Characteristics of IgG subclasses and complement deposition in BP230-type bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP180 is the primary autoantigen of BP, and in a portion of BP cases, BP230 is the only target of autoantibodies. Such BP is called BP230-type BP. BP230-type BP tends to show milder clinical phenotypes than conventional BP, but the reason is unclear. The pathogenic roles of autoantibodies and complement activation have been shown in conventional BP, but the distribution of IgG subclasses and the degree of complement deposition in BP230-type BP remain unclear. OBJECTIVE: To compare the distribution of IgG subclasses and the degree of complement deposition in BP230-type BP with those in conventional BP with autoantibodies to BP180 and BP230 (BP180-BP230-type BP). METHODS: The diagnosis of BP was confirmed by the histopathology of the lesions, the deposition of IgG and complement in the perilesional skin and the presence of circulating autoantibodies to BP180 and BP230. The disease severity was determined by bullous pemphigoid disease area index. The deposition of IgG subclasses and complement deposition were examined by direct immunofluorescence of the perilesional skin in 6 BP230-type BP cases and 11 BP180-BP230-type BP cases. RESULTS: Sixty seven percent of BP230-type BP cases show a mild clinical phenotype. All BP230-type BP cases and 82% of BP180-BP230-type BP cases were found to demonstrate the clear deposition of IgG4 at the basement membrane zone of skin specimens. Notably, the deposition of IgG1 and IgG3 was faint or negative in all of the BP230-type BP cases, whereas they were clearly detected in 91% and 64% of the BP180-BP230-type BP cases, respectively. The deposition of complement C3 tended to be weaker in BP230-type BP than in BP180-BP230-type BP. CONCLUSION: The mild clinical phenotype of BP230-type BP may correlate with the weaker deposition of IgG1, IgG3 and complement in the skin lesions.

Transformation-specific matrix metalloproteinases (MMP)-7 and MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas.

BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have an increased risk of developing rapidly progressive and metastatic cutaneous squamous cell carcinomas (SCC). It is unclear why these SCC behave more aggressively than sporadic SCC. Matrix metalloproteinases (MMP) are a family of endopeptidases that contribute to growth, invasion and metastasis of SCC. The role of MMP in RDEB-associated SCC is not known. OBJECTIVES: To investigate the expression of MMP-7, MMP-13 and MMP-9 in RDEB-associated SCC in comparison with sporadic SCC and Bowen's disease. METHODS: Immunohistochemical analysis of 25 RDEB-associated SCC, 61 sporadic SCC and 28 sporadic lesions of Bowen's disease was carried out using monoclonal antibodies for MMP-7, MMP-9, MMP-13 and E-cadherin and syndecan-1. RESULTS: MMP-7 was detected in all RDEB-associated SCC, in tumour cells within the invasive edge, where E-cadherin and syndecan-1 were markedly diminished or absent. MMP-7 expression was also observed in 98% of sporadic SCC and in 68% of Bowen's diseases. MMP-7 staining was significantly stronger in RDEB-associated SCC than in sporadic SCC, and was most abundant in poorly differentiated tumours. MMP-13 was detected in tumour cells in 96% of RDEB-associated SCC and in all sporadic cutaneous SCC. MMP-9 was detected in the inflammatory cells in all SCC examined. CONCLUSIONS: These results identify MMP-7 and MMP-13 as tumour cell-specific markers for SCC progression and as potential therapeutic targets in RDEB-associated SCC. The pattern of immunolabelling suggests that MMP-7 may shed E-cadherin and syndecan-1 from the SCC cell surface.

Leukaemic dissemination of Merkel cell carcinoma in a patient with systemic lupus erythematosus.

We describe an unusual bone-marrow metastasis of Merkel cell carcinoma (MCC) arising in the right cheek of a 73-year-old woman with systemic lupus erythematosus (SLE) and Sjögren's syndrome, who had been treated with oral prednisolone and methotrexate for 10 years. Seven months after wide local excision followed by local irradiation, the patient presented with thrombocytopaenia. Her bone marrow had been completely replaced by metastatic MCC cells, and metastatic cytokeratin 20-positive cells were also identified in the peripheral blood. To our knowledge, in the English literature, only six cases have been described previously of MCC bone-marrow involvement. Of these six cases, four were immunosuppressed, similar to our case. The high incidence of MCC in immunosuppressed patients such as those with SLE has been discussed previously. We consider that immunosuppression might be associated with bone-marrow metastasis, which is a rare form of MCC.

Eccrine porocarcinoma and Bowen's disease arising in a seborrhoeic keratosis.

An association between seborrhoeic keratosis (SK) and malignant tumours is considered to be rare. We observed a case of eccrine porocarcinoma and Bowen's disease (BD) occurring synchronously, forming one lesion in a SK on the abdomen. It is controversial whether malignant neoplasms arising in SK occur only by chance or if pre-existing SK plays a role in pathogenesis. This case suggests an implication of pre-existing SK in the subsequent development of both BD and eccrine porocarcinoma.

Multiple nodules on the face and in the nasal cavity are the symptoms of vegetative pyoderma gangrenosum complicated with myelodysplastic syndrome.

We have encountered and treated an unusual case of pyoderma gangrenosum (PG) characterized by multiple nodular lesions on the face and in the nasal meatus, which was complicated by myelodysplastic syndrome.

Two cases of atypical melanocytic lesions in recessive dystrophic epidermolysis bullosa infants.

Summary Atypical melanocytic lesions (AtML) are known to be associated with epidermolysis bullosa (EB), mainly with the junctional subtype. We report two cases of AtML in two female infants with recessive dystrophic epidermolysis bullosa (RDEB). Both lesions were dark brown- to black-coloured, asymmetric-shaped macules, 3-4 cm in size, with an irregular border and were located on the forearms of two unrelated, 1-year-old female infants. On a clinical and pathological basis, the pigmented macules were diagnosed as AtML in EB patients. There are only a few reports describing in detail the clinical and histopathological features of AtML in RDEB, especially in infant cases. AtML may easily be misdiagnosed as malignant melanoma and, even in infant patients with RDEB, this should be included as one of the differential diagnosis of pigmented lesions.

Detection of 1733insC mutations in an Asian family with Birt-Hogg-Dubé syndrome.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant genodermatosis characterized by skin tumours, including multiple fibrofolliculomas, trichodiscomas and acrochordons. BHD patients also may suffer from associated renal and colonic carcinomas. The defective gene in BHD has been recently identified and is suspected of being a tumour suppressor gene. Several mutations of the BHD gene have been reported only in Caucasian patients. OBJECTIVES: This study reports the first Asian family that has been demonstrated to carry a BHD mutation. PATIENTS/METHODS: The proband was a 26-year-old Japanese man with multiple asymptomatic, soft skin-coloured papules on his face, neck and trunk, which were clinically thought to be acrochordon. His father was also affected. Histopathologically, the papules revealed a fibrofolliculoma that had a circumscribed proliferation of fibroblasts and collagen fibres surrounding an abnormal hair follicle. RESULTS: Mutational analysis of the BHD gene of the proband and the father detected 1733insC, a cytosine insertion mutation in an eight-cytosine tract (nucleotides 1733-1740) in exon 11. Analysis of fibrofolliculoma in the proband showed heterozygous 1733insC mutation, suggesting the absence of loss of heterozygosity. Interestingly, previous mutational analysis in Caucasian patients revealed that both1733insC and 1733delC mutations were hot spots. CONCLUSIONS: This study is the first to find the same hot-spot 1733insC mutation in Asian kindred. The mutations in this polycytosine tract may have a wide, global distribution despite their arising from a different ethnic background.

Rapid remission of severe pruritus from angiolymphoid hyperplasia with eosinophilia by pulsed dye laser therapy.

A 48-year-old Japanese woman with angiolymphoid hyperplasia with eosinophilia (ALHE) was successfully treated with a flashlamp pulsed dye laser (585 nm, 450 micros pulse duration). The lesion was severely pruritic and had been enlarging slowly for 2 years but was resistant to conventional therapies, including topical, intralesional, and systemic corticosteroid, and cryotherapy. The severe pruritus immediately improved after the first treatment using the pulsed dye laser. The erythema and papules gradually improved without scarring and this was followed by further five treatments over approximately a 4-month interval. No clinical recurrences have been observed 1 year after completion of the treatment. We think that pulsed dye laser therapy is an effective treatment for ALHE in both Japanese as well as Caucasian patients. Pulsed dye laser therapy is also helpful in reducing the pruritus in ALHE patients.

A novel A97P amino acid substitution in alpha-galactosidase A leads to a classical Fabry disease with cardiac manifestations.

BACKGROUND: Fabry disease results from a genetic deficiency of alpha-galactosidase A (GLA) activity. Phenotype-genotype correlations in this condition have not as yet been fully elucidated. OBJECTIVE: To report a case of a male patient with classical Fabry disease and his mother, a heterozygous female with Fabry disease, showing cardiac involvement, and to identify the underlying GLA gene mutation in this particular phenotype. PATIENTS/METHODS: Genomic DNA was extracted from the patient, his mother and the unaffected family members. Biopsy specimens of skin, heart and kidney were examined using light and electron microscopy. The mutation was identified by polymerase chain reaction and direct sequencing and was confirmed by restriction enzyme fragment length polymorphism. RESULTS: The G-->C transversion was identified in codon 97 of the GLA gene and resulted in an A97P amino acid substitution that was a novel pathogenic GLA gene mutation. The male patient who had classical Fabry disease was hemizygous and his mother was heterozygous for this mutation. CONCLUSIONS: These results indicate that the A97P amino acid substitution in GLA might tend to induce classical Fabry disease.

Serological and immunohistochemical detection of human herpesvirus 8 in Kaposi's sarcoma after immunosuppressive therapy for bullous pemphigoid.

Kaposi's sarcoma (KS) developed in an 87-year-old human immunodeficiency virus-negative woman from Hokkaido island 4 months after oral administration of prednisolone for the treatment of bullous pemphigoid (BP), and rapidly disseminated to almost the entire body within 2 months. The open reading frame (ORF) 59 and ORF73 proteins encoded by human herpesvirus 8 (HHV-8) were detected immunohistochemically in the nuclei of the tumour cells of KS. The protein coded by ORF73, latent protein, was detected in most of the nuclei of the tumour cells, but only a few tumour nuclei were positive for the ORF59 protein, a lytic protein expressed during active infection. The antibodies against both lytic and latent proteins of HHV-8 were detected retrospectively in the serum 4 months before the appearance of KS and before prednisolone therapy had been started. Immunosuppression associated with the treatment for BP possibly activated latent HHV-8 infection and induced the development of KS.

Distribution of IL-18 and IL-18 receptor in human skin: various forms of IL-18 are produced in keratinocytes.

Human interleukin-18 (IL-18) enhances IL-12-mediated IFN-gamma production by lymphocytes and Fas/perforin-mediated cytolysis by NK cells. IL-18 is synthesized as a 24 kDa proform, and the proform is processed in the cytoplasm into an 18 kDa mature form. Active and precursor forms of IL-18 have been detected in immunocompetent cells, and active IL-18 exerts its functions through its receptor. We sought to determine which human skin cells are responsible for production of IL-18 and which express its receptor. Monoclonal antibodies against human IL-18 and polyclonal antibody against IL-18 receptor were provided for this analysis. Formalin-embedded and frozen sections of human epidermis were analyzed by immunoperoxidase and immunofluorescence staining. IL-18 was detected in all living cell layers of the epidermis, hair follicles, arrectores pilorum, eccrine ducts and endothelial cells. IL-18 was localized in the cytoplasm of cells in living epidermal cell layers. In contrast, IL-18 receptor was mainly detected in keratinocytes and expressed in the cell periphery in living cell layers. Since keratinocytes were the main source of IL-18 and its receptor, cultured human keratinocytes were further analyzed by immunoblotting. IL-18 receptor was identified as an 80 kDa single band. The mature 18 kDa and precursor 24 kDa forms of IL-18 were detected by our monoclonal antibody (mAb) 21 and mAb 132, respectively, while only the 18 kDa form was detected by a commercial mAb, 125-2H. Cultured keratinocytes showed positive granular staining for IL-18 in the cytoplasm and positive staining for IL-18 receptor mainly in the cell periphery. Our findings indicate that mature IL-18, precursor IL-18 and IL-18 receptor are simultaneously expressed with different localizations by human epidermal keratinocytes. Keratinocytes might be activated by their own IL-18 in an autocrine or paracrine fashion.