The localization of target antigens and autoantibodies in linear IgA disease is variable: correlation of immunogold electron microscopy and immunoblotting

Linear IgA disease (LAD) of adults and children is a dapsone-responsive, autoimmune subepidermal blistering disease characterized by linear IgA deposits at the basement membrane zone (BMZ) of the skin and mucosa. Circulating IgA antibodies to BMZ components are often present. In this study we investigated the ultrastructural localization of the antigens and autoantibodies in six patients with LAD (five adults and one child). Using a direct postembedding immunogold electron microscopy (EM) technique, three different patterns of IgA antibody deposition were seen in the skin of four patients with LAD. The IgA deposits localized within the uppermost part of the lamina lucida and to the basal surface of the hemidesmosome in two patients, to the lamina lucida in one, and to the lamina densa in the fourth patient. Using an indirect immunogold EM technique and serum or purified blister fluid from two additional LAD patients, we showed that the serum autoantibodies of one patient bound to the hemidesmosome of the BMZ, while the autoantibodies in the blister fluid of the other patient bound to the lamina densa and sublamina densa including the anchoring fibrils in a labelling pattern similar to that of the monoclonal antibody (LH7.2) to collagen VII. All the autoantibodies binding to the hemidesmosome or lamina lucida recognized a protein in epidermal extracts of molecular weight 180 kDa or its breakdown product of 97 kDa, 200 kDa or 230 kDa. The antibodies binding to the lamina densa recognized proteins of 180 and 285 kDa. The antibodies that bound to the lamina densa and anchoring fibrils recognized collagen VII. In this immunogold EM study we have shown four patterns of IgA labelling in six patients with LAD, associated with five different antigens as recognized by immunoblotting. These results, together with our previous immunofluorescence and immunoblotting findings add support to the contention that LAD is a heterogeneous disease as regards both the target antigens and epitopes.     

Chronic bullous dermatosis in childhood (linear IgA dermatosis)

A 5-year-old boy presented with disseminated, partly grouped blisters indicative of chronic bullous dermatosis of childhood (CBDC) following a gastrointestinal infection 2 weeks earlier. CBDC has long been differentiated from adult linear IgA disease. Clinical and laboratory studies revealed substantial clinical and immunological overlap between the two blistering disorders, whereas recent investigations suggest heterogeneity of the target antigen involved. Pathohistological and immunofluorescence-microscopical characteristics of a subepidermal blister and linear IgA and granular C3 deposition at the basement membrane together with the typical history and clinical signs were decisive in the differential diagnosis. The disease promptly cleared up after daily administration of 16 mg methylprednisolone-21-acetate tapering and 25 mg dapsone. Immunohistological detection of collagen IV at the base of a blister made it possible to localize the split above the lamina densa. The demonstration of collagen IV stresses the importance of immunodermatopathology in the differential diagnosis of subepidermal blistering diseases.     

Immunogold localization of the 97-kD antigen of linear IgA bullous dermatosis (LABD) detected with patients'' sera

The classification of linear IgA bullous dermatosis in the group of subepidermal blistering diseases is still a matter of controversy. This situation is due partly to the considerable clinical heterogeneity of the disease but also results from the difficulties in characterization and localization of the specific basement membrane zone antigen(s) recognized by immunoglobulin (Ig)A antibodies. In the present study, we have combined the Western blot detection of circulating autoantibodies with an ultrastructural immunogold labeling of human skin antigens using the same patients' sera. Our results, obtained with a short series of sera showing exclusive IgA class reactivity with the epidermal portion of salt-split skin, indicate that the antibodies recognizing the 97-kD antigen on immunoblot bind to the hemidesmosomal plaques of basal keratinocytes and the adjacent lamina lucida. These homogeneous laboratory results remain in striking contrast to the heterogeneity of clinical pictures in the patients studied, suggesting a participation of complementary, possibly not humoral, phenomena in the pathogenesis of linear IgA bullous dermatosis.     

Arthritis with an inflammatory dermatosis resembling Sweet's syndrome. Report of a unique case and review of the literature on arthritis associated with the inflammatory dermatoses

A patient with a unique case of chronic episodic arthritis coincident with flares of acneform, pustular, nodular and ulcerating skin lesions was observed over a five-year period. This patient and a review of the literature on arthritis associated with the inflammatory dermatoses provide evidence which may interrelate several of these nosologically confusing skin conditions, e.g., the family of leukocytoclastic angiitides with the newly posited acute febrile neutrophilic dermatosis of Sweet. Systemic manifestations and a variety of acneform, pustular, nodular and ulcerating cutaneous lesions in the inflammatory dermatoses are best explained by small vessel involvement, with individual syndromes being determined by the type and degree of vascular change. Perivascular neutrophilic infiltration is the unifying histologic feature of these small vessel diseases. Neutrophil infiltration differentiates these entities, and our patient, from the histologically nonspecific inflammations of the skin, e.g., Behcet's disease and pyoderma gangrenosum, which, although capable of causing identically appearing skin lesions, consist predominantly of lymphocytic dermal infiltrates even in the earlier stages. It appears important to recognized these morphologically varied acute inflammatory dermatoses with perivascular neutrophilic infiltration in view of their systemic features and the dramatic efficacy of corticosteroid therapy.     

Establishing a cancer risk evaluation program

Most of the clinical, histological and immunohistological features of fogo selvagem resemble those of idiopathic pemphigus foliaceus (PF). Both diseases are clinically characterized by small flaccid bullae evolving into to scaly and crusted lesions, sometimes with pustules, mainly in seborrheic areas of the skin. Mucosal surfaces are mostly spared. The main histologic feature of endemic pemphigus foliaceus is a subcorneal acantholytic blister. Standard immunofluorescence studies demonstrate intercellular IgG deposits throughout the entire epidermis. These IgG antibodies are mainly of the IgG4-subclass. Almost all patients have circulating IgG-autoantibodies in their serum directed against stratified epithelial desmosomes. The fogo selvagem autoantibodies and the PF antibodies are directed against the 160 kD desmosomal glycoprotein desmoglein 1 which together with plakoglobin (85 kD) forms a complex of adhesion proteins with desmosomes of stratified epithelia. Fogo selvagem occurs in endemic foci in some areas of Brazil and possibly in neighbouring South American countries, very often in children, adolescents and young adults. The etiology of fogo selvagem is still unknown. The frequent association with insect bites has lead to the concept of fogo selvagem being a transmissible disease with acquired immunity in adulthood. However, the infectious agent and possible vectors have not yet been identified.     

Linear immunoglobulin A (IgA) bullous dermatosis of childhood: identification of the target antigens and study of the cellular sources

A 4-year-old girl developed numerous tense blisters on the body. The blisters healed without scarring. Histopathological and immunofluorescence studies showed findings consistent with linear immunoglobulin A (IgA) bullous dermatosis of childhood. Immunoelectron microscopy revealed deposition of IgA in the lamina lucida of the basement membrane zone of the dermal-epidermal junction. Circulating IgA autoantibody was positive at the titre of 1 : 128 and recognized the antigens located on epidermal sites of 1 mol/l NaCl-split skin. Immunofluorescence staining of cultured normal human fibroblasts and cultured DJM-1 cells (derived from human squamous cell carcinoma of skin) with the patient's sera demonstrated that both of these cells synthesize the antigens in vitro, although fibroblasts produce the antigens more abundantly. When DJM-1 cells were injected intracutaneously into nude mice, the antigens recognized by the sera were present mainly around the tumour cell islands in a linear pattern, while the dermal-epidermal junction of mouse skin was negative, suggesting that epidermal cells may contribute directly to synthesis and deposition of the antigens at the basement membrane. By immunoprecipitation using cultured normal human fibroblasts, the patient's sera could precipitate at least two specific molecules at 100-kDa and 145-kDa molecular weight.     

Bullous IgA linear dermatosis of children in Mali

INTRODUCTION: Bullous IgA linear dermatosis is relatively frequent in children in Africa. The aim of this study was to evaluate the frequency of this disease among autoimmune bullous diseases in children in Mali. PATIENTS AND METHODS: Children with chronic bullous disease seen at the Marchoux Institute in Bamako and for whom direct immunofluorescence of the perilesional skin demonstrated immunoglobulin and/or complement deposits were included in the study population. RESULTS: Twelve children were included. Direct immunofluorescence showed linear IgA deposit along the dermo-epidermal junction in 10, once with a pemphigoid aspect and once with a pemphigus aspect. The skin lesions in the children with linear IgA deposits were stereotypic: disseminated bullae, rosettes (9 out of 10), involving the external genital organs (10/10), the limbs, the face and the trunk. Histology showed subepidermal bullae (10/10), with neutrophil papillar abscesses (9/10). Indirect immunofluorescence of the cleaved skin NaCl in 5 patients showed that the cleavage always lied at the roof of the cleavage. All the children responded to dapsone (1 to 2.5 mg/kg/d) which gave complete (7/10), or incomplete remission. Local corticosteroids were used in 2 patients and general corticosteroids in 1. DISCUSSION: This confirms the frequency of bullous IgA linear dermatosis in Africa, in contrast with uncommon dermatitis herpetiformis. Diagnosis is facilitated with immunofluorescence. The low cost of this test makes it a useful diagnostic tool in these countries.     

Phenytoin penetration into brain after administration of phenytoin or fosphenytoin

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease that occurs in association with underlying neoplasms. PNP patients develop characteristic autoantibodies directed against multiple antigens, mostly identified as members of the plakin family of cytoplasmic proteins (desmoplakin I and II, bullous pemphigoid antigen I, envoplakin, and periplakin). HD1/plectin, another member of the plakin family, has not previously been detected in the characteristic PNP antigen complex, which may relate to practical difficulties associated with its large size (molecular weight approximately 500 kDa). In this study, a combination of immunoprecipitation and immunoblot is used to demonstrate that HD1/plectin is also recognized by sera from PNP patients. Thirteen of 16 PNP sera tested were positive for HD1/plectin compared with none of 43 control sera (11 pemphigus vulgaris, 11 pemphigus foliaceus, 11 bullous pemphigoid, and 10 normal individuals). Combined with our recent finding that desmoglein 3 and desmoglein 1 are cell surface target antigens in PNP, this demonstration of plectin/HD1 as another component of the antigen complex in PNP confirms that PNP is an autoimmune disease against desmoglein and plakin family molecules.     

Dependence of apparent diffusion coefficients on axonal spacing, membrane permeability, and diffusion time in spinal cord white matter

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease that occurs in association with underlying neoplasms. Patients with PNP develop characteristic IgG autoantibodies directed against multiple antigens, most of which have been identified as cytoplasmic proteins of the plakin family (desmoplakin I, II, BPAG1, envoplakin, and periplakin). This study identified cell surface target antigens of PNP. We focused on desmoglein (Dsg) 3 and Dsg1, the autoantigens of pemphigus vulgaris and pemphigus foliaceus. ELISA using baculovirus-expressed recombinant Dsgs (rDsg3, rDsg1) has revealed that 25 out of 25 PNP sera tested were positive against Dsg3 and 16 of 25 were positive against Dsg1. All of 12 PNP sera tested immunoprecipitated Dsg3. Removal of anti-Dsg3 autoantibodies by immunoadsorption was sufficient to eliminate the ability of PNP sera to induce cutaneous blisters in neonatal mice in vivo. Furthermore, anti-Dsg3-specific antibodies that were affinity purified from PNP sera were proven to be pathogenic and caused blisters in neonatal mice. These findings indicate that Dsg3 and Dsg1 are the cell surface target antigens in PNP and that IgG autoantibodies against Dsg3 in PNP sera play a pathogenic role in inducing loss of cell adhesion of keratinocytes and causing blister formation.     

Linear IgA bullous dermatosis after contact with sodium hypochlorite

The onset of linear IgA bullous dermatosis (LABD) is generally spontaneous, but a number of cases of LABD have been reported either following drug exposure or in association with malignancies. We describe a patient who developed a vesicular eruption shortly after an irritant dermatitis caused by the contact with a detergent containing sodium hypochlorite. Direct immunofluorescence revealed linear deposits of IgA and C3 in the epidermal basement membrane. The patient's serum contained IgA that immunoblotted a 180-kD polypeptide in extracts of human keratinocytes. The patient responded promptly to therapy with dapsone. We suggest a possible pathogenetic relationship between the chemical dermatitis and LABD in this patient.     

A preliminary assessment of the efficacy of anticancer measures in malignant stomach neoplasms

Three cases of erosive pustular dermatosis of the scalp are reported. In all patients the dermatosis was characterized by pustular, erosive, and crusted lesions; in addition, two patients had areas of scarring alopecia. The results of laboratory tests, bacteriologic and mycologic investigations, and histopathologic examination were nondiagnostic. Although erosive pustular dermatosis of the scalp is characterized by a nonpathognomonic clinical and histopathologic picture, it probably represents a disease entity.     

Role of mucosal IgA in the resistance to Acanthamoeba keratitis

PURPOSE: To determine whether oral immunization with Acanthamoeba castellanii antigens elicits mucosal antibodies of the IgA isotype and whether mucosal antibodies affect parasite adhesion to the corneal epithelium. METHODS: Chinese hamsters were immunized with 100 microg aqueous Acanthamoeba antigen mixed with cholera toxin (Ac-CT) and subsequently challenged with parasite-laden contact lenses that were applied to abraded corneal surfaces. Tears and stool samples were examined for the presence of Acanthamoeba-specific IgA antibodies by enzyme-linked immunosorbent assay (ELISA). The effect of mucosal antibody on trophozoite binding to corneal epithelium and viability of trophozoites was examined in vitro. RESULTS: Hamsters immunized orally with Ac-CT showed significantly lower infection rates than did control groups (21.4% versus 72.6%). ELISA analysis of mucosal specimens showed the presence of parasite-specific IgA in stool samples and tears from hamsters orally immunized with Ac-CT, but not in control animals. In vitro assays showed that anti-Acanthamoeba IgA did not affect parasite viability. However, mucosal anti-Acanthamoeba IgA profoundly inhibited (>75%) the binding of parasites to corneal epithelial cells in vitro. CONCLUSIONS: Oral immunization with Ac-CT induces the production of parasite-specific IgA in mucosal secretions and prevents corneal infection. Mucosal antibody does not affect the viability of Acanthamoeba trophozoites but seems to prevent infection by inhibiting parasite binding to the corneal epithelium.     

Autoantigens of cicatricial pemphigoid and their pathogenetic significance

Cicatrical pemphigoid (CP) comprises a group of patients with a chronic subepidermal blistering disease which primarily involves mucous membranes; lesions characteristically heal with scarring. Immunofluorescence investigations typically demonstrate deposits of tissue bound and circulating immunoreactants of the IgG and less frequently of the IgA class in a linear pattern along the basement membrane zone. These autoantibodies are thought to play an important role in the blister formation of CP. Most patients show binding to the bullous pemphigoid antigen 2 (BPag2), collagen type XVII, with a molecular-weight of 180 kD. A smaller group of patients with CP have autoantibodies to laminin 5. Animal models confirm that autoantibodies binding to these two adhesion molecules (BPag2 and laminin 5) are important in blister formation. There are other autoantigens described in CP; however, they are only found in small groups of CP patients and most of them are not further characterised. The described molecules are part of the hemidesmosomal adhesion complex. Impaired function of any component of this complex may lead to a separation of the epidermis from the dermis; better knowledge about the single molecules and the exact localisation of epitopes within these molecules may lead to further understanding of the clinical picture.     

Relationship between keratinocyte adhesion and death: anoikis in acantholytic diseases

Loss of attachment to the substratum may trigger apoptosis in epithelial cells (anoikis). It is less clear whether apoptosis may be triggered by disruption of cell-cell contacts, as happens in acantholytic diseases. Biopsy specimens were obtained from the border of skin lesions from four patients with pemphigus vulgaris (PV), four patients with pemphigus foliaceus (PF), three patients with Darier's disease (DD), two patients with Darier's-type Grover's disease (GD), and two patients with benign familial pemphigus Hailey-Hailey disease (HH). Control skin was obtained from five healthy volunteers. TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) and confocal laser scanning microscopy was employed to detect the nuclei containing fragmented DNA in apoptotic cells. In PV and PF, TUNEL-stained apoptotic keratinocytes were abundantly present in the regions of acantholysis and in the cohesive epidermis below the blisters. Apoptotic keratinocytes had pyknotic, condensed nuclei. In DD, GD and HH, the number of TUNEL-stained keratinocytes was lower, apoptotic keratinocytes were confined to the regions of dyskeratosis and acantholysis, and pyknosis was absent. In conclusion, disruption of cell-cell contacts in acantholytic skin disorders may in some cases cause apoptosis of keratinocytes. Further studies are needed to determine whether the observed differences in the pattern of apoptosis are due to targeting of different junctional elements (adherens junctions in PV and PF versus desmosomes in DD, GD and HH).     

A case of nonscarring inflammatory epidermolysis bullosa acquisita: characterization of IgG autoantibodies by immunofluorescence, immunoblotting and immunogold electron microscopy

We report a case of nonscarring inflammatory epidermolysis bullosa acquisita in a 59-year-old Japanese woman. She developed blisters and erosions on her lip, trunk and extremities. Sodium aurothiomalate was effective for the skin lesions. The patient had been free from bullous skin lesions for the last 13 years and had shown no scarring. Indirect immunofluorescence (IF) study on 1 M NaCl-split skin revealed IgG autoantibodies against the dermal side of the split skin. Immunoblotting using normal human dermal extracts disclosed IgG autoantibodies reactive with the 290 and 145 kD antigens. Circulating IgG autoantibodies were deposited on the lamina densa by immunoelectron microscopy. IF mapping using several antibodies for the components of the basement membrane zone revealed blister formation at the lamina densa. These results suggest that the cleavage at the lamina lucida does not necessarily exclude the diagnosis of EBA and that the definite diagnosis of EBA should be confirmed by immunoblotting or immunoelectron microscopic study.     

Immunoglobulin A class fibroblast antibodies in patients with Graves' disease and pretibial myxedema

The involvement of autoantibodies in the extrathyroidal manifestations of Graves' disease has been the subject of extensive investigation, with fairly inconclusive results to date. We investigated the presence of immunoglobulin A (IgA) and IgG antibodies in patients with Graves' disease and pretibial myxedema (PTM; n = 21) as well as those with Graves' disease with thyroid-associated ophthalmopathy (TAO; n = 10), Graves' disease with no clinical evidence of extrathyroidal manifestations (n = 11), Hashimoto's thyroiditis (n = 9), type 1 diabetes mellitus (n = 10), systemic lupus erythematosus (n = 9) and normal individuals (n = 17). We looked for antibodies to both retroocular muscle and dermal fibroblasts as well as to thyroid peroxidase, thyroid microsomal antigen, thyroglobulin, and human eye muscle membranes. IgA class antibodies to microsomal antigen (30-50% of patients), thyroid peroxidase (5-20%), and human eye muscle membrane (0-26%) antigens were found in the various groups of patients with Graves' disease. With each of these antigens, serum from patients with PTM showed the greatest binding. Highly significant IgA binding was shown by PTM serum to both dermal (P < 0.001) and retroocular muscle (P < 0.001) fibroblasts from 12 different donors. Serum from Graves' patients with and without TAO and that from Hashimoto's thyroiditis patients reacted significantly with 4 of the 12 fibroblasts lines. In contrast, IgG binding was only found for 3 of the 12 fibroblast lines using patient serum. The IgA binding to fibroblasts shown by PTM patients was predominantly of the IgA2 subclass. The activity was absorbed out by both fibroblasts and thyroid cells. In immunoblotting studies, PTM patient serum reacted with a 54-kilodalton dermal fibroblast antigen and a 66-kilodalton retroocular fibroblast antigen. No binding to these antigens was seen with serum from normal controls or patients without PTM. Further elucidation of the nature of this fibroblast antigen will help to determine the role of IgA autoantibodies in the extrathyroidal manifestations of Graves' disease.     

Pemphigus with features of both vulgaris and foliaceus variants, associated with antibodies to 160 and 130 kDa antigens

We report an unusual variant of pemphigus in a 44-year-old man. He presented with scaly and crusted erosions associated with pruritic vesicles and erythema mainly on the chest, abdomen, back and face. Histology showed acantholysis with neutrophilic spongiosis in the granular layer and subcorneal region of the epidermis. Intercellular IgG in the epidermis was positive on direct immunofluorescence. Indirect immunofluorescence showed intercellular antibodies at a titre of 1 : 2 in the suprabasal epidermis. Circulating autoantibodies to 130 kDa and 160 kDa antigens were detected in the patient's serum by immunoblot analysis using epidermal extracts. These two antibodies eluted from individual nitrocellulose membranes reacted with the intercellular space in the epidermis on indirect immunofluorescence. This observation suggests that these antibodies correspond to desmogleins 3 and 1, respectively. The clinical symptoms almost completely disappeared after 28 days treatment with oral prednisolone (30 mg/day), leaving brown pigmented flecks on the lesional sites. These findings suggest that this patient's pemphigus has features of both the vulgaris and foliaceus variants, with antibodies against desmogleins 3 and 1.     

Reactions to less common species of fire ants

The BP180 antigen, a component of the epidermal anchoring complex, has been identified as one of the major antigenic targets of autoantibodies associated with the blistering skin disease, bullous pemphigoid. Our research group has recently demonstrated that reactivity of bullous pemphigoid autoantibodies to the BP180 ectodomain is almost entirely restricted to a set of four antigenic sites clustered within the membrane-proximal noncollagenous stretch (NC16A). Using a passive transfer mouse model, antibodies to the corresponding noncollagenous region of murine BP180 were shown to trigger an inflammatory subepidermal blistering disease that closely mimics bullous pemphigoid. We now report the development of an enzyme-linked immunoabsorbent assay system that is extremely sensitive in detecting disease-specific autoantibodies in the sera of bullous pemphigoid patients. The target antigen in this assay is a recombinant form of the BP180 NC16A domain that contains all four of the well-defined bullous pemphigoid-associated antigenic sites. Of 50 randomly selected bullous pemphigoid sera tested, 47 (94%) were positive in this assay, whereas no specific reactivity was detected in any of the 107 controls. Interestingly, all three of the bullous pemphigoid sera that were negative in this assay had been obtained from patients who were already undergoing treatment. The NC16A enzyme-linked immunosorbent assay is more sensitive than any of the standard techniques for detecting circulating bullous pemphigoid autoantibodies, including other enzyme-linked immunosorbent assays, immunoblotting, and indirect immunofluorescence. Finally, the NC16A enzyme-linked immunosorbent assay provides immunologic information that cannot be obtained from direct immunofluorescence studies of skin biopsies, and that may well be relevant in the diagnosis and treatment of bullous pemphigoid.     

A case of herpetiform pemphigus associated with autoimmune hemolytic anemia: detection of autoantibodies against multiple epidermal antigens

We report a case who was clinically and histopathologically diagnosed as herpetiform pemphigus (HP) and associated with autoimmune hemolytic anemia (AIHA). However, immunofluorescence studies demonstrated concurrent anti-cell-surface and anti-basement-membrane-zone antibodies in the patient's serum. Immunochemical studies showed that the patient's serum reacted with both the pemphigus foliaceus antigen and the two bullous pemphigoid antigens. Subsequently, the patient developed AIHA. Both anemia and skin lesions were successfully treated with oral prednisolone. We believe that this is the first case with HP in association with AIHA. The presence of autoantibodies against multiple antigens suggests an abnormal immunologic tolerance in the antibody production system in this patient.     

Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris

In patients with pemphigus vulgaris (PV), autoantibodies against desmoglein 3 (Dsg3) cause loss of cell-cell adhesion of keratinocytes in the basal and immediate suprabasal layers of stratified squamous epithelia. The pathology, at least partially, may depend on protease release from keratinocytes, but might also result from antibodies interfering with an adhesion function of Dsg3. However, a direct role of desmogleins in cell adhesion has not been shown. To test whether Dsg3 mediates adhesion, we genetically engineered mice with a targeted disruption of the DSG3 gene. DSG3 -/- mice had no DSG3 mRNA by RNase protection assay and no Dsg3 protein by immunofluorescence (IF) and immunoblots. These mice were normal at birth, but by 8-10 d weighed less than DSG3 +/- or +/+ littermates, and at around day 18 were grossly runted. We speculated that oral lesions (typical in PV patients) might be inhibiting food intake, causing this runting. Indeed, oropharyngeal biopsies showed erosions with histology typical of PV, including suprabasilar acantholysis and "tombstoning" of basal cells. EM showed separation of desmosomes. Traumatized skin also had crusting and suprabasilar acantholysis. Runted mice showed hair loss at weaning. The runting and hair loss phenotype of DSG3 -/- mice is identical to that of a previously reported mouse mutant, balding (bal). Breeding indicated that bal is coallelic with the targeted mutation. We also showed that bal mice lack Dsg3 by IF, have typical PV oral lesions, and have a DSG3 gene mutation. These results demonstrate the critical importance of Dsg3 for adhesion in deep stratified squamous epithelia and suggest that pemphigus autoantibodies might interfere directly with such a function.