Immunoglobulin A antibodies against desmoglein 1, envoplakin, periplakin and BP230 in a patient with atypical bullous pemphigoid


Fumi Yamaki, M.D., Department of Dermatology, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan. Email:


Bullous pemphigoid is an autoimmune subepidermal blistering disease associated with autoantibodies against BP180 and BP230. We report herein a rare case of bullous pemphigoid with newly formed annular erythematous lesions when bullous skin lesions were in remission. Various immunological studies revealed immunoglobulin (Ig)A antibodies against desmoglein 1, envoplakin, periplakin and BP230 in addition to IgG antibodies against BP180 and BP230. These clinical and immunological changes in a patient are a rare event, suggesting an epitope-spreading phenomenon.


An 81-year-old Japanese woman presented with a 1-month history of numerous tense blisters and erythemas on the trunk and limbs in 2003 (Fig. 1a). The mucous membranes were not involved. Histopathology of the lesional skin of the abdomen demonstrated a subepidermal blister with infiltration of lymphocytes and eosinophils (Fig. 1b). Direct immunofluorescence revealed a linear immunoglobulin (Ig)G and C3 deposition at the basement membrane zone (Fig. 1c). IgG anti-basement membrane zone autoantibodies were detected by indirect immunofluorescence using normal human skin and enzyme-linked immunosorbent assay (ELISA) showed antibodies against BP180. From these findings, the patient was diagnosed as having bullous pemphigoid (BP) and treated with oral prednisolone (20 mg/day). Two weeks after starting the treatment, the skin lesions eventually resolved. Then, the dose of prednisolone was tapered.

Figure 1.

 Characteristics of the patient in 2003. (a) Tense blisters and erythema on the trunk. (b) Subepidermal blister with infiltration of lymphocytes and eosinophils (original magnification ×40). (c) Indirect immunofluorescence (original magnification ×100). Immunoglobulin G antibodies to basement membrane zone.

In February 2007, when she received prednisolone 5 mg daily, new eruptions developed around the umbilicus. Lesions were annular erythematous and partially double-edged with small vesicles (Fig. 2a). We excluded diagnosis of fungal infection or impetigo by microscopy and bacterial culture. The patient refused additional biopsy testing. Indirect immunofluorescence showed not only IgG anti-basement membrane zone antibodies (Fig. 2b), but also IgA anti-keratinocyte cell surface antibodies (Fig. 2c). Immunoblot assay using normal human epidermal extracts revealed the presence of IgG antibodies against BP230, periplakin and BP180, and IgA antibodies against envoplakin, periplakin and BP230 (Fig. 2d, left). Immunoblot assay using recombinant protein of BP180-NC16a domain revealed IgG antibodies with this protein (Fig. 2d, right). Furthermore, ELISA detected IgG anti-BP180 antibodies (index 70.79; positive >15), but not IgG anti-BP230 antibodies (index 2.29; positive >9). ELISA detected IgA anti-desmoglein (Dsg)1 antibodies (optical density 0.249; positive >0.15), but not IgA anti-Dsg3 antibodies (0.087; positive >0.15). ELISA did not detect either IgG anti-Dsg1 antibodies (index 8.0; positive >20) or IgG anti-Dsg3 antibodies (index 0.57; positive >20). IgA antibodies to desmocollins 1 were not detected by cDNA transfection method using cDNA of desmocollin 1. Increase of prednisolone to 10 mg/day was not effective for the skin lesions. Therefore, oral dapsone 25 mg daily was added, and then skin lesions were significantly improved.

Figure 2.

 Characteristics of the patient in 2007. (a) Annular erythemas and partially double rings with vesicles. (b) Indirect immunofluorescence. Immunoglobulin (Ig)G antibodies to basement membrane zone. (c) Indirect immunofluorescence. IgA antibodies to keratinocyte cell surfaces. (d) Immunoblot assays using normal human epidermal extracts (left) and recombinant protein of BP180 NC16a domain (right). In immunoblotting of epidermal extracts, control pemphigus vulgaris (PV) serum reacted with the 160-kDa desmoglein (Dsg)1 and the 130-kDa Dsg3, control paraneoplastic pemphigus (PNP) serum reacted with the 210-kDa envoplakin and the 190-kDa periplakin, and control BP serum reacted with BP230 and BP180. IgG antibodies of this patient (patient, IgG) reacted with BP230, periplakin and weakly BP180. IgA antibodies of this patient (patient, IgA) reacted with BP230, envoplakin and periplakin. In immunoblotting using the BP180 NC16a domain recombinant protein, control BP serum (BP) reacted with this protein but normal control serum (normal) did not. IgG antibodies of this patient (patient, IgG) reacted clearly with this recombinant protein. RP, recombinant protein.


Generally, autoimmune blistering diseases of the skin were divided into two groups, pemphigus and BP. The presence of autoantibodies against the keratinocyte cell surfaces and the basement membrane zone are hallmarks of the diagnosis, respectively. In four classical types of pemphigus, including pemphigus foliaceus, pemphigus erythematosus, pemphigus vulgaris and pemphigus vegetans, target antigens have been identified as Dsg1 and Dsg3.1,2 In addition, several pemphigus variants have been proposed, including herpetiform pemphigus, paraneoplastic pemphigus and IgA pemphigus.

On the other hand, BP and herpes gestationis have been shown to exhibit IgG antibodies against BP230 and BP180.3,4 Other diseases, which contain anti-basement membrane zone autoantibodies, include mucous membrane pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita and bullous systemic lupus erythematosus.

There have been a number of reports of patients with atypical antibody profiles. Some cases showed mixed features of pemphigus and BP clinically and histologically with concurrent autoantibodies against Dsg1, Dsg3 and BP antigens.5–7 Hashimoto et al.8 reported a case of BP who had typical clinical features of BP but whose serum showed additional reactivity with desmoplakin. Izumi et al.9 reported a case of BP with typical clinical features of BP, whose serum had anti-BP180 and anti-laminin 5 antibodies, after development of graft versus host disease due to bone marrow transplantation. Other cases of atypical BP contained autoantibodies against a 105-kDa dermal antigen10 or 125-kDa dermal antigen.11 Other uncommon cases have been reported.12–15

Inui et al.16 reported a case of atypical pemphigus involving the esophagus with IgG antibodies to Dsg3 and IgA antibodies to Dsg1. The multiple esophageal erosions showed the suprabasal desquamation consistent with pemphigus vulgaris, while the histopathological findings of the annular erythematous lesions with pustules and vesicles were identical to those for intraepidermal neutrophilic IgA dermatosis type IgA pemphigus, the target antigen of which is now unknown.

Unfortunately, we cannot show the histopathological finding of the second skin lesions, because we could not obtain the patient’s consent. Therefore, we are not sure whether the multiple antibodies detected at the second skin lesion caused the clinical features of annular erythema of the patient. Thus, it may be possible to consider that histopathological findings of BP-like tense blisters at the first stage of the disease are caused by IgG antibodies to BP180, while annular erythematous lesions are caused by IgA class autoantibodies. The real mechanism for the alteration of autoimmune reactivity remains to be elucidated, some reports suggested that secondary autoantibodies are derived from the primary autoimmune reactivity through the phenomenon called epitope-spreading.17,18 This term indicates that some tissue damages due to the primary autoimmune or inflammatory process may expose certain hidden protein components to the immune system and evoke a secondary autoimmune response. The epitope-spreading phenomenon may occur either within the same molecule or among different proteins.17,19 In our case, immunological condition and clinical manifestation may have been changed as a consequence of epitope-spreading. We reported herein a rare case of BP exhibiting uncommon clinical features and unique antibody-profile during disease progression, suggesting an epitope-spreading phenomenon.