Cutaneous pemphigus vulgaris with absence of desmoglein 1 autoantibodies. An example of the extended desmoglein compensation theory

A 79 year‐old male patient presented clinically as a typical case of pemphigus foliaceus. He displayed a seborrhoeic pattern of crusting and erosions with an absence of oral involvement. Surprisingly, a biopsy showed suprabasilar acantholysis and direct immunofluorescence consistent with pemphigus vulgaris. Indirect pemphigus antibodies were positive for desmoglein 3 (DSG‐3) but negative for DSG‐1 antibodies. Most cases of cutaneous pemphigus are reported to have both DSG‐1 and DSG‐3 antibodies. A rare cutaneous subtype of pemphigus vulgaris is reported in the literature that may present clinically as seen in our patient. Our patient is clinically similar to these previous reported cases but with a negative DSG‐1 antibody titre. The extended DSG compensation theory explains the differences of clinical expression in pemphigus based on the variable pathogenicity of DSG antibodies as well as the distribution of DSG‐1 and DSG‐3. We discuss this case, highlighting the theories of the pathogenesis of pemphigus and, in particular, the cutaneous pemphigus subtype.     

A case of pemphigus vulgaris in a six-year-old girl

A case of pemphigus vulgaris in a six-year-old Japanese girl is presented. She first developed vesicles and ulcerations in oral and laryngeal mucous membranes, showing a hoarse voice and fits of coughing with excessive slavering. She had skin blisters six months later. Biopsy of the skin lesion demonstrated the intraepidermal blister in a suprabasal location. Direct immunofluorescence (IF) of the skin lesion revealed deposits of IgG and C3. Indirect IF showed serum anti-ICS antibody titer at 1:640. She was diagnosed as having pemphigus vulgaris. Treatment with oral prednisolone (1 mg/kg) proved effective. This is the first case of infantile pemphigus vulgaris in Japan.     

抗Dsg—3 EC3—4的单链抗体片段在寻常型天疱疮鼠模型中的作用

目的 探讨抗桥粒芯糖蛋白3(Dsg-3)EC3-4的单链抗体片段(ScFv)在寻常型天疱疮(PV)鼠模型中的作用。方法 在不同时间点。将抗Dsg-3 EC3-4的ScFv通过皮下注射至BALB/c新生鼠,从临床表现、组织病理和免疫荧光三方面评价其对PV鼠模型构建的影响。结果 单独注射抗Dsg-3 EC3-4的ScFv不能在BALB/c新生鼠中诱导出PV的改变,任何时间点注射抗Dsg-3 EC3-4的ScFv都不能阻断PV患者血清对BALB/c新生鼠的致病作用。结论 单独注射抗Dsg-3 EC3-4的ScFv缺乏致病性,也不能阻断PV患者血清对BALB/c新生鼠的致病作用。     

口服他克莫司联合糖皮质激素治疗难治性寻常型天疱疮一例

报道口服他克莫司联合糖皮质激素治疗难治性寻常型天疱疮1例。患者,男,55岁,确诊为天疱疮后给予甲泼尼龙64 mg每日1次,口服他克莫司胶囊1 mg每日2次以及其他对症治疗,治疗5周后,原有黏膜及皮肤糜烂面愈合出院。出院时患者泼尼松60 mg分2次口服,他克莫司胶囊1 mg每日2次。8个月后Dsg1抗体、Dsg3抗体转阴,泼尼松减量至15 mg每日1次,他克莫司1 mg每日1次,患者病情稳定,现仍在随访中。     

Pemphigus vulgaris in association with silicosis

We report on a sixty-seven year old miner with pemphigus vulgaris characterised clinically by a three month history of relapsing oral lesions and blisters/erosions on the trunk, axillae and extremities, histologically by suprabasal cleavage due to acantholysis, immunologically by the epidermal intercellular net-like pattern due to deposits of IgG- and IgM-antibodies and complement C3 in the direct immunofluorescence as well as by serum antibodies to desmoglein 3 (130 KD) and plakoglobin (85 KD) by immunoblotting analysis. Silicosis has already been known for 6 years. In addition, antinuclear antibodies, anti-ssDNA-antibodies and anti-topoisomerase antibodies were found. Clinical improvement and clearing of skin symptoms could be achieved by systemic steroids in combination with cyclophosphamide. However, the patient died of sepsis deriving from recalcitrant pneumonia. Although the association of silicosis with various autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and dermatomyositis has been reported many times, our patient is, to the best of our knowledge, the second case with features of the two diseases: pemphigus vulgaris and silicosis.     

Autoreactive T cells in the immune pathogenesis of pemphigus vulgaris

Pemphigus vulgaris is a life‐threatening autoimmune blistering disease caused by anti‐desmoglein IgG autoantibodies that finally lead to acantholysis presenting clinically as progressive blistering. Whilst the production of pathogenic antibodies is key to the development of pemphigus vulgaris, many immunological steps are required prior to autoantibody induction. We review advances in the understanding of these immunologic processes with a focus on human leucocyte antigen polymorphisms and antigen recognition, epitope spreading, central and peripheral tolerance, T helper differentiation, induction of pro‐ and anti‐inflammatory cytokines and T‐cell regulation of B cells. Targeting autoaggressive T cells as regulators and stimulators of B‐cell antibody production should allow for more specific therapeutic immune interventions, avoiding the global immunosuppression seen with many commonly used immunosuppressants in pemphigus vulgaris.     

Signalling pathways in pemphigus vulgaris

Acantholysis in pemphigus vulgaris is induced by binding of autoantibodies to desmoglein 3 (Dsg3). The roles of signalling pathways on development of acantholysis have recently been extensively studied. In the study by Sayar et al., recently published in Exp Dermatol, epidermal growth factor receptor (EGFR) signalling was activated in both in vivo and in vitro pemphigus vulgaris experimental models. However, while EGFR inhibitors suppressed activity of p38 mitogen‐activated protein kinase (p38MAPK) linearly, they suppressed activity of c‐Myc and acantholysis in a non‐linear, V‐shaped relationship. These findings indicated complicated interactions among EGFR, p38MAPK and c‐Myc in pemphigus vulgaris pathology.     

Pemphigus vegetans – immunopathological findings in a rare variant of pemphigus vulgaris

A patient with painful erosions of the oral cavity and the labia minora developed multifocal blisters in inter‐triginous areas. These blisters eroded and evolved into papillomatous erosive vegetations. Histopathology and immunopathological investigations confirmed the diagnosis of pemphigus vegetans, mediated by IgG autoantibodies. The circulating IgG1 and IgG4 autoantibodies were exclusively directed against desmoglein 3, as shown by ELISA and indirect immunofluorescence studies. These IgG1 and IgG4 isotypes were also in vivo bound, as demonstrated with immunoperoxidase staining of perilesional skin. Our clinical, biochemical and immunopathological observations confirm the hypothesis that pemphigus vegetans is a variant of pemphigus vulgaris.     

Case of pemphigus vulgaris in oral mucosa showing an extension to the body surface with recurrent varicella

A 60-year-old female with pemphigus vulgaris limited to the oral mucosa being treated with prednisolone showed a widespread extension of lesions to the body and extremities over a short period. The eruptions on the body began as small vesicles that looked unlike the blisters of pemphigus vulgaris, and increased to large blisters and erosions compatible with pemphigus. A smear test of the vesicles in the early stage demonstrated multinucleated acantholytic keratinocytes, which were positively stained with an antivaricella zoster virus (VZV) antibody by the immunoperoxidase method. The widespread eruptions improved immediately after 5 days' administration of valaciclovir hydrochloride tablets and increased dosage of prednisolone, leaving tiny shallow scars and pigmentation. The anti-VZV antibody in the serum was not elevated, and there were no zosteriform eruptions noted during the course. We thought that widespread extension of the pemphigus vulgaris in this case was provoked by recurrent varicella, in a similar fashion to Koebner phenomenon.     

A case of neonatal pemphigus vulgaris with co-existing BP180 autoantibodies

A male neonate was born with blisters on the trunk to a 37-year-old primigravid woman with a past medical history of recurrent, painful, topical steroid-responsive oral blisters. The diagnosis of neonatal pemphigus was made after the neonate and mother were found to have elevated desmoglein 3 (Dsg3) antibodies in conjunction with histopathologic features of pemphigus vulgaris. Interestingly, both neonate and mother also had elevated levels of BP180 antibodies, classically seen in bullous pemphigoid. This case is unique in that it portrays neonatal pemphigus, an already rare condition, complicated by the presence of BP180 antibodies.     

Case of subepidermal autoimmune bullous disease with psoriasis vulgaris reacting to both BP180 C‐terminal domain and laminin gamma‐1

A number of cases of psoriasis vulgaris developing bullous skin lesions have been diagnosed as either bullous pemphigoid with antibodies to the 180‐kDa bullous pemphigoid antigen (BP180) non‐collagenous 16a (NC16a) domain or anti‐laminin‐γ1 (p200) pemphigoid. We report a case of subepidermal bullous disease with psoriasis vulgaris, showing antibodies to both BP180 C‐terminal domain and laminin‐γ1. A 64‐year‐old Japanese man with psoriasis vulgaris developed exudative erythemas and tense bullae on the whole body but he did not have mucosal involvement. The blistering lesion showed subepidermal blisters histopathologically. In indirect immunofluorescence of 1 mol/L NaCl‐split skin, immunoglobulin (Ig)G antibodies reacted with both the epidermal and dermal side. Immunoblotting showed positive IgG with recombinant protein of BP180 C‐terminal domain and 200‐kDa laminin‐γ1 in normal human dermal extract.     

Neonatal pemphigus vulgaris

A male newborn with skin erosions was born to a 32-year-old woman who was under treatment for pemphigus vulgaris that had been diagnosed 16 months earlier. Antibodies to desmoglein (Dsg)1 and Dsg3 were analyzed by enzyme-linked immunosorbent assay. Index values of antibodies to Dsg1 and Dsg3 were 49 (normal index values, <14) and 121 (normal index values, <7), respectively. Those findings concluded a diagnosis of neonatal pemphigus vulgaris. No new vesicles or bullae appeared in the newborn after the birth. Non-corticosteroid ointments produced prompt epithelialization on the erosive lesions. All the eruptions disappeared in 3 weeks. The level of serum anti-Dsg3 autoantibodies when measured at the 76th day was negative (<5).     

In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. The mechanism of blister formation in pemphigus has not been defined; however, in vitro data suggest a role for activation of intracellular signalling cascades. OBJECTIVES: To investigate the contribution of these signalling pathways to the mechanism of PV IgG-induced acantholysis in vivo. METHODS: We used the passive transfer mouse model. Mice were injected with IgG fractions of sera from a patient with PV, with or without pretreatment with inhibitors of proteins that mediate intracellular signalling cascades. RESULTS: Inhibitors of tyrosine kinases, phospholipase C, calmodulin and the serine/threonine kinase protein kinase C prevented PV IgG-induced acantholysis in vivo. CONCLUSIONS: These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced acantholysis.     

Diagnosis and clinical features of pemphigus vulgaris

Autoimmune bullous diseases are associated with autoimmunity against structural components that maintain cell-cell and cell-matrix adhesion in the skin and mucous membranes. They include those where the skin blisters at the basement membrane zone and those where the skin blisters within the epidermis (pemphigus vulgaris, pemphigus foliaceus, and other subtypes of pemphigus). The variants of pemphigus are determined according to the level of intraepidermal split formation. There are 5 main variants of pemphigus: pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, drug-induced pemphigus, and paraneoplastic pemphigus. This review focuses only on pemphigus vulgaris.     

Immunologic and histopathologic characterization of an active disease mouse model for pemphigus vulgaris

Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes that is caused by anti-desmoglein 3 IgG autoantibodies. Recently, we generated an active disease mouse model for pemphigus vulgaris by adoptive transfer of splenocytes from immunized desmoglein 3-/- mice to Rag2-/- mice. In this study, we performed immunologic and histopathologic studies using this pemphigus vulgaris model in mice and compared the gross and microscopic phenotypes of pemphigus vulgaris model mice and desmoglein 3-/- mice. Pemphigus vulgaris model mice showed strong in vivo IgG, and weak IgA deposition on keratinocyte cell surfaces in stratified squamous epithelia, and produced circulating anti-desmoglein 3 IgG antibodies without apparent cross-reactivity to desmoglein 1, in enzyme-linked immunosorbent assays. The predominant IgG subclass was IgG1. Pemphigus vulgaris model mice and desmoglein 3-/- mice were almost indistinguishable in terms of both gross and microscopic findings. Both types of mice showed suprabasilar acantholysis in the stratified squamous epithelia, including the oral mucous membranes and traumatized skin around the snout or paws; however, some pemphigus vulgaris model mice demonstrated a more severe phenotype than desmoglein 3-/- mice. The esophagus and forestomach were affected in some pemphigus vulgaris model mice, but not in desmoglein 3-/- mice. Furthermore, eosinophilic spongiosis, which is found in early pemphigus vulgaris lesions in patients, was observed in pemphigus vulgaris model mice but not in desmoglein 3-/- mice. Pemphigus vulgaris model mice reflect several of the histopathologic and immunologic features seen in pemphigus vulgaris patients, and provide a valuable tool to investigate the pathophysiologic mechanisms of pemphigus vulgaris.     

A Case of pemphigus foliaceus which occurred after five years of remission from pemphigus vulgaris

A 77-year-old Japanese female developed pemphigus foliaceus (PF) after 5 years of remission from pemphigus vulgaris (PV). The patient had painful erosions in her mouth and flaccid blisters of the skin and was diagnosed as having PV, which responded well to corticosteroid treatment. She was then free from any lesion of PV for 5 years with a low dose of corticosteroid. Then she developed scaly erythematous lesions on the skin and was diagnosed as suffering from PF. Enzyme-linked immunosorbent assay (ELISA) using recombinant desmoglein 1 (Dsg-1) and Dsg-3 revealed that she had anti-Dsg-3 IgG in the PV stage, no antibodies during remission and anti-Dsg-1 IgG in the PF stage. These findings indicate that the target antigen was shifted from Dsg-3 to Dsg-1 along with the phenotype after a 5-year interval in this patient.     

Successful treatment of adolescent pemphigus vulgaris by immunoadsorption method.

A 15-year-old girl with pemphigus vulgaris did not respond to oral administration of prednisolone at 45 mg/day. The skin and oral mucous membrane lesions recurred after effective treatments with methylprednisolone pulse therapy and combination therapy with prednisolone and cyclosporine. The finally successful treatment involved eleven cycles of immunoadsorption using a tryptophan column and administration of a moderate dose of prednisolone. Serum gamma-globulin level and anti-intercellular antibody titer decreased from 1.08 g/dl to 0.5 g/dl and 1:320 to 1:20, respectively. She has been well controlled with 21.5 mg/day prednisolone for 8 months after the final adsorption. Considering the physical, mental and social situation of adolescent student patients, immunoadsorption is a highly preferable choice among a variety of treatment modalities for pemphigus vulgaris because it makes the term of hospitalization shorter and avoids undesirable side effects from initial high dose corticosteroids.     

The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic

Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic.     

Pemphigus vulgaris localized to the vagina presenting as chronic vaginal discharge

Involvement in pemphigus vulgaris of the female genital tract including the vulva, vagina and cervix has previously been described. In all these cases other cutaneous and mucosal sites have also been affected at some time. We describe a case of pemphigus vulgaris which only involved the vaginal mucosa. The patient presented with a persistent vaginal discharge and examination showed extensive vaginal erosions. Histology of vaginal biopsies was non-diagnostic. The recognition that the vaginal changes may represent an immunobullous disease led to further vaginal biopsies on which direct immunofluorescence studies were performed. These biopsies showed IgG and C3 in the intercellular epidermis, suggesting a diagnosis of pemphigus vulgaris. During the 3-year period that the patient has been under review there have never been any other cutaneous or mucosal lesions. To our knowledge, this is the first case of pemphigus vulgaris localized exclusively to the vaginal mucosa. There was considerable delay in diagnosis and this case highlights how important it is to recognize that chronic mucosal lesions at genital sites may be caused by immunobullous diseases such as cicatricial pemphigoid and pemphigus, and to institute appropriate investigations.     

Paraneoplastic pemphigus with circulating antibodies directed exclusively against the pemphigus vulgaris antigen desmoglein 3

A patient with follicular B-cell lymphoma presented with erythroderma associated with cutaneous and mucosal blisters. Histologic and direct immunofluorescence analysis of lesional skin showed a typical pattern of paraneoplastic pemphigus (PNP). Interestingly, indirect immunofluorescence on rat bladder was negative and immunoblot analysis of the patient's serum on epidermal extracts demonstrated antiepidermal antibodies that only recognized the pemphigus vulgaris antigen desmoglein 3, with no antibodies directed against the different proteins of the plakin family. To our knowledge this has never been reported in the literature. It exemplifies the overlap between pemphigus vulgaris and PNP and the pathogenic role of anti-desmoglein 3 antibodies in PNP. Moreover, it underscores the need to consider clinical, histologic, and immunologic features for the diagnosis of PNP.