Autoantibodies Against Multiple Epitopes in Bp180 and Laminin Gamma-1 in Subepidermal Blistering Skin Disease Associated with Psoriatic Erythroderma

Abstract

We report a 79-year-old Japanese man who developed subepidermal blistering skin disease after an 8-year history of psoriasis. Histology of a bullous lesion revealed a subepidermal blister with a mixed inflammatory cell infiltrate and fibrin nets. Indirect immunofluorescence using normal human skin sections revealed IgG and IgA autoantibodies in the patient serum, which bound to the epidermal side of 1M NaCl-split skin sections. Immunoblot analysis revealed that both IgA and IgG antibodies reacted with the BP180 NC16a domain and the 120-kDa LAD-1 and that IgG antibodies also reacted with the BP180 C-terminal domain and laminin gamma-1. These findings indicated that autoantibodies to laminin gamma-1 and multiple epitopes in BP180 ectodomain played a role in the pathogenesis of this unique autoimmune subepidermal blistering skin disease associated with psoriasis.

What was known?

Association of subepidermal blistering skin diseases with psoriasis.

Introduction

A patient of subepidermal skin blistering with psoriasis vulgaris has been reported. Bullous pemphigoid is most frequently associated with psoriasis. Linear IgA bullous disease (LAD), epidermolysis bullosa acquisita (EBA) and mucous membrane pemphigoid (MMP) are reported less frequently. We described a patient of subepidermal blistering skin associated with psoriatic erythroderma. Interestingly, by immunoblot analysis it was found that the patient sera contained IgG and IgA antibodies to multiple BP180 epitopes and IgG antibodies to laminin gamma-1.

Case Report

A 79-year-old Japanese man suffered from plaque-type psoriasis vulgaris for 8 years and was treated with topical steroids, oral antihistamine, 5-10 mg oral prednisolone daily and 50 mg oral cyclosporine daily at a dermatologic clinic. After he stopped oral prednisolone 3 months earlier, his condition worsened and he finally developed erythroderma. The patient was febrile and had scaly erythema covering most of his body and multiple tense vesicles and bullae on his trunk and extremities [Figure 1]. The blisters measured 5-20 mm in diameter, but did not show an annular arrangement. No mucous membranes were involved.

Figure 1.

Clinical appearance of the upper arm. Large tense blisters on the erythema

Histopathological examination of the specimen obtained from a bullous lesion showed a subepidermal blister containing fibrin nets and eosinophils [Figure 2]. Another skin biopsy from an erythematous lesion revealed a subcorneal neutrophilic infiltration forming Munro's microabscess and club-shaped extension of the epidermis.

Figure 2.

Histopathological finding. Subepidermal blister with infiltration of eosinophils and lymphocytes (H and E stain, original magnification ×400)

Indirect immunofluorescence, in which normal human skin was used as a substrate, demonstrated a high titer of circulating IgG autoantibodies against the basement membrane zone (BMZ) (a titer: >1: 160). Indirect immunofluorescence 1M NaCl-split skin revealed circulating IgA and IgG autoantibodies, (both titers; 1: 40) that bound to the epidermal side of the split skin [Figure 3a and b]. Through an ELISA using a BP180 NC16a domain recombinant protein, the index value was found to be 195.95 (normal range: <15).

Figure 3.

Indirect immunofluorescence using 1M NaCl-split normal human skin showed IgG (a) and IgA (b) antibodies bound to the epidermal side of the split

Immunoblot analysis using normal human epidermal extracts detected circulating IgG autoantibodies against the BP180 antigen [Figure 4a]. Interestingly, both IgG and IgA antibodies reacted with the BP180 NC16a domain recombinant protein [Figure 4b]. In addition, IgG antibodies reacted with the BP180 C-terminal domain recombinant protein, [Figure 4c] and both IgA and IgG antibodies showed reactivity with the 120-kDa LAD-1 by immunoblot analysis using concentrated HaCaT cell supernatant [Figure 5a]. Furthermore, immunoblot analysis using normal human dermal extracts detected IgG antibodies against a 200-kDa antigen (laminin gamma-1) [Figure 5b].

Figure 4.

(a) Normal human epidermal extracts demonstrated that IgG antibodies reacted with clearly with BP180 (lane 4). (b) BP180 NC16a domain demonstrated both IgG (lane 3) and IgA (lane 4) antibodies. (c) BP180 C-terminal domain revealed IgG antibodies (lane 3)

Figure 5.

(a) HaCaT cell culture supernatant revealed that both IgG (lane 3) and IgA (lane 4) antibodies reacted with 120-kDa LAD-1. (b) Normal human dermal extract demonstrated that IgG reacted strongly with a 200-kDa protein (laminin gamma-1) (lane 3)

After the patient was treated with oral prednisolone at a dose of 20 mg daily, the number of blisters decreased. No new blisters developed 1 week after initiation of the treatment. Since then, the dose of prednisolone tapered.

Discussion

Although the pathogenic mechanism of coexisting psoriasis vulgaris and subepidermal blistering skin disease is unclear, a common immunogenetic mechanism might be involved.[1] This case developed erythroderma from plaque-type psoriasis. It is supposed that withdrawal of steroids had precipitated this condition. Treatments, such as PUVA, UVB, tar, dithranol and immunomoduratory therapies, were implicated in the development of BP. Our patient had low-dose cyclosporine therapy. It is hypothesized that anti-psoriatic treatments increase immunogenicity of BMZ proteins, resulting in a higher risk of autoantibodies production.[2]

The majority of BP patients reveal IgG autoantibodies against two major hemidesmosomal components: 230-kDa antigen (BP230 or BPAG1) and 180-kDa antigen (BP180, BPAG2/type XVII collagen). We found that IgG autoantibodies were reactive with the BP180 NC16a domain recombinant protein in both immunoblot test and ELISA. In addition, IgG autoantibodies against the C-terminal domain of BP180 were detected. Immunoreactivity with C-terminus of BP180 ectodomain might be responsible for the scarring phenotype in patients with MMP.[3] Nakatani et al. examined the immunoreactivity of 110 BP sera against the NC16a and C-terminal domains of BP, and found that 21 (19%) sera of the 110 BP sera recognized both the NC16a and C-terminal domains.[4]

Our patient possessed IgG and IgA autoantibodies to the 120-kDa LAD-1. LAD is an autoimmune subepidermal blistering disorder characterized by linear deposits of IgA at BMZ. In LAD, multiple target antigens, such as the 120-kDa and 97-kDa LAD-1, 180-kDa protein or 290-kDa protein, have been demonstrated by immunoblot analysis. There is a strong antigenic relationship between the 120-kDa/97-kDa LAD-1 and BP180,[5] and LAD-1 was shown to be generated as a proteolytic cleavage product of the BP180 ectodomain.[6] This 120-kDa/97-kDa soluble ectodomain of BP180 is recognized by autoantibodies in patients with BP and LAD.

Our patient sera also demonstrated IgG antibodies to laminin gamma-1 (p200) by immunoblot analysis using dermal extracts. Sera from 90% patients with anti-p200 pemphigoid showed reactivity with laminin gamma-1, therefore, the name of anti-laminin gamma-1 pemphigoid was proposed.[7] Many of anti-laminin gamma-1 pemphigoid developed in psoriasis were reported. However, to our knowledge, there is only one case of psoriatic erythroderma associated with anti-laminin gamma-1 pemphigoid.[8]

A further observation was that our patient sera contained IgA autoantibodies to the BP180 NC16a domain and LAD-1. BP is mainly characterized by IgG autoantibodies, whereas the autoantibodies to LAD and MMP usually IgG and/or IgA autoantibodies. A dual IgG and IgA anti-BMZ antibody response was associated with severity and persistent disease course in MMP.[9] MMP patients with severe clinical phenotype demonstrated IgG and IgA reactivity to both BP180 and LAD-1. However, our patient sera contained IgG and IgA autoantibodies to multiple domains of BP180 without displaying the characteristic clinical features of MMP and the skin lesions were well controlled with prednisolone.

In summary, we described a subepidermal blistering skin disease associated with psoriatic erythroderma showing autoantibodies targeting various antigenic sites. Notably, a dual IgG and IgA autoimmune response against multiple BP180 epitopes and IgG autoantibodies to laminin gamma-1 were observed by immunoblot analysis. Antigenic reactive regions other than the NC16a domain of BP180 may be relevant to blister formation. Epitope spreading may cause this rare autoimmune response to multiple autoantigens.[10]

What is new?

Subepidermal blistering skin disease associated with psoriasis caused by multiple target autoantigens.