On October 23rd, 2014, we updated our
By continuing to use LinkedIn’s SlideShare service, you agree to the revised terms, so please take a few minutes to review them.
18 D. Tsuruta et al.and alopecia areata. In this review, we focus on autoimmune bullousdiseases. Combinations of various diagnostic tools are used for thediagnosis.The major cell–cell adhesion moieties in keratinocytes are the des-mosomes (4), the major components of which are grouped threeprotein families: cadherins, plakins, and armadillo proteins (Fig. 1)(4). Desmosomal cadherins are divided into two transmembraneprotein families: desmogleins 1–4 and desmocollins 1–3 (4). Theircytoplasmic tails bind to armadillo family members, plakoglobin,plakophilins 1–3, and p0071 (4). Desmoplakin, a plakin familyprotein, tethers these molecules to keratin intermediate ﬁlamentsin the cytoplasm (5).Isoform-speciﬁc expression of desmogleins and desmocollins isobserved in the epithelium and epidermis (4). Simple epitheliaexpress only desmoglein 2 and desmocollin 2 (4). In contrast, theepidermis shows high expression of desmogleins 1 and 3, and des-mocollins 1 and 3, but low expression of desmoglein 2 and desmo-collin 2 (4). Desmoglein 4 is concentrated in the granular andcorniﬁed layers as well as hair follicles (4). Desmogleins are themajor targets in pemphigus, the prototype of autoimmune bullousdisease (6).2. MolecularPathogenesis ofCell–Cell AdhesionLoss in theEpidermisFig. 1. Schematic diagram of the most important molecules for keratinocyte cell–cell adhesion. PP plakophilin, PGplakoglobin, DP desmoplakin.
192 Diagnosis of Autoimmune DiseasesThe major structures for cell–extracellular matrix adhesion inkeratinocytes are hemidesmosomes (Fig. 2) (7). Major hemides-mosomal transmembrane proteins are BP180/collagen XVII, inte-grin α6 subunit, integrin β4 subunit, and CD151 tetraspanin (8).Both BP180 and α6β4 integrin interact with laminin-332 in thebasement membrane zone (9). In the cytoplasm, α6β4 integrinassociates with keratin intermediate ﬁlaments (10). The cytoplas-mic tail of β4 integrin has a unique long stretch of 1,000 aminoacids (7). Through this cytoplasmic tail, α6β4 integrin binds toBP180, BP230, and plectin (7). The latter two proteins belong tothe plakin family and mediate the indirect connection of α6β4integrin not only to keratin intermediate ﬁlaments but also micro-tubules and actin microﬁlaments (10). Hemidesmosomal compo-nents are targets of autoantibodies in subepidermal autoimmunebullous diseases.Pemphigus is an autoimmune bullous disease whose autoantigensare the desmogleins, main desmosomal constituents (6). The pem-phigus disease variants and the associated autoantigens are summa-rizedinTable1.Histopathologically,itischaracterizedbyacantholysis3. MolecularPathogenesisof Cell–MatrixAdhesion Lossin the Skin4. AutoimmuneBullous DiseasesTargetingKeratinocyteCell–Cell AdhesionFig. 2. Schematic diagram for the main molecules for keratinocyte–extracellular matrixadhesion. LN laminin.
20 D. Tsuruta et al.and intraepidermal blister formation (11). Pemphigus is divided intotwo main types: pemphigus vulgaris (PV) and pemphigus foliaceus(PF) (12). Pemphigus vegetans is a rare variant of PV, and pemphiguserythematosus resembles PF (13). In addition, further very rareentities of the pemphigus group are represented by IgA pemphigusand tumor-related paraneoplastic pemphigus (13, 14).The expression of desmogleins 1 and 3 is different in the skinand the oral mucosa (Fig. 3). Desmoglein compensation theorycan explain the difference of clinical ﬁndings between PV reactivewith desmoglein 3 and PF reactive with desmoglein 1. In the skin,desmoglein 1 is strongly expressed throughout the epidermis, beingstronger in the superﬁcial epidermis (15). The expression of des-moglein 3 is primarily observed in the basal and suprabasal epider-mis. In contrast, in the oral mucosa, desmoglein 1 and 3 are foundthroughout the entire epithelium, although the expression of des-moglein 1 is much weaker than desmoglein 3. First, why mucosal-dominant lesions are found in PV, while skin-dominant lesions arefound in PF? This is essentially due to the fact that in the oralmucosa, anti-desmoglein 3 antibodies in PV disrupt epithelial cell–cell adhesions, which are not compensated by small amount of des-moglein 1, whereas anti-desmoglein 1 antibodies cannot disruptdesmoglein 3-rich epithelial cell. Second, in the skin, anti-desmoglein3 antibodies cannot disrupt cell–cell adhesion because desmoglein1 compensates the loss of desmoglein 3-mediated adhesion. Incontrast, anti-desmoglein 1 antibodies cause disruption in theupper epidermis, where no desmoglein 3 is present (Fig. 2).Table 1Classiﬁcation, antibody classes and autoantigens forautoimmune bullous diseases which target keratinocytecell–cell adhesionDisease Ab class AutoantigenPemphigus vulgarisMucosal-dominant type IgG Dsg3Mucocutaneous type IgG Dsg3, Dsg1Pemphigus vegetans IgG Dsg3, Dsg1, DscsPemphifus foliaceus IgG Dsg1Pemphigus erythematosus IgG Dsg1Pemphigus herpetiformis IgG Dsg3, Dsg1, DscsParaneoplastic pemphigus IgG Dsg3, Dsg1, Desmoplakin I, II,BP230, envoplakin, periplakin,plectin, epiplakin, Dscs, A2ML1Drug-induced pemphigus IgG Multiple (mainly Dsg1)IgA pemphigusSPD type IgA Dsc 1IEN type IgA unidentiﬁedDsc desmocollin
212 Diagnosis of Autoimmune DiseasesIn PV, most patients suffer from refractory erosions or ulcers onthe oral mucosae including the lips and tongue (12, 16). Some PVpatients also show ﬂaccid bullae and erosions on the skin (12). PVpatients may also have erosions on other mucosae including larynx,pharynx, esophagus, conjunctiva, and vagina (17–19). Pemphigusvegetans is a variant of PV (13).The diagnosis of PV and pemphigus vegetans is made by com-bination method of direct immunoﬂuorescence showing the depo-sition of IgG and/or C3 at the keratinocyte cell surfaces (20) andenzyme-linked immunosorbent assays for IgG antibodies to des-moglein 3 and desmoglein 1. This is required for the correct diag-nosis of all pemphigus group diseases (21). In mucosal-dominanttype PV, anti-desmoglein 3 but not anti-desmoglein 1 antibodiesare present (21). In contrast, in mucocutaneous type PV, antibod-ies for both desmoglein 1 and desmoglein 3 are present (21).PF is characterized by superﬁcial erosions and bullae and erythema,preferentially on the seborrheic regions (6). Oral mucosal lesionsare not present (6). Pemphigus erythematosus is a variant of PF.The butterﬂy shadow is characteristic of pemphigus erythematosus(13). The diagnosis of PF and pemphigus erythematosus is madevia the same methodology as PV, described above.5. PemphigusVulgaris andPemphigusVegetans6. PemphigusFoliaceus andPemphigusErythematosusFig. 3.The distribution of desmogleins in the epidermis for the explanation for desmogleincompensation theory. Dsg1 desmoglein 1, Dsg3 desmoglein 3.
22 D. Tsuruta et al.Clinically, pemphigus herpetiformis is characterized by small vesi-cles arranged in an annular fashion on the pruritic erythemas,resembling clinically dermatitis herpetiformis Duhring (22). Thediagnosis of pemphigus herpetiformis is exclusively on the basis ofits characteristic clinical features associated with histopathologicalintraepidermal eosinophilic pustules with minimal acantholysis(23). IgG autoantibodies to desmocollins may contribute to pem-phigus herpetiformis, although they are not always found (22, 24).The detection of autoantibodies to desmocollins is done by indi-rect immunoﬂuorescence using desmocollin cDNA-transfectedCOS7 cells (24).IgA pemphigus is clinically deﬁned by generalized multiple ﬂaccidpustules or vesicles (25). The hallmark ﬁnding of IgA pemphigusis deposition of IgA on keratinocyte cell surfaces by directimmunoﬂuorescence (25). IgA pemphigus is subdivided intosubcorneal pustular dermatosis type and intraepidermal neutro-philic IgA dermatosis type (25). The autoantigen of the former isdesmocollin 1, but that of the latter is unidentiﬁed yet (25). IgAautoantibodies to desmocollin 1 were ﬁrst detected by indirectimmunoﬂuorescence using desmocollin 1 cDNA-transfectedCOS7 cells (26).Paraneoplastic pemphigus is characterized by pseudomembranousconjunctivitis and refractory stomatitis (27). The skin symptoms arevariable, including erythema, ﬂaccid bullae, tense bullae, erosion,erythema multiforme-like lesions, and/or lichen planus-like lesions(28). Paraneoplastic pemphigus is associated with the presence ofinternal benign or malignant tumors, including Castleman’s disease,malignant lymphomas and other solid cancers (14). If treatment isineffective, cases with bronchiolitis obliterans are mostly fatal (29).Diagnosis of paraneoplastic pemphigus is now made by the positiveIgG reaction by indirect immunoﬂuorescence using rat bladder sec-tions and a double-positive reaction to the 210 kDa envoplakin and190 kDa periplakin by immunoblotting using normal epidermalextracts (30, 31). In addition, anti-desmoplakin and anti-plectin anti-bodies are sometimes also found by immunoblotting (14).7. PemphigusHerpetiformis8. IgA Pemphigus9. ParaneoplasticPemphigus
232 Diagnosis of Autoimmune DiseasesThe autoimmune bullous diseases which target the basement mem-brane zone and their autoantigens are presented in Table 2. Bullouspemphigoid is the most common among all autoimmune bullousdiseases (32).Bullous pemphigoid is the most common autoimmune bullousdisease seen in the elderly, and is characterized by itchy erythemaand tense bullae, caused by IgG autoantibodies to the hemidesmo-somal proteins, BP180 and BP230 (33). Bullous pemphigoidpatients occasionally develop mucosal lesions (33). Bullous pem-phigoid is believed to have higher association of internal malig-nancy (34). As a pathomechanism, autoantibodies to BP180 causemigration of neutrophils and eosinophils and activation of pro-teases, resulting in proteolysis of the basement membrane zone(35, 36). The diagnosis of bullous pemphigoid is made by directand indirect immunoﬂuorescence, immunoblotting and ELISA(37, 38). Direct immunoﬂuorescence using patient skin showsdeposition of C3 and/or IgG to the basement membrane zone(37). Indirect immunoﬂuorescence using normal human skin sec-tions detects circulating IgG antibodies to the basement membranezone (37). Additionally, by indirect immunoﬂuorescence usingsections of 1 M NaCl-split normal human skin, patient sera reactwith the epidermal side of the split (37, 38). By immunoblotting,IgG in the patient sera reacts with BP180 and/or BP230 (33).ELISA with either the recombinant NC16a domain of BP180 andmixture of C- and N-terminal domains of BP230 protein shows asensitivity of about 85% (39, 40). However, when the both testswere performed, sensitivity raises to 96% (40).Patients with mucous membrane pemphigoid occasionally developskin lesions similar to bullous pemphigoid, which tend to heal withscars (41). However, predominant clinical manifestations are ery-themas, bullae, and erosions on the oral, nasal, and ocular muco-sae (42). Blindness caused by adhesive conjunctivitis is the mostsevere complication for mucous membrane pemphigoid (43). Thetwo major target autoantigens are the C-terminus of BP180 and10. AutoimmuneDiseases TargetingStructuresMediating Cell–Matrix Adhesion11. BullousPemphigoid12. MucousMembranePemphigoid
24 D. Tsuruta et al.laminin-332 (44, 45). Diagnosis is made by direct and indirectimmunoﬂuorescence and immunoblotting. The ﬁndings of directand indirect immunoﬂuorescence using normal human skin sec-tions and 1 M salt split skin sections for anti-BP180-type mucousmembrane pemphigoid are the same as for bullous pemphigoid,except that IgA is also frequently detected (46, 47). The IgG andIgA antibodies react with BP180 in epidermal extracts and recom-binant protein of BP180 C-terminus domain by immunoblotting(48). IgG antibodies in the sera of anti-laminin-332 mucous mem-brane pemphigoid react with dermal side of split skin and withlaminin-332 by immunoblotting using human laminin-332puriﬁed from normal human keratinocyte culture media (49). Inaddition, autoantibodies to α6β4 integrin are reported to be asso-ciated with ocular-type mucous membrane pemphigoid (50).Anti-laminin γ1 pemphigoid is characterized by tense bullae anderosions and is frequently associated with psoriasis (51).Histopathologically, it is characterized by subepidermal blisterswith neutrophilic inﬁltrations (51). Although directimmunoﬂuorescence and indirect immunoﬂuorescence using normalhuman skin sections give the same results as bullous pemphigoid,13. Anti-Lamining1 (p200)PemphigoidTable 2Classiﬁcation, antibody classes, and autoantigens for autoimmune bullousdiseases which target keratinocyte–extracellular matrix adhesionDisease Ab class AutoantigenBullous pemphigoid IgG BP180, BP230Herpes gestationis IgG BP180Mucous membrane pemphigoidanti-BP180 type IgG, IgA BP180anti-laminin-332 type IgG Laminin-332ocular type IgG Integrin β4 subunitLinear IgA bullous dermatosislamina lucida type IgA 97/120 kDa LAD-1sub-lamina densa type IgA Unidentiﬁed (type VII collagen)Epidermolysis bullosa acquisita IgG Type VII collagenBullous SLE IgG Type VII collagenAnti-laminin γ1 pemphigoid IgG Laminin γ1 subunitDermatitis herpetiformis Duhring IgA Transglutaminase 3
252 Diagnosis of Autoimmune Diseasespatient IgG reacts with the dermal side of split skin (50).Immunoblotting using dermal extracts shows IgG reactivity with a200 kDa protein (50), which was identiﬁed as laminin γ1 (52).Herpes (pemphigoid) gestationis occurs during pregnancy andearly postpartum, or in patients with hydatidiform moles or chori-oepithelioma (53). Clinically, it is characterized by severe pruritusand tense bullae on the urticarial inﬁltrative erythema (54). Themain autoantigen is the NC16a domain of BP180, as in bullouspemphigoid (54–56). Most patients enter remission after preg-nancy, but a few cases show a prolonged clinical course (54).Although the reason why herpes gestationis occurs only in preg-nancy is not known, some studies have suggested the role of HLArelated immunogenetics (57, 58).Dermatitis herpetiformis clinically shows tense vesicles on the peripheryof annular inﬁltrative exudative erythema, which exhibit symmetricaldistribution on the knees, elbows, and buttocks (59). In Caucasian,but not Japanese, patients dermatitis herpetiformis Duhring is associ-ated with celiac disease (60). Direct immunoﬂuorescence showsgranular deposits of IgA and C3 in the papillary dermis (61). In addi-tion, recently, the target autoantigen has been identiﬁed as epidermaltransglutaminase (transglutaminase 3) (62, 63).Clinically, linear IgA bullous dermatosis develops pruritic smallvesicles in the periphery of annular inﬁltrative erythemas, similar todermatitis herpetiformis Duhring (64). The linear deposition ofIgA at the basement membrane zone seen in direct and indirectimmunoﬂuorescence is a hallmark for the diagnosis of the diseaseand the origin of its name (64). The target autoantigen is97/120 kDa LAD-1, a shedding product of BP180, excised prob-ably by a protease of ADAM family (65). IgA autoantibodies toLAD-1 are detected by immunoblotting using concentratedHaCaT cell culture media (64). In addition, an ELISA system wasdeveloped for the detection of IgA autoantibodies against BP180in linear IgA bullous dermatosis (66).14. HerpesGestationis15. DermatitisHerpetiformisDuhring16. Linear IgABullousDermatosis
26 D. Tsuruta et al.Epidermolysis bullosa acquisita is divided into inﬂammatory andnon-inﬂammatory types; the former shows bullous pemphigoid-like skin lesion, and the latter shows non-erythematous blistersleaving scarring and milia (67). The target autoantigen is type VIIcollagen, a major component of the anchoring ﬁbrils (67). Findingsin indirect immunoﬂuorescence using sections of normal humanskin and salt-split skin are the same as those in anti-laminin-γ1pemphigoid and anti-laminin-332 mucous membrane pemphigoid(67). The detection of autoantibodies to type VII collagen byimmunoblotting using normal dermal extracts as substrates is help-ful for diagnosis (67).Direct immunoﬂuorescence for IgG, IgA, and C3 is performed inorder to distinguish between pemphigus group diseases, varioustypes of pemphigoid, and dermatitis herpetiformis Duhring (6, 33,68). Deposition of IgG and IgA to the keratinocyte cell surfaces isindicative of the diagnosis of various types of pemphigus (6), andIgA pemphigus (25), respectively. Deposition of IgG and IgA tothe basement membrane zone is characteristic for diseases of thepemphigoid group (33), and linear IgA bullous dermatosis (69),respectively. Dermatitis herpetiformis Duhring shows granular orﬁbrillar deposition of IgA and/or C3 in dermal papillae (68).By indirect immunoﬂuorescence using normal human skin sec-tions, IgG from pemphigus patients reacts with the keratinocytecell surfaces, while IgG from pemphigoid patients reacts with thebasement membrane zone (6, 33). In mucous membrane pemphi-goid, IgG and IgA to the basement membrane zone are frequentlynegative because of their low titers (70). IgA from linear IgAbullous dermatosis patients reacts with the basement membranezone, although false-negative reactions are also occasionally seen,due to the low titer of the autoantibodies (71).Indirect immunoﬂuorescence using salt-split normal humanskin sections is used for differential diagnosis of pemphigoid groupdiseases. 1 M NaCl treatment results in a split at the level of thelamina lucida. Sera from patients with bullous pemphigoid, anti-BP180-type mucous membrane pemphigoid and linear IgAbullous dermatosis react to the epidermal side of the split, whilesera from patients with anti-laminin γ1 pemphigoid, epidermoly-sis bullosa acquisita, and anti-laminin-332 mucous membranepemphigoid react with dermal side (33, 52, 64, 67, 72).Complement immunoﬂuorescence is used for diagnosis of herpes17. EpidermolysisBullosa Acquisita18. DiagnosticTechniques for theAutoimmuneBullous Diseases18.1. Immuno-ﬂuorescence
272 Diagnosis of Autoimmune Diseasesgestationis (55). Moreover, indirect immunoﬂuorescence usingrat bladder sections detects anti-plakin antibodies in paraneoplas-tic pemphigus, and indirect immunoﬂuorescence using COS7cells transfected with cDNAs of desmocollins 1–3 is used to detectIgA anti-desmocollin 1 antibodies in subcorneal pustular derma-tosis type IgA pemphigus and IgG antibodies to desmocollins 1–3in pemphigus herpetiformis, pemphigus vegetans, or paraneoplas-tic pemphigus (26, 31).The enzyme-linked immunosorbent assay is used to diagnose andto monitor the clinical course for pemphigus group diseases andbullous pemphigoid (21, 39, 40). The recombinant proteins areprepared by baculovirus expression for desmoglein 1 and desmog-lein 3 or by E. coli expression for NC16a domain of BP180 andN- and C-terminal domains of BP230 (21, 39, 40). A limitation ofcurrent enzyme-linked immunosorbent assays is that the results arenot always correlated with disease severity. This is thought to bemostly due to the presence of nonpathogenic antibodies (73).Therefore, future development of enzyme-linked immunosorbentassays speciﬁc for the pathogenic epitopes is required. Enzyme-linked immunosorbent assay for envoplakin is now commerciallyavailable, too (74). At the experimental stage, ELISA systems fordetecting desmocollins, periplakin, type VII collagen, LAD-1,laminin γ1, and A2ML1 are already available, but are not yetreleased for routine clinical diagnostic use (42, 66, 75, 76).Immunoblotting is performed as follows: normal human epider-mal or dermal extracts, or keratinocyte cell lysates are electropho-retically separated and then transferred to nitrocellulose or PVDFmembranes. Patient sera are then reacted with these membranes.In addition, recombinant proteins for various antigens, puriﬁedlaminin-332 and concentrated culture medium of HaCaT cells arealso used for subepidermal autoimmune bullous diseases. The sub-strates used in immunoblotting studies for each disease are sum-marized in Table 3.An algorithm for the differential diagnosis for each disease isshown in Fig. 4. Using this methodology, we can logically diag-nose all autoimmune bullous diseases. However, rapid progress inmolecular techniques suggests that this algorithm will needsequential modiﬁcation and updating. In particular, in the nearfuture, diagnostic enzyme-linked immunosorbent assays for theentire list of the aforementioned autoantigens should be intro-duced for clinical use.18.2. Enzyme-LinkedImmunosorbentAssays18.3. ImmunoblotAnalyses19. Conclusions
28 D. Tsuruta et al.Table 3The substrates used in immunoblotting studies for autoimmune bullous diseasesSubstrates DiseasesHuman epidermal extract Pemphigus, BP, herpes gestationisHuman dermal extract EBA, anti-laminin γ1 pemphigoidHaCaT cell culture medium LABDPuriﬁed laminin-332 Laminin-332 type MMPRecombinant proteinsBP180 NC16a domain BP, herpes gestationisBP180 C-terminus BP180 type MMPBP230 BPType VII collagen EBAEnvoplakin, periplakin PNPBP bullous pemphigoid, EBA epidermolysis bullosa acquisita, LABD linear IgA bullous dermatosis, MMPmucous membrane pemphigoid, PNP paraneoplastic pemphigusFig. 4 Algorithm for the diagnosis for all autoimmune bullous diseases. BMZ basement membrane zone, CIF complementimmunoﬂuorescence, CS cell surface, C-ter carboxy terminus, der dermal, Dsc desmocollin, Dsg1 desmoglein 1, Dsg3desmoglein 3, EBA epidermolysis bullosa acquisita, epi epidermal, IB immunoblot, IEN intraepithelial neutrophilic IgAdermatosis, IIF indirect immunoﬂuorescence, LAD linear IgA bullous dermatosis, lam laminin, MMP mucous membranepemphigoid, m-PV mucosal-dominant type pemphigus vulgaris, mc-PV mucocutaneous type pemphigus vulgaris, PE pem-phigus erythematosus, pem pemphigus, PF pemphigus foliaceus, PH pemphigus herpetiformis, PNP paraneoplasticpemphigus, Pveg pemphigus vegetans, rec recombinant, SPD subcorneal pustular dermatosis, VII col type VII collagen.
292 Diagnosis of Autoimmune DiseasesAcknowledgmentWe greatly appreciate Ms. Ayumi Suzuki, Ms. Takako Ishikawa,and Ms. Sachiko Sakaguchi for technical assistance, and Ms. AkikoTanaka, Ms. Yasuko Nakayama, Ms. Emiko Hara, Ms. HanakoTomita, Ms. Mihoko Ikeda, Ms. Kyoko Akashi, and Ms. NobukoIshii for secretarial work.References1. Lleo A, Invernizzi P, Gao B, Podda M,Gershwin ME (2010) Deﬁnition of humanautoimmunity-autoantibodies versus autoim-mune disease. Autoimmun Rev 9:A259–A2662. Lin YS, Yeh TM, Lin CF, Wan SW, ChuangYC, Hsu TK, Liu HS, Liu CC, Anderson R, LeiHY (2011) Molecular mimicry between virusand host and its implications for dengue diseasepathogenesis. Exp Biol Med (Maywood)236:515–5233. Vasanthakumari R (2007) Autoimmunity. In:Vasanthakumari R (ed) Textbook of micro-biology, BI Publications Pvt Ltd, New Delhi,pp 154–1584. Green KJ, Simpson CL (2007) Desmosomes:new perspectives on a classic. J Invest Dermatol127:2499–25155. Hatsell S, Cowin P (2001) Deconstructingdesmoplakin. Nat Cell Biol 3:E270–2726. Stanley JR (2008) Pemphigus. In: Wolff K,Goldsmith LA, Katz SI, Gilchrest BA, PallerAS, Leffell DJ (eds) Fitzpatrick’s Dermatologyin General Medicine, 7th edn. McGraw Hill,New York, pp 459–4687. Tsuruta D, Hashimoto T, Hamill KJ, Jones JC(2011) Hemidesmosomes and focal contactproteins: functions and cross-talk in keratino-cytes, bullous diseases and wound healing.J Dermatol Sci 62:1–78. Sterk LM, Geuijen CA, Oomen LC, Calafat J,Janssen H, Sonnenberg A (2000) The tetraspanmolecule CD151, a novel constituent of hemi-desmosomes, associates with the integrin alpha-6beta4 and may regulate the spatial organizationof hemidesmosomes. J Cell Biol 149:969–9829. Tsuruta D, Kobayashi H, Imanishi H, SugawaraK, Ishii M, Jones JC (2008) Laminin-332-integrin interaction: a target for cancer therapy?Curr Med Chem 15:1968–197510. Jones JC, Hopkinson SB, Goldﬁnger LE(1998) Structure and assembly of hemidesmo-somes. Bioessays 20:488–49411. Sitaru C, Zillikens D (2005) Mechanismsof blister induction by autoantibodies. ExpDermatol 14:861–87512. Hashimoto T (2003) Recent advances in thestudy of the pathophysiology of pemphigus.Arch Dermatol Res 295(Suppl 1):S2–1113. Huilgol SC, Black MM (1995) Management ofthe immunobullous disorders. II. Pemphigus.Clin Exp Dermatol 20:283–29314. Zimmermann J, Bahmer F, Rose C, ZillikensD, Schmidt E (2010) Clinical and immunop-athological spectrum of paraneoplastic pemphi-gus. J Dtsch Dermatol Ges 8:598–60615. Amagai M (1999) Autoimmunity against des-mosomal cadherins in pemphigus. J DermatolSci 20:92–10216. Payne AS, Hanakawa Y, Amagai M, Stanley JR(2004) Desmosomes and disease: pemphigusand bullous impetigo. Curr Opin Cell Biol16:536–54317. Barnes LM, Clark ML, Estes SA, BongiovanniGL (1987) Pemphigus vulgaris involving theesophagus. A case report and review of theliterature. Dig Dis Sci 32:655–65918. Frohlich (1951) Pemphigus vulgaris of thelower lip, tongue and conjunctiva. Z HautGeschlechtskr 11:xi19. Onuma K, Kanbour-Shakir A, Modery J,Kanbour A (2009) Pemphigus vulgaris of thevagina—its cytomorphologic features on liq-uid-based cytology and pitfalls: case report andcytological differential diagnosis. DiagnCytopathol 37:832–83520. Pohla-Gubo G, Hintner H (2011) Direct andindirect immunoﬂuorescence for the diagnosisof bullous autoimmune diseases. Dermatol Clin29:365–37221. Ishii K, Amagai M, Hall RP, Hashimoto T,Takayanagi A, Gamou S, Shimizu N, NishikawaT (1997) Characterization of autoantibodies inpemphigus using antigen-speciﬁc enzyme-linked immunosorbent assays with baculovirus-expressedrecombinantdesmogleins.JImmunol159:2010–201722. Tateishi C, Tsuruta D, Nakanishi T, UeharaS, Kobayashi H, Ishii M, Hashimoto T(2010) Antidesmocollin-1 antibody-positive,antidesmoglein antibody-negative pemphigus
30 D. Tsuruta et al.herpetiformis. J Am Acad Dermatol 63:e8–1023. Maciejowska E, Jablonska S, Chorzelski T(1987) Is pemphigus herpetiformis an entity?Int J Dermatol 26:571–57724. Kozlowska A, Hashimoto T, Jarzabek-Chorzelska M, Amagai A, Nagata Y, Strasz Z,Jablonska S (2003) Pemphigus herpetiformiswith IgA and IgG antibodies to desmoglein 1and IgG antibodies to desmocollin 3. J AmAcad Dermatol 48:117–12225. Tsuruta D, Ishii N, Hamada T, Ohyama B,Fukuda S, Koga H, Imamura K, Kobayashi H,KarashimaT,NakamaT,DainichiT,HashimotoT (2011) IgA pemphigus. Clin Dermatol29:437–44226. Hashimoto T, Kiyokawa C, Mori O, MiyasatoM, Chidgey MA, Garrod DR, Kobayashi Y,Komori K, Ishii K, Amagai M, Nishikawa T(1997) Human desmocollin 1 (Dsc1) is anautoantigen for the subcorneal pustular derma-tosis type of IgA pemphigus. J Invest Dermatol109:127–13127. Niimi Y, Kawana S, Hashimoto T, Kusunoki T(2003) Paraneoplastic pemphigus associatedwith uterine carcinoma. J Am Acad Dermatol48:S69–7228. Frew JW, Murrell DF (2011) Paraneoplasticpemphigus (paraneoplastic autoimmune mul-tiorgan syndrome): clinical presentations andpathogenesis. Dermatol Clin 29:419–42529. Anhalt GJ (2004) Paraneoplastic pemphigus.J Investig Dermatol Symp Proc 9:29–3330. Lee SE, Kim HR, Hashimoto T, Kim SC(2008) Paraneoplastic pemphigus developedshortly after resection of follicular dendritic cellsarcoma. Acta Derm Venereol 88:410–41231. Niimi Y, Ohyama B, Di Zenzo G, Calabresi V,Hashimoto T, Kawana S (2010) Paraneoplasticpemphigus presenting as mild cutaneous fea-tures of pemphigus foliaceus and lichenoidstomatitis with antidesmoglein 1 antibodies.Dermatol Res Pract pii:93134032. Kulthanan K, Chularojanamontri L, TuchindaP, Sirikudta W, Pinkaew S (2011) Prevalenceand clinical features of Thai patients withbullous pemphigoid. Asian Pac J AllergyImmunol 29:66–7233. Stanley JR (2008) Bullous pemphigoid. In:Wolff K, Goldsmith LA, Katz SI, Gilchrest BA,Paller AS, Leffell DJ (eds) Fitzpatrick’s derma-tology in general medicine, 7th edn. McGrawHill, New York, pp 475–48034. Ogawa H, Sakuma M, Morioka S, Kitamura K,Sasai Y, Imamura S, Inaba Y (1995) The inci-dence of internal malignancies in pemphigusand bullous pemphigoid in Japan. J DermatolSci 9:136–14135. Ujiie H, Shibaki A, Nishie W, Shimizu H(2010) What’s new in bullous pemphigoid.J Dermatol 37:194–20436. Liu Z, Giudice GJ, Swartz SJ, Fairley JA, TillGO, Troy JL, Diaz LA (1995) The role ofcomplement in experimental bullous pemphig-oid. J Clin Invest 95:1539–154437. Schmidt E, Della Torre R, Borradori L (2011)Clinical features and practical diagnosis of bullouspemphigoid. Dermatol Clin 29:427–43838. Barnadas MA, Gelpi C, Curell R, de Moragas JM,Alomar A (1999) Repeat direct immuno-ﬂuorescence (DIF) test, using, 1 M NaCl treatedskin, in the subepidermal autoimmune bullousdiseases that contain IgG at the dermal epidermaljunction. J Cutan Pathol 26:37–4139. Kobayashi M, Amagai M, Kuroda-Kinoshita K,Hashimoto T, Shirakata Y, Hashimoto K,Nishikawa T (2002) BP180 ELISA using bac-terial recombinant NC16a protein as a diag-nostic and monitoring tool for bullouspemphigoid. J Dermatol Sci 30:224–23240. Yoshida M, Hamada T, Amagai M, HashimotoK, Uehara R, Yamaguchi K, Imamura K,Okamoto E, Yasumoto S, Hashimoto T (2006)Enzyme-linked immunosorbent assay usingbacterial recombinant proteins of humanBP230 as a diagnostic tool for bullous pemphi-goid. J Dermatol Sci 41:21–3041. Egan CA, Yancey KB (2000) The clinical andimmunopathological manifestations of anti-epiligrin cicatricial pemphigoid, a recentlydeﬁned subepithelial autoimmune blisteringdisease. Eur J Dermatol 10:585–58942. Groth S, Recke A, Vaﬁa K, Ludwig RJ,Hashimoto T, Zillikens D, Schmidt E (2011)Development of a simple enzyme-linked immu-nosorbent assay for the detection of autoanti-bodies in anti-p200 pemphigoid. Br J Dermatol164:76–8243. Fleming TE, Korman NJ (2000) Cicatricialpemphigoid. J Am Acad Dermatol 43:571–591, quiz 591–57444. Zillikens D (2002) BP180 as the commonautoantigen in blistering diseases with differentclinical phenotypes. Keio J Med 51:21–2845. Dainichi T, Takeshita H, Moroi Y, Urabe K,Yoshida M, Hisamatsu Y, Komai A, Duan H,Koga T, Hashimoto T, Furue M (2005)Cicatricial pemphigoid with autoantibodiesagainst the laminin 5 gamma 2 subunit. Eur JDermatol 15:189–19346. Balding SD, Prost C, Diaz LA, Bernard P,Bedane C, Aberdam D, Giudice GJ (1996)
312 Diagnosis of Autoimmune DiseasesCicatricial pemphigoid autoantibodies reactwith multiple sites on the BP180 extracellulardomain. J Invest Dermatol 106:141–14647. Horvath B, Niedermeier A, Podstawa E, MullerR, Hunzelmann N, Karpati S, Hertl M (2010)IgA autoantibodies in the pemphigoids and lin-ear IgA bullous dermatosis. Exp Dermatol19:648–65348. Kobayashi K, Tanaka M, Nakajima S, Ito H,Harada T, Hashimoto T (2009) Simultaneousoccurrence of anti-BP180 mucous membranepemphigoid and mucosal-dominant pemphigusvulgaris. Clin Exp Dermatol 34:e785–e78849. Lazarova Z, Salato VK, Lanschuetzer CM,Janson M, Fairley JA, Yancey KB (2008) IgGanti-laminin-332 autoantibodies are present ina subset of patients with mucous membrane,but not bullous, pemphigoid. J Am AcadDermatol 58:951–95850. Bhol KC, Dans MJ, Simmons RK, Foster CS,Giancotti FG, Ahmed AR (2000) The autoan-tibodies to alpha 6 beta 4 integrin of patientsaffected by ocular cicatricial pemphigoid pre-dominantly epitopes within the large cytoplas-mic doman of human beta 4. J Immunol165:2824–282951. Dilling A, Rose C, Hashimoto T, Zillikens D,Shimanovich I (2007) Anti-p200 pemphigoid:a novel autoimmune subepidermal blisteringdisease. J Dermatol 34:1–852. Dainichi T, Kurono S, Ohyama B, Ishii N,Sanzen N, Hayashi M, Shimono C, TaniguchiY, Koga H, Karashima T, Yasumoto S, ZillikensD, Sekiguchi K, Hashimoto T (2009) Anti-laminin gamma-1 pemphigoid. Proc Natl AcadSci U S A 106:2800–280553. Halkier-Sorensen L, Beck HI, Sogaard H(1985) Herpes gestationis in association withneoplasma malignum generalisata. A casereport. Acta Derm Venereol Suppl (Stockh)120:96–10054. Intong LR, Murrell DF (2011) Pemphigoidgestationis: pathogenesis and clinical features.Dermatol Clin 29:447–45255. Murakami H, Amagai M, Higashiyama M,Hashimoto K, Chorzelski TP, Bhogal BS,Jenkins RE, Black MM, Zillikens D, NishikawaT, Hashimoto T (1996) Analysis of antigensrecognized by autoantibodies in herpes gesta-tionis. Usefulness of immunoblotting using afusion protein representing an extracellulardomain of the 180 kD bullous pemphigoidantigen. J Dermatol Sci 13:112–11756. Matsumura K, Amagai M, Nishikawa T,Hashimoto T (1996) The majority of bullouspemphigoid and herpes gestationis serumsamples react with the NC16a domain of the180-kDa bullous pemphigoid antigen. ArchDermatol Res 288:507–50957. Semkova K, Black M (2009) Pemphigoidgestationis: current insights into pathogenesisand treatment. Eur J Obstet Gynecol ReprodBiol 145:138–14458. Al-Fouzan AW, Galadari I, Oumeish I, OumeishOY (2006) Herpes gestationis (Pemphigoidgestationis). Clin Dermatol 24:109–11259. Rose C, Brocker EB, Zillikens D (2010)Clinical, histological and immunopathologicalﬁndings in 32 patients with dermatitis herpeti-formis Duhring. J Dtsch Dermatol Ges 8:265–270, 265–27160. Marks J, Shuster S, Watson AJ (1966) Small-bowel changes in dermatitis herpetiformis.Lancet 2:1280–128261. Zone JJ, Meyer LJ, Petersen MJ (1996)Deposition of granular IgA relative to clinicallesions in dermatitis herpetiformis. ArchDermatol 132:912–91862. Rose C, Armbruster FP, Ruppert J, Igl BW,Zillikens D, Shimanovich I (2009)Autoantibodies against epidermal transglutam-inase are a sensitive diagnostic marker inpatients with dermatitis herpetiformis on a nor-mal or gluten-free diet. J Am Acad Dermatol61:39–4363. Asano Y, Makino T, Ishida W, Furuichi M,Shimizu T (2011) Detection of antibodies toepidermal transglutaminase but not tissue trans-glutaminase in Japanese patients with dermati-tis herpetiformis. Br J Dermatol 164:883–88464. Horiguchi Y, Ikoma A, Sakai R, Masatsugu A,Ohta M, Hashimoto T (2008) Linear IgA der-matosis: report of an infantile case and analysisof 213 cases in Japan. J Dermatol 35:737–74365. Franzke CW, Bruckner-Tuderman L, BlobelCP (2009) Shedding of collagen XVII/BP180in skin depends on both ADAM10 andADAM9. J Biol Chem 284:23386–2339666. Csorba K, Schmidt S, Florea F, Ishii N,Hashimoto T, Hertl M, Karpati S, Bruckner-Tuderman L, Nishie W, Sitaru C (2011)Development of an ELISA for sensitive andspeciﬁc detection of IgA autoantibodies aganistBP180 in pemphigoid diseases. Orphanet JRare Dis 6:3167. Ishii N, Hamada T, Dainichi T, Karashima T,Nakama T, Yasumoto S, Zillikens D, HashimotoT (2010) Epidermolysis bullosa acquisita:what’s new? J Dermatol 37:220–23068. Cardones AR, Hall RP 3rd (2011)Pathophysiology of dermatitis herpetiformis: amodel for cutaneous manifestations of gastro-intestinal inﬂammation. Dermatol Clin 29:469–477
32 D. Tsuruta et al.69. Yanagihara S, Mizuno N, Naruse A, Tateishi C,Tsuruta D, Ishii M (2011) Linear immunoglob-ulin G/immunoglobulin A bullous dermatosisassociated with Vogt-Koyanagi-Harada disease.J Dermatol 38:798–80170. Murakami H, Nishioka S, Setterﬁeld J, BhogalBS, Black MM, Zillikens D, Yancey KB, BaldingSD, Giudice GJ, Diaz LA, Nishikawa T,Kiyokawa C, Hashimoto T (1998) Analysis ofantigens targeted by circulating IgG and IgAautoantibodies in 50 patients with cicatricialpemphigoid. J Dermatol Sci 17:39–4471. Kharﬁ M, Khaled A, Karaa A, Zaraa I, Fazaa B,Kamoun MR (2010) Linear IgA bullous der-matosis: the more frequent bullous dermatosisof children. Dermatol Online J 16:272. Challacombe SJ, Setterﬁeld J, Shirlaw P,Harman K, Scully C, Black MM (2001)Immunodiagnosis of pemphigus and mucousmembrane pemphigoid. Acta Odontol Scand59:226–23473. Yokouchi M, Saleh MA, Kuroda K, Hachiya T,Stanley JR, Amagai M, Ishii K (2009)Pathogenic epitopes of autoantibodies inpemphigus reside in the amino-terminaladhesive region of desmogleins which areunmasked by proteolytic processing of prose-quence. J Invest Dermatol 129:2156–216674. Schmidt E, Zillikens D (2010) Modern diag-nosis of autoimmune blistering skin diseases.Autoimmun Rev 10:84–8975. Saleh MA, Ishii K, Kim YJ, Murakami A, IshiiN, Hashimoto T, Schmidt E, Zillikens D,Shirakata Y, Hashimoto K, Kitajima Y, AmagaiM (2011) Development of NC1 and NC2domains of Type VII collagen ELISA for thediagnosis and analysis of the time course of epi-dermolysisbullosaacquisitapatients.JDermatolSci 62:169–17576. Probst C, Schlumberger W, Stocker W, ReckeA, Schmidt E, Hashimoto T, Zhu XJ, ZillikensD, Komorowski L (2009) Development ofELISA for the speciﬁc determination of autoan-tibodies against envoplakin and periplakin inparaneoplastic pemphigus. Clin Chim Acta410:13–18