132(3 Pt 2):776-84.

35. Katz SI. The epidermal basement membrane zone--structure, ontogeny, and role in disease. J Am Acad Dermatol . 1984;11(6 ): 1025-37 Abreu-Velez AM, Howard MS. Collagen IV in Normal Skin and in Pathological Processes. N Am J Med Sci. 2012;4(1 ):1-8

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