Review K E y WORDS bullous disbrders, hereditary, autoimmune, desmosome, hemi- desmosome, components, targets, pathoge- netic role, review Desmosome, hemidesmosome and bullous disorders Bullnus d-isorders due to heredita-,y or acquired desmosome or hemklesmosome impairment A short survey A. Kansky SUMMARY Some aspects of the pathogenetic mechanisms of autoimmune bullous disorders as well as of bullous hereditary disorders are shortly reviewed. The known components of desmosomes and hemidesmosomes, to which specific autoantibodies are directed in autoimmune disorders, are listed. The molecular defi- ciencies of dem osorne and hemidesmosome components incriminated to cause hereditary bullous dis- orders, are also mentioned. The authors believe that clinicians should be familiar with the newest devel- opment in basic sciences concerning the pathogenetic role of desmosome and hemidesmosome. Introduction Bullous skin disorders especially pemphigus and bullous pemphigoid presented unsurpassed therapeu- tic problems to dermatologists until the late fifties, when corticosteroids were introduced. The prognosis became adclitionally more favorable by simultaneous use of corticosteroids and immunosuppressives. Numerous studies have proven that autoimmunity is the main pathogenic mechanism in acquired bullous cliseases , whereas DNA mutations are responsible in hereclitary bullous clisorders. Many details remain however stili to be cleared. In the current literature our readers frequently en- counter information on clesmosome ancl hemiclesmo- some components, which are mentionecl as the main targets or pathogenetic factors in bullous skin disorders. In order to make more transparent to our readers, which component is linked to a given b~11lous dermatosis, we tried to review shortly the problem using a few schemes and tables. We realize that this is a rather clifficult task as only the active investigators understand these prob- lems in details and even their opinions sometimes dit'-- fer. Franke stressed it cluring his lecture at the 39th ESDR Annual Meeting in Berlin that the physit:ochemical and immunologic characteristics of an isolated component depend at least partially on the methods applied for its isolation. Epidermis, basal membrane ancl associated tissues represent living systems, which are constantly uncler- Acta Dermatoven APA Vol 10, 2001, No 2 - - --------- - -------- ------ -------- - 39 Desmosome, hemidesmosome and bullous disorders Table 1. Intraepidermal bullous diseases due to autoimmune response to components of the desmosome Disease Antigen ... Pemphigus vulgaris Desmoglein 3 Desmoglein 1 Cholinergic receptor Pemphigus foliaceus Desmoglein 1 Pemphigus paraneoplasticus Envoplakin, periplakin Desmoglein Desmoplakin 3 BP 230 IgA pemphigus subcorneal Desmocollin 1 pust:ulosis IgA pemphigus intraepidermalis neutrophilicus 'Pemphigus herpetiformis Desmoglein 1 Desmoglein 3 going changes. In principle the biological processes going on in the epidermis can be divided into df/feren- tiation and activation. During the process of differen- tiation the epidermal cells are undergoing complicated biochemical processes e.g. transformation of basal cells into corneocytes, whereas in the process of activation the cells react to injuries and to various signaling mol- Antibody Author Reference IgG Stanley 1993 (6) Amagal 1998 (7) Ding 1999 (8) Nguyen 1998 (8) IgG Ding 1999 (8) IgG Kiyokawa 1998 (10) Kazerounian 2000 (11) Green 2000 (12) Amagal 1998 (7) Stanley 1993 (6) IgA Tagami 1983 (13) Hashimoto 1997 (14) IgA Huff 1985 (15) IgG Ishii 1998 (16) ecules. Both processes are regulated by complicated signaling mechanisms in which a cornucopia of mol- ecules cooperate: peptides (e. g. interferons), growth factors (e. g. epidermal growth factor, EGF), interleukins (IL 1-12), receptor molecules as well as others (1, 2). Thus desmosomes and hemidesmosomes are too con- stantly undergoing changes. Table 2. Hereclitary intraepidermal bullous clisorders due to deficiency of desmosome components Disease Deficiency Gene Author Darier clisease Desmoglein ATPA2A 12q23-24 Sotoyama Sakuhtabhai Hailey-Hai]ey clisease Ergastpl Ca pump ATP2Cl Mackiewicz Ectoclerm c.lyspl/skin fragil sy Plakophilin 1 Erythrokerat fig variabi]is Connexin 31 Keratodermia palm plant striat Desmoplakin Desmoglein Dysplasia ectocl hypohicfrotica transmembrane protein Legend ATPA2A - calcium ATP ase isoform 2 GJB3 - Cap ju neti on fl3 protein McGrath GJB3 lp34-36 Richard Whittock X qll-21 Kere Reference Lesion 1999 (17) Acantholysis 1999 (18) 2000 (19) Acantholysis 1997 (20) scaling, erythema, blisters 1998 (21) Papillomatosis, Parakeratosis 1999 (22) Hyperkeratosis 1996 (43) scaling, sparse hair, hypoclontia Review 40 Acta Dermatoven APA Vol 10, 2001, No 2 Review Figure l. Shematic presentation of a desmosome stn.icture. Legend: DC - desmocollin 1-3 (transmembrane proteins); DSG - desmoglein 1-3 (transmembrane proteins); P - plakoglobins; IF - intermediate filaments; CD - central disc of desmosome; PM - plasma membrane; N - nucleus; AP - attachment plaque; plakoglobin, plakophylin, periplakin, endoplakin, envoplakin DSP - desmoplakin I, II LL iLO Polymer network: colll1gen IV heparan sulfate proteoglye;:an Desmosome, hemidesmosome and bullous disorders The main structures responsible for the cohesion between epidermal cells are desmosomes and hemi- desmosomes, but other structures like adherens junc- tions, gap junctions and tight junctions also fulfill im- portant functions. We hope that the more biochemical minded readers would understand our didactic intent and accept the simplifications we were constrained to make. Desmosome Desmosomes have been visualized long ago by light microscopy and later by electron microscopy. The ba- sic components of the desmosome are the desmosomal plaque and the transmembrane adhesion molecules desmocollins 1-3 and desmogleins 1-3, which are con- necting two neighboring desmosomes. Plaque compo- nents are plakoglobin, plakophilin, periplakin, desmo- calmin, endoplakin and envoplakin as well as desmo- plakins II and l Plakoglobin seems to be attached pri- marily to desmocollin and desmoglein, while desmo- plakins I and II appear to merge with the intermediate filaments (IF). A schematic presentation of the desmo- some, as shown in Figure 1, might be helpful to readers in following the further explanations (3,4,5). In autoimmune bullous disorders one or more com- ponents of the desmosome might become target of spe- cific autoantibodies and thus trigger off the develop- ment of the disease. A good example is pemphigus vul- garis in which antibodies to desmoglein 3 (6,7) and to a lesser extent to desmoglein 1 (8) or to cholinergic receptors (9) cause the disruption of desmosomes and consequently the formation of intraepidermal clefts, vesicles or bullae (acantholysis). Desmoglein 1 is the main antigen in pemphigus foliaceus (8). Antigens re- sponsible for other intraepidermal acantholytic derma- toses of autoimmune origin like pemphigus paraneo- plasticus (10,11,12) or IgA pemphigus (13,14, 15,16) are listed in Table 1. It has to be emphasized that some- times these disorders are characterized by simultaneous presence of autoantibodies directed to more than one desmosome component. Figure 2. Shematic presentation of the epidermal-dermal junction. Legend: BC - basal celi; N -nucleus; IF - intermediate filaments; HO - hemidesmosome; LL ·_ lamina lucida; LD - lamina densa; PL - plectin; BP 230 - bullous pemphigoid antigen, BPAg1; BP 180 - bul/ous pemphigoid antigen, BPAg2 (col/agen XVII); I - integrin; L 5 - laminin 5; a til - anchoring filaments; a fib - anchoring fibrils; a plaque - anchoring plaque Acta Dermatoven APA Vol 10, 2001, No 2 - --------------------------------- 41 Desmosome, hemidesmosome and bullous disorders Table 3. Subepidermal bullous disorders caused by autoantibodies directed to components of hemidesmosome and basal membrane Disease Antigen Antibody Author Reference Pemphigoid bullosus BP180/ NC16A IgG > IgA Cook 1990 (23) BP230 Stanley 1993 (5) Desmoplakin Bedane 1997 (24) Plectin Riou 2000 (25) Herpes gestationis BP180/ NC16A IgG Perriard 1999 (26) Pemphigoid cicatricans BP 180 IgG>IgA>IgM Bernard 1992 (27) Laminin5 Domlogue 1993 (28) Balding 1996 (29) Integrin ~4 Mohinen 1993 (30) Linear IgA dermatosis 285 kD* IgA > IgG Wojnarovska 1998 (4) 97/120 kD* BP180, BP230 Kromings 2000 (32) Anch fib Lichen planus pemphigoides BP180/ NC16A IgG Zilikens 1998 (33) 200 kD Braun-Falco 2000 (34) Epidermolysis bullosa acquisita Collagen VII/ NCl IgG, IgA Shimizu 1990 (35) Aronsen 1998 (36) Legend BP 180 - bullous pemphigoid antigen 2 (BPAG 2, collagen XVII) BP/NC16A - non-cellularfragment 16A ofBP 180, the most immunologic domain EP 230 - bullous pemphigoid antigen I (EPAG 1) 285 kD, 97/120 /eD - specifzc antigensfor linear IgA anchfib - anchoringfibrils collagen VIIINC I - non-collagen I doma in of anchoring.fzbrils Intraepiclermal acantholysis is the main symptom also in a number of hereditary disorders which are caused by mutation of genes coding for individual des- mosome components. In Darier disease acantholysis was attributed to deficient desmoglein (17), but the !at- est investigations incriminate the gene for the enzyme ATPase A2A, which is located on chromosome 12q23- 24 (18). In the benign familial pemphigus (Hailey-Hailey disease) acantholysis is due to the deficient enzyme ATPase 2Cl (19). In the ectodermal dysplasia/ skin fra- gility syndrome the deficient molecule is plakophilin 1 (20), while e1ythrokeratodermia figurata variabilis is attributed to to the deficient connexin 31 (21) and in keratoclermia palmoplantaris striata to desmoplakin and clesmoglein (22). Table 2. Hemidesmosome Hemidesmosomes are special structures on the der- mal side of basal cells connecting basal cells with the basement membrane and consequently with the der- mis. The components ofthe hemidesmosome to which intermediate filaments (IF) are attachecl are plectin and hullous pemphigoid 230 kD protein (EP 230 antigen, EPAGl). The transmembrane molecule integrin with its components a6 and b4 connects the hemidesmo- some to the laminin 5 component of the lamina lu- cida, while the bullous pemphigoid antigen 180 kD (EP 180 antigen, EPAG2, collagen XVII) links it to the lamina densa and its polymer network composed mainly of type IV collagen and heparan sulf'ate proteo- Review 42 ~ -------- ------------ - ------------Acta Dermatoven APA Vo l 10, 2001, No 2 Review Desmosome, hemidesmosome and bullous disorders Table 4. Bullous heredita1y junctional disorders caused by mutations in components of hemidesmosome and basal membrane + ·- Disease Deficient .component Gene Author Reference Epidermol hered junct Herlitz Laminin ~3 chain Epidermol letalis, atresia pylori Integrin ~4 subunit Epidermol non- Herlitz Epidermol dystr Legend Integrin ~4 subunit Anchoring fibrils J LAMB3 LAMA3 Integrin gene LAMA3 Collagen VII ' Nakano 2000 (38) Uitto 1998 (39) Micheloni 2000 (40) Castiglia 2000 (37) Frank 1998 (41) Epidermolysis bullosa hereditaria junctionalis letalis Herlitz Epidermolysis bullosa hereditaria letalis cum atresia pylori Epidermolysis bullosa hereditaria junctionalis non-Herlitz LAMB 3 - laminin beta 3 gene LAMA 3 - laminin alfa 3 gene glycans. Important constituents of lamina lucida are in aclclition to laminins also anchoringfilaments. The base- ment membrane is connected w ith the dermis through the anchoring .fzbrils (collagen VII structures). Figure 2. A number of autoimmune subepiclermal bullous skin clisorclers are linkecl to specific autoantiboclies clirected towards components ofthe hemidesmosome. In blood serum of patients with bullous pemphigoicl specific antiboclies to EP 180(23,24), EP 230, desmoplakinancl plectin (25) were described. In herpes gestationis the autoantiboclies are directed to the 16A non-cellular clo- main ofBP 180 (NC16A/BP180) (26), in cicatricial pem- phigoid to BP 180 (27), laminin 5 (28) ancl integrin 84 (29,30,31). The autontiboclies to 285 kD ancl 97/120 kD hemidesmosome components are specific for the lin- ear IgA dermatosis ( 4,32), but other antigens like BP180 and BP 230 are also involvecl. Aclclitionally to IgA, IgG autoantiboclies may also be present. In lichen planus pemphigoides the antibodies are clirectecl to the BP180NC16A (33) and to a 200 kD antigen (34) , while in the epidermolysis bullosa acquisita the target is the non-collagen clomain 1 of collagen VII (35,36). The main hereclita1y bullous dermatoses linkecl to the hemiclesmosome and to the basal membrane are the epidermolysis bullosa hereditaria junctionalis (EBHJ, JEB), actually more variants of this disorder are known. For the relatively benign non-Herlitz EBHJ a cleficient integrin 84 molecule expressed by the LAMA 3 gene is responsible (37). For the lethal Herlitz EBHJ the defi- cient laminin 83 molecule codecl by either LAMA 3, LAMB 3 gene (38) and for the EBHJ with atresia pylori the integrin 84 expressed by COL7Al or LAMC 2 gene is responsible (39,40) . Further rare variants ofEBHJ have been clescribed, but their clescription would exceed the aim of this short review. At last we would like just to mention the most severe, the dystrophic form of epi- dermolysis. Numerous investigations have shown deficient or even absent anchoring .fzbrils, which link the lamina, clensa with the dermis ancl are coclecl by mutated col- lagen VII genes (COL7A). This clisorcler is not directly linked to hemidesmosome, for this reason just refer to two references mentioning mutations of the COL7Al gene (41,42). Conclusion The above mentionecl new clata will most probably have in the future an impact on treatmept. Attempts will be made to fincl out how to interfere with the reaction between specific autoantiboclies ancl their target anti- gens, on the other sicle gene replacement therapy is a subject of intensive studies. Acta Dermatoven APA Vol 10, 2001, No 2 - -------------------- ---------- ---- 43 Desmosome, hemidesmosome and bu/lous disorders REFERENCE S l. Komine M, Freedberg IM, Blumenberg M. The activated keratinocytes. Acta Dermatoven APA 1995; 4: 169-73 2. Blumenberg M. Keratinocyte differentiation and activation. Acta Dermatoven APA 1997; 6: 127-35 3. Eady RAJ, Leigh IM, Pope FM. Anatomy and organization of the skin. Rook et al: Textbook of Derma- tology. Champion RH et al eds. 61' ed, 1998. Blackwell science, Oxford, 43-57. 4. 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