Immunohistochemical Distribution Pattern of 3, Desmocollin 1 and 1,2 in the of Oral Mucosa and Skin

Li-Hong Wang1,Ken-ichiKatube1, Wei-Wen Jiang1,Ling-YunLi2, Norihiko Okada3and Minoru Takagi1 1Molecular Pathology, Department of Oral Restitution, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University Tokyo, Jpan, 2Dermatology Research Institute of Shenyang, Shenyang, People’s Republic of China, 3Diagnostic Oral Pathol- ogy, Department of Oral Restitation, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

Wang L-H, Katube K, Jiang W-W, Li L-Y, Okada N and Takagi M: Immunohistochemical distri- bution pattern of desmocollin 3, desmocollin 1 and desmoglein 1,2 in the pemphigus of oral mu- cosa and skin. Oral Med Pathol 2000; 5: 87-94, ISSN 1342-0984.

Pemphigus is an autoimmune disease in which autoantibodies play a pathogenic role, causing loss of epithelial with resulting blister formation. In the present study, the distri- bution patterns of desmocollin 3 (Dsc 3), desmocollin 1 (Dsc 1) and desmoglein 1 and 2 (Dsg 1,2) in (PV) and pemphigus erythematosus (PE) were investigated by immuno- histochemistry. Dsc 3 was distributed at the cell membrane of the basal and suprabasal layers of the normal oral mucosa and skin . Dsc 1 was distributed only at the cell mem- brane of the upper spinous layers of normal skin, and was not visible in normal oral mucosa epithelium. Dsg 1,2 was distributed at the cell membrane of the suprabasal layers of normal oral mucosa and skin epithelium. The distribution of Dsc 3 and Dsg 1,2 was obviously sparser in the oral PV and cutaneous PV than in normal control epithelium. Internalization of Dsc 3, Dsc 1 and Dsg 1,2 occurred specifically in PV and PE, giving staining patterns resembling cytoplas- mic patchy granules, rings and dense clumps. Internalization of Dsc 3 was more frequent in cu- taneous PV (60%) and PE (60%) than in oral PV (30%). These findings suggest that internaliza- tion of Dsc 3 is closely associated with disease duration (P<0.01) and disease severity (P<0.05) in PV, and that not only desmogleins but also may play an etiological role.

Key words: desmocollin, desmoglein, pemphigus, oral mucosa, skin, immunohistochemistry

Correspondence: Li-Hong Wang, Molecular Pathology, Department of Oral Restitution, Division of Oral Health Sciences , Graduate School , Tokyo Medical and Dental University , 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan Phone: 81-3-5803-5453, Fax: 81-3-5803-0188, E-mail: [email protected]

Introduction 3), as does Dsg (Dsg 1, Dsg 2 and Dsg 3) (5). Pemphigus is an autoimmune blistering disease In the present study using immunohistochemistry, targeting principally the oral mucosa and skin, in which we examined the distributions of Dsc 3, Dsc 1 and Dsg 1, autoantibodies play a pathogenic role, inducing loss of 2 antigens in PV of the oral mucosa and skin and PE of epithelial cell adhesion with resulting blister formation the skin, in order to clarify the pathogenic significance of (1). Pemphigus is classified into two types: pemphigus Dsc and Dsg. vulgaris (PV), including pemphigus vegetans, and pem- phigus foliaceus (PF), including pemphigus erythemato- Materials and Methods sus (PE). The autoimmune targets in PV and PF have Tissue specimens been identified as desmoglein 3 (Dsg 3) and desmoglein 1 Thirty-five tissue specimens were used. These in- (Dsg 1), respectively, by cDNA cloning (2). Acantholysis is cluded 10 cases of oral PV collected from the 1987-1998 pathognomonic in pemphigus and may be mediated by archives of Tokyo Medical and Dental University, and 15 antigen- binding and subsequent dissolution of cases of cutaneous PV and 10 cases of cutaneous PE col- the antigens of Dsg and Dsc (3, 4). Both Dsc and Dsg are lected from the 1992-1998 archives of the Department of members of the superfamily of cell adhesion Dermatology, Affiliated Hospital of Shengyang Medical molecules. Dsc has three subtypes (Dsc 1, Dsc 2 and Dsc College. The patients included 16 men and 19 women 88 Wang et al Immunohistochemical distribution of desmocollin in pemphigus ranging in age from 28 to 85 years. In addition, 23 normal Statistical analysis tissue specimens for use as controls were obtained from Disease duration and the skin surface in PV were Tokyo Medical and Dental University. assessed from the onset of illness to the date of diagnosis. Assessment of clinical disease activity for cutane- Pearson chi-squared test (χ2 test) was used to determine ous PV and PE was performed using a scale of disease se- the significance of differences between internalization verity reflecting the amount of the skin surface involved and non-internalization of Dsc and Dsg in PV. (10%, 10-30% or 30%). Results Immunohistochemistry Normal oral mucosa Paraffin sections (4 µm thick) were stained with he- Dsc 3 staining was seen in the spinous and basal matoxylin and eosin and examined by light microscopy. A layers, being apparently stronger in the basal and lower histofine SAB-PO kit (Nichirei Co., Japan) was used. Af- spinous layers (Fig.1 a). Dsc 1 staining was not detected ter deparaffinization, and dehydration in increasing dilu- in any cell layer. Dsg 1,2 staining was seen in the spi- tions of ethanol, an antigen retrieval step consisting of nous layer, being more intense in the upper spinous layer, heating in a microwave oven (three to five times for 5 min, but was not expressed in the basal layer (Fig.1 b). Similar 600 W) in 10 mM sodium citrate (pH 6.0) was employed, to normal skin, Dsg 2 was confined to the basal cell layer, followed by immersion in Tris-buffered saline (TBS; 0.5 its level being particularly low in the , at which M Tris/HCl, pH 7.8, diluted 1:10 with 0.15 M NaCl), and siteitmightbeabsent(Datanotshown). washing with phosphate-buffered saline (PBS). The endo- genous peroxidase activity was blocked using 0.3% H2O2 Normal skin in methanol for 20 min , and the sections were then Dsc 3 staining was also seen in the spinous and ba- treated with blocking reagent (normal mouse serum) for sal layers (Fig.2 a). Dsc 1 staining was detected in the up- 15 min. The primary used were anti-Dsc 1 (U- per spinous layer, but was not detected in the basal and 100, mouse monoclonal, ready to use, Progen Biotechnid, lower spinous layers (Fig.2 b). Dsg 1,2 staining was seen Germany), anti-Dsc 3 (U-114, mouse monoclonal, ready in the spinous layer, more intensely superficially, and to use, Progen Biotechnid) and anti-Dsg 1,2 (DG 3.10, was not expressed in the basal layer (Fig.2 c). mouse monoclonal, diluted 1:10 with PBS, Progen Biote- chnid). Incubation with the primary antibodies was per- Oral pemphigus vulgaris formed in a humid chamber overnight at 4℃.Asasecon- The distribution of Dsc 3 and Dsg 1,2 in oral PV dary antibody, biotinylated anti-mouse IgG was applied was different from that in normal oral mucosa. Dsc 3 was for 20 min at room temperature. Peroxidase-labelled stre- widely distributed in 5 of the 10 cases, with an expression ptavidin was added for 7 min. The staining reaction was pattern similar to that in normal epithelium; was absent performed using 3,3’ -diaminobenzidine tetrahydrochlo- in 1 case; and was weakly expressed at the cell mem- ride (DAB) and H2O2 for 5 min, and counterstaining was brane in 4 cases where the epithelium was markedly af- done with methyl green (6). Negative controls were pre- fected (Fig.3 a) (Table 1). Dsg 1,2 was widely distributed pared by applying PBS instead of a primary antibody. in 4 out of the 10 cases, with an expression pattern simi- Immunohistochemical staining intensity was lar to that in normal epithelium; was absent in one case; judged using the following categorize − negative; + and was weakly expressed at the cell membrane in 5 weakly positive; ++ strongly positive (7). cases where the epithelium was affected (Fig.3 b). In the

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Fig. 1: Normal oral mucosa. (a) Strong staining for Dsc 3 is seen in the basal and spinous layers (original magnification ×400). (b) Strong staining for Dsg 1, 2 is observed in the spinous cell layer (original magnification ×400). Oral Med Pathol 5(2000) 89

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Fig. 2: Normal skin. (a) Strong staining for Dsc 3 is seen in the basal and spinous cell layers (original magnification ×400). (b) Strong staining for Dsc 1 is seen in the upper spinous and granular cell layers (original magnification ×400). (c) Strong staining for Dsg 1,2 is seen in the upper spinous and granular cell layers (original magnification ×400).

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Fig. 3: Oral PV. (a) Dsc 3 staining is weak partially at the cell membrane of periblister cells ( original magnification × 200). (b) Dsg 1,2 staining is weak at the cell membrane of acantholytic cells and blister roof cells (original magnifi- cation ×400). (c) Clumped dots of Dsc 3 staining are seen in the cytoplasm of some affected cells (original magnifica- tion ×1000). 90 Wang et al Immunohistochemical distribution of desmocollin in pemphigus

Table 1: distribution of Dsc 3, Dsc 1 and Dsg 1,2 in normal epithelium, oral PV, cutaneous PV and cutaneous PE NOM1 Oral PV NS2 Cutaneous PV Cutaneous PE Dsc 3 − 1 4 0 +4 106 ++ 15 5 8 1 4 Total 15 10 8 15 10 Dsc 1 − 2 1 +53 ++ 8 8 6 Total 8 15 10 Dsg 1,2 − 1 3 3 +5 54 ++ 15 4 8 7 3 Total 15 10 8 15 10 1. Normal oral mucosa 2. Normal skin

Table 2: Internalization of Dsc 3, Dsc 1 and Dsg 1,2 in normal epithelium, oral PV, cutaneous PV and cutaneous PE Dsc ３ Dsc １ Dsg 1,2 ＋－Total ＋－Total ＋－Total Normal oral mucosa 15 15 15 15 Normal skin ８８ ８８ ８８ Oral PV ３７10 ３７10 Cutaneous PV ９６15 ４ 11 15 ６９15 Cutaneous PE ６４10 ４６10 ６４10

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Fig. 4: Cutaneous PV. (a) Staining for Dsc 3 is weak at the cell membrane of blister roof cells, and a diffuse pattern is seen in the cytoplasm (original magnification ×400). (b) Staining for Dsc 1 is weak at the cell membrane of blister roof cells and acantholytic cells. A diffuse pattern of Dsc 1 staining is also evident in the cytoplasm (original magnifi- cation ×400). (c) Staining for Dsg 1,2 is weak at the cell membrane and a patchy granular pattern is seen in the cytoplasm (original magnification ×400). Oral Med Pathol 5(2000) 91 cytoplasm, Dsc 3 and Dsg 1,2 staining was also observed the 15 cases examined, strong staining was seen in 1 case in 3 of the 10 cases, the staining pattern appearing as for Dsc 3, 8 cases for Dsc 1 and 7 cases for Dsg 1,2 at the dense clumps, patchy granules or diffuse areas (Fig.3 c). cell membrane of most cells . On the other hand , in Internalization of Dsc 3 and Dsg 1,2 was evident in only 3 periblister cells, 4 of the 15 cases showed no staining for cases of oral PV (Table 2). Dsc 3 at the cell membrane and 10 cases showed weak staining (Fig.4 a) (Table 1). Staining for Dsc 1 was absent Cutaneous pemphigus vulgaris and weak at the cell membrane in 2 and 5 of the 15 cases, The distribution of Dsc 3, Dsc 1 and Dsg 1,2 in cuta- respectively (Fig.4 b). Three cases showed no staining for neous PV was different from that in normal skin. Among Dsg 1,2 and 5 cases were weakly stained at the cell mem-

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Fig. 5: Cutaneous PE. (a) Staining for Dsc 3 is weak at the cell membrane of periblister cells and a diffuse pattern is seen in the cytoplasm (original magnification ×400). (b) Stain- ing for Dsc 1 is strong at the membrane of periblister cells and a diffuse particle is seen in the cytoplasm (original magnification ×400). (c) The patchy granular staining is observed in the cytoplasm of the affected cells and its dis- tribution is weak at the cell membrane for Dsg 1,2 (origi- nal magnification ×400).

Table 3: Relationship between internalization of Dsc 3, Dsc 1 and Dsg 1,2 and clinical manifesta- tions in PV Dsc 3 Dsc 1 Dsg 1,2 Inter Non-Inter P Inter Non-Inter P Inter Non-Inter P Disease duration of oral PV <6 month １６ １６ ≧6month ２１ ２１ Total ３７>0.05 ３７>0.05

Disease duration of cutaneous PV <6 month １５ １５ ２４ ≧6mouth ８１ ３６ ４５ Total ９６<0.01 ４ 11 >0.05 ６９>0.05 Disease scale of cutaneous PV ≦10% ０４ １３ ２２ 10%~30% ５２ ３４ ２５ ≧30% ４０ ０４ ２２ Total ９６<0.01 ４ 11 >0.05 ６９>0.05 inter: internalization non-inter: non-internalization 92 Wang et al Immunohistochemical distribution of desmocollin in pemphigus brane of most cells (Fig.4 c). In the cytoplasm, staining cell layers (13). Dsg 1 is expressed throughout the epider- for Dsc 3 was found in 9 cases (Table 2). A diffuse stain- mis, but more intensely superficially (17). Dsg 2 is con- ing pattern was seen in acantholytic cells and periblister fined to the basal cell layer, its level of expression being cells. In 4 cases, diffuse staining for Dsc 1 was found in particularly low in the epidermis, where it may be absent acantholytic cells and periblister cells and in 6 cases, Dsg (5). 1,2 showed a patchy granular staining pattern in blister Pemphigus vulgaris generally occurs during the roof and periblister cells. fourth and fifth decades of life, but may occur in all age groups including children (18). The distribution and fre- Cutaneous pemphigus erythematosus quency of PV in Chinese patients in terms of age and sex The distribution of Dsc 3, Dsc 1 and Dsg 1,2 in cuta- were similar to those in Japanese patients (19). Yang et neous PE differed from that in normal skin. Strong stain- al . (20) reported the use of anti-idiotype monoclonal anti- ing at the cell membrane of most cells was seen in 4 of the bodies against pemphigus and purified pemphigus anti- 10 cases for Dsc 3, 6 cases for Dsc 1, and 3 cases for Dsg body (PAb) from the serum of a patient with active pem- 1,2 (Table 1). The distribution of Dsc 3 was sparse in 6 phigus to establish an ELISA system for detecting PAb. cases at the cell membrane where the epithelium was There have been a few reports about the relation- markedly affected (Fig.5 a). Dsc 1 was absent in the cell ship between the distribution of Dsc in patients suffering membrane of the blister roof in 1 case , and weakly from pemphigus , especially PV , and the clinical and stained in 3 cases (Fig.5 b). Dsg 1,2 was absent in the pathogenic significance of Dsc autoantibodies (15). Hashi- membrane of most cells of the affected epithelium in 3 moto et al . (21) reported that serum from a PV patient re- cases, and was weakly expressed in 4 cases (Fig.5 c). In acted with both human and bovine Dsc 2. Antibodies the cytoplasm, strong staining was seen in 6 of the 10 against Dsc were also present in serum from pemphigus cases for Dsc 3, 4 cases for Dsc 1, and 6 cases for Dsg 1,2 patients, further suggesting the significance of anti-Dsc (Table 2). autoantibodies in this disease (22-24). Burge et al .(25) reported that there were changes in the distribution of Relationship between internalization of Dsc 3, Dsc 1 and desmosomal components of the epithelium in different Dsg 1,2 and clinical manifestations in oral and cutaneous forms of pemphigus. Alteration of the desmosomal compo- pemphigus vulgaris nents has been a controversial issue in acantholytic dis- There was a general trend for patients with a orders including PV , Hailey-Hailey’s disease , Darier’s longer duration of cutaneous PV (over 6 months) to ex- disease, and Grover’s disease (25-30). A consistent obser- hibit internalization of Dsc 3 (P<0.01) (Table 3). Patients vation in the present study was loss of the dotted pattern with a large area of skin surface involvement of cutane- on the cell membrane and that antigens appear in the cy- ous PV (>10%) were more likely to exhibit internalization toplasm of some cells for Dsc 3, Dsc 1 and Dsg 1,2. The of Dsc 3 (P<0.05). However, the relationship between in- distribution of Dsc 3,Dsc 1 and Dsg 1,2 in PV and PE was ternalization of Dsc 1, Dsg 1,2 and disease duration and different from that in normal epithelium. Normally, anti- severity of oral and cutaneous PV was not significant (P> bodies against desmosomal components stain the periph- 0.05). ery of cells in a uniform pattern. However, we found that staining for Dsc 3 and Dsg 1,2 was weak or absent at the Discussion membrane of most cells in the epithelium, and in acan- It has been postulated that pemphigus autoantibod- tholytic cells in oral and cutaneous PV. Endocytosis of ies may interfere directly with desmosome assembly (8) antigen-antibody complex with conformational changes or may stimulate to release plasminogen or proteolytic breakdown of the epitopes might result in activator, which in turn lyses the (9-11). Re- loss of staining after acantholysis (26). Cell-cell adhesion cently, there have been notable advances in the molecu- may be weakened by internalization, and acantholysis lar biological characterization and epitope mapping of the may be initiated, while in pemphigus dissolution is the autoantigens, and the pathogenic significance of these initial event (29). The change in Dsc 3 distribution was autoantibodies has been recognized ( 12 ) . Desmosomal more significant than that of Dsc 1 in cutaneous PV. In make an important contribution to the adhe- PE, staining of both Dsc 3 and Dsc 1 was less intense sion functions of desmosomes, and are differentially dis- than that in normal epithelium. Dsc 3 and Dsc 1 was sig- tributed in various layers of the stratified squamous epi- nificant in PE. thelium. This group comprises three shorter Dscs (Dsc 1, In PV, acantholysis occurs predominantly between Dsc 2 and Dsc 3), which are characterized by relatively the epidermal basal cells and suprabasal layers, where short cytoplasmic portions (13, 14), and three longer Dsgs the PV antigen probably has greatest importance for cell- (Dsg 1,Dsg 2 and Dsg 3), which have relatively long cyto- cell adhesion. In PE, intraepidermal cleavage is higher in plasmic portions (15, 16). Dsc 1 is present in the upper the epidermis, being usually located in or just below the spinous and granular cell layers, but not in the basal and granular layer. Pemphigus autoantibodies were reported lower spinous cell layers of the stratified epithelium (13) to be capable of inducing acantholysis in an in vitro organ and Dsc 3 is present in the basal, spinous and granular culture model (32) and inducing blistering at a specific Oral Med Pathol 5(2000) 93 level in the epidermis when it was passively transferred that not only , but also desmocollins play an to mice (33). Autoantibody binding might alter the behav- etiological role in PV. ior or localization of epithelial cadherins, interfere with the formation of desmosomes, or influence the function of Acknowledgement other desmosomal components (29). This work was supported by a Grant-in Aid Some investigators have demonstrated that inter- ( 11470375 ) from the Ministry of Education , Science , nalization of desmosomal antigens such as Dsg and Dsc Sports and Culture, Japan. occurs specifically in pemphigus, giving a pattern of cyto- plasmic patchy granules, ring staining and dense clumps References (25, 30). In the present study, three types of staining pat- 1. Stanley JR. Pemphigus. Dermatology in General Medicine . tern were observed in the cytoplasm. The clumping of Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF staining might be caused by patching of transmembrane (eds). Mac Graw-Hill. New York. 1993: 606-14. glycoproteins in the cell membrane. Patching might in- 2. Amagai M, Klaus-Kovtun V and Stanley JR. Autoantibodies terfere directly with the function of epithelial cadherins against a novel epithelial cadherin in pemphigus vulgaris, a or the assembly of desmosomes (25). Also, ring-like stain- disease of cell adhesion. Cell 1991; 67: 869-77. ing was observed within the acantholytic cells in some 3. Hashimoto T, Ogawa MM, Konohana A, et al . Detection of sections stained for Dsc 3 and Dsc 1, indicating internali- pemphigus vulgaris and pemphigus foliaceous antigens by zation of this transmembrane protein after the break- immunoblot analysis using different antigen sources. JIn- down of desmosomes (25). A few alterations of desmoso- vest Dermatol 1990; 94: 327-31. mal components were noted in early PV lesions, such as 4. Ebihara T, Hashimoto T, Iwatsuki K, et al . Autoantigens for those in oral PV, compared with cutaneous PV in which IgA anti-intercellular antibodies of intercellular IgA vesicu- cytoplasmic patchy granules, ring-like staining and dense lopustular dermatosis. J Invest Dermatol 1991; 97: 742-5. clumps occurred within the acantholysis cells and around 5. Chidgey MAJ. Desmosomes and disease. Histol Histopathol the blister. This discrepancy might reflect differences in 1997; 12: 1159-68. the disease activity and sensitivity of immunostaining 6. Demirkesen C, Hoede N and Moll R. Epithelial markers and studies because cytoplasmic granules were seldom de- differentiation in adnexal neoplasms of the skin: An immu- tected in patients who had mild PV. nohistochemical study including individual cytokeratins. J To clarify the relationship between internalization Cutan Pathol 1995; 22: 518-35. of Dscs and clinical manifestation in cutaneous PV, we 7. Tronnier M, Alexander M and Wolff HH. Adhesion molecule investigated lesions and disease duration in 10 cases of expression in normal skin and melanocytic lesions. JCutan oral PV and 15 cases of cutaneous PV. There was a gen- Pathol 1997; 24: 278-85. eral trend for patients with longer disease duration and a 8. Amagai M. Adhesion molecules. I: -keratinocyte large area of affected skin to exhibit internalization of interactions; cadherins and pemphigus. J Invest Dermatol Dsc 3 and Dsc 1,compared with those with a shorter dis- 1995; 104: 146-52. ease duration and less extensive involvement. Four cases 9. Hashimoto K, Shafran KM, Webber PS, et al . Anti-cell sur- of cutaneous PV showed internalization of Dsc 1, 9 cases face pemphigus autoantibody stimulates plasminogen acti- showed internalization of Dsc 3, and 3 cases showed in- vator activity of human epidermal cells. A mechanism for the ternalization of both Dsc 3 and Dsc 1, indicating that Dsc loss of epidermal cohesion and blister formation. J Exp Med 3 might work together with Dsc 1 in the pathogenic proc- 1983; 157: 259-72. ess of PV. The autoantigens recognized by PV and PF 10. Morioka S, Lazarus GS, Jensen PJ, et al . Involvement of autoantibodies have been identified as Dsg 3 and Dsg 1, urokinase-type plasminogen activator in acantholysis in- respectively (2). Patients with pemphigus have anti-Dsg duced by pemphigus IgG. J Invest Dermatol 1987; 89: 474-7 1 and/or anti-Dsg 3 IgG autoantibodies, but no anti-Dsg 2 11. Seishima M, Esaki C, Osada K, et al . Pemphigus IgG, but not antibodies (17). It has been reported recently that anti- bullous pemphigoid IgG, causes a transient increase in intra- Dsg 1 autoantibodies in sera from PV patients are patho- cellular calcium and inositol 1,4,5-trisphosphate in DJM-1 genic (31). In the present study, Dsg 1,2 was evident in cells , a squamous cell carcinoma line . J Invest Dermatol desmosomes in 7 cases and the cytoplasm in 6 cases of cu- 1995; 104: 33-7 taneous PV, and in desmosomes in 4 cases and the cyto- 12. Robinson ND, Hashimoto T, Amagai M, et al . The new pem- plasm in 3 cases of oral PV. Also, in PE, Dsg 1,2 was evi- phigus variants. J Am Acad Dermatol 1999; 40: 649-71. dent in desmosomes in 3 cases and in the cytoplasm in 6 13. King IA, Arnemann J, Spurr NK, et al . Cloning of the cDNA cases. These results provide strong evidence that autoan- (DSC 1) coding for human type 1 desmocollin and its assign- tibodies against Dsg 1 participate in the immune injury ment to chromosome 18. Genomics 1993; 18: 185-94. to the epidermis and mucosal tissues in patients with PV 14. Nuber UA, Schafer S, Stehr S, et al . Patterns of desmocollin and PE, as reported previously. synthesis in human epithelia: immunolocalization of desmo- In conclusion, all of these findings suggest that the collins 1 and 3 in special epithelia and in cultured cells. Eur internalization of Dsc 3 and Dsc 1 is closely associated JCellBiol 1996; 71: 1-13. with the disease duration, severity and stage of PV, and 15. Koch PJ and Franke WW. Desmosomal cadherins: another 94 Wang et al Immunohistochemical distribution of desmocollin in pemphigus

growing multigene family of adhesion molecules. Curr Opin study of desmosomal components in pemphigus. Br J Derma- Cell Biol 1994; 6: 682-7. tol 1993; 128: 363-70. 16. Kowalczyk AP, Stappenbeck TS, Parry DA, et al . Structure 26. Hashimoto K, Fujiwara K, Tada J, et al . Desmosomal disso- and function of desmosomal transmembrane core and plaque lution in Grover’s disease, Hailey-Hailey’s disease and Dar- molecules. Biophys Chem 1994; 50: 97-112. ier’s disease. JCutanPathol 1995; 22: 488-501. 17. Amagai M. Autoimmunity against desmosomal cadherins in 27. Setoyama M, Choi KC, Hashimoto K, et al .Ⅰ pemphigus. J Dermatol Scien 1999; 20: 92-102. and Ⅱ in acantholytic dermatoses: Preservation in pemphi- 18. Rebert EJ. Pemphigus.InDermatology in General Medicine. gus vulgaris and pemphigus erythematosus and dissolution Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF in Hailey-Hailey’s disease and Darier’s disease. J Dermatol (eds). McGraw-Hill. New York. 1993: 571-9. Sci 1991; 2: 9-17. 19. Jinbu Y, Akasaka Y. Autoimmune bullous diseases in oral 28. Tada J and Hashimoto K. Ultrastructural localization of cell mucosa. Molecular mechanisms of cell adhesion and blister junctional components (desmoglein, , E-cadherin, formation. J Oral Mucosa 1998; 4: 25-43 (in Japanese). and β-catenin) in Hailey-Hailey disease, Darier’s disease, and 20. Weibing Y, Qingchun D and Qingyi Y. Detection of pem- pemphigus vulgaris. JCutanPathol 1998; 25: 106-15. phigus antibodies with indirect-ELISA and ABC-ELISA . 29. Tada J and Hashimoto K . Curvicircular intracytoplasmic ChinJDermatol 1998; 31: 218-20 (in Chinese with English membranous structures in keratinocytes of pemphigus foli- abstract) . aceus. JCutanPathol 1996; 23: 511-7. 21. Hashimoto T, Amagai M, Watanabe K, et al .Acaseofpem- 30. Iwatsuki K, Han G-W, Fukuti R, et al . Internalization of con- phigus vulgaris showing reactivity with pemphigus antigens stitutive desmogleins with the subsequent induction of des- (Dsg 1 and Dsg 3)and desmocollins. J Invest Dermatol 1995; moglein 2 in pemphigus lesions. Br J Dermatol 1999; 140: 104: 541-4. 35-43. 22. Hashimoto T, Kiyokawa C, Mori O, et al . Human desmocollin 31. Ding X, Diaz LA, Fairley JA, et al . The anti-desmoglein 1 1 (Dsc 1) is an autoantigen for the subcorneal pustular der- autoantibodies in pemphigus vulgaris sera are pathogenic. J matosis type of IgA pemphigus. J Invest Dermatol 1997; 109: Invest Dermatol 1999; 112: 739-43. 127-31. 32. Hashimoto K, Singer KH, Lide WB, et al . Plasminogen acti- 23. Hashimoto K, Hashimoto T, Higashiyama M, et al . Detection vator in cultured human epidermal cells. J Invest Dermatol of anti-desmocollinsⅠandⅡautoantibodies in two cases of 1983; 81: 424-9. Hallopeau type pemphigus vegetans by immunoblot analysis. 33. Anhalt GJ, Labib RS, Voorhess JJ, et al . Induction of pem- J Dermatol Sci 1994; 7: 100-6. phigus in neonatal mice by passive transfer of IgG from pa- 24. Dmochowski M, Hashimoto T, Chidgey MA, et al . Demon- tients with the disease. N Engl J Med 1982; 306: 1189-96. stration of antibodies to bovine desmocollin isoforms in cer- tain pemphigus sera. Br J Dermatol 1995; 133: 519-25. (Accepted for publication October 16, 2000) 25. Burge SM, Wilson CL, Dean D, et al . An immunohistological