Shinichiro Yasumoto

Epidermolysis bullosa acquisita: What's new?

Type VII collagen is an adhesion molecule of the extracellular matrix in epithelial basement membranes, and the main constituent of anchoring fibrils at the dermal–epidermal junction (DEJ). Autoimmunity against this protein is causing the rare organ‐specific epidermolysis bullosa acquisita (EBA). EBA is a rare acquired, heterogeneous, chronic blistering disease of skin disease of skin and mucous membranes characterized by subepidermal blisters and tissue‐bound as well as circulating autoantibodies to the DEJ. EBA has several distinct clinical presentations with other subepidermal bullous diseases, such as mainly dystrophic epidermolysis bullosa or bullous pemphigoid. The circulating immunoglobulin G autoantibodies for EBA react with a 290‐kDa dermal protein, type VII collagen, as detected by immunoblot analysis using dermal extracts. The pathogenicity of these autoantibodies has been demonstrated by experimental animal models, in which anti‐type VII collagen antibodies injected into a mouse produced an EBA‐like blistering disease in the animal. EBA cases often require high doses of systemic corticosteroids and a variety of immunosuppressants. Although treatment for EBA is frequently difficult and unsatisfactory, some therapeutic success has been reported with colchicine, dapsone, infliximab and i.v. immunoglobulin. In this review, we will focus on recent progress in our understanding of the clinical manifestations, the etiopathogenesis as well as the management of EBA.

From anti-p200 pemphigoid to anti-laminin γ1 pemphigoid

Anti‐laminin γ1 pemphigoid is an autoimmune subepidermal bullous disease first described in 1996, and has been distinct from previously known subepidermal blistering diseases, such as bullous pemphigoid and epidermolysis bullosa acquisita. Circulating autoantibodies of the patients do not react to any known autoantigen of the skin, but react to a 200‐kDa molecule (p200) from dermal extracts. The identity of p200 was unmasked as laminin γ1, an extracellular matrix glycoprotein composing several forms of laminin heterotrimers. We renamed this disease from the previously used anti‐p200 pemphigoid to anti‐laminin γ1 pemphigoid, a new entity of an autoimmune bullous disease. In this decade, we have experienced over 70 cases of this disease. Although the number of the cases of anti‐laminin γ1 pemphigoid is half as many as the number of definitely diagnosed cases of epidermolysis bullosa acquisita in the same duration, a considerable number of the cases could be clinically misdiagnosed as epidermolysis bullosa acquisita. Unveiling the pathogenicity and development of a useful diagnostic method is necessary for appropriate management of this new disease.

Lesional Th17 cells and regulatory T cells in bullous pemphigoid

Abstract:  Th17 cells play crucial roles in the pathogenesis of autoimmune diseases. We previously reported that Th17 cells are recruited to the lesional skin in pemphigus vulgaris (PV) and pemphigus foliaceus (PF). The aim of this study was to evaluate lesional Th17 cells and Treg cells in bullous pemphigoid (BP). Correlations between these cells and disease severity of BP were also evaluated. Immunohistochemical studies showed that both IL‐17+ and Foxp3+ cells were present in higher numbers in BP lesions, compared with control skin. IL‐17/CD4 ratio in BP was significantly higher than that in PF. Foxp3/CD4 ratio in BP was significantly less than that in either PV or PF. There were no obvious correlations between these cells and disease severity of BP. This study suggests that, compared with pemphigus, BP shows more Th17 cell‐related inflammation and less Treg‐related regulation.

Molecular and clinical characterization in Japanese and Korean patients with Hailey–Hailey disease: Six new mutations in the ATP2C1 gene

BACKGROUND The autosomal dominant disorder Hailey-Hailey disease (HHD) results from mutations in the ATP2C1 gene, which encodes the human secretory pathway Ca2+/Mn2+ -ATPase protein 1. To date, over 90 pathological mutations scattered throughout ATP2C1 have been described with no indication of mutational hotspots or clustering of mutations. No paradigm for genotype-phenotype correlation has emerged. OBJECTIVES To determine the pathogenic ATP2C1 abnormality in additional patients with HHD in order to provide further contributions to the understanding of the molecular basis of this disorder and to add the data to the known mutation database. METHODS In this study, we investigated eight unrelated Japanese and Korean patients with HHD. We performed direct nucleotide sequencing of the ATP2C1 gene in all patients and RT-PCR analysis, using RNA extracted from a skin biopsy, in a patient with the mildest clinical features. RESULTS We identified seven different heterozygous mutations in seven of the eight investigated patients, including three new single nucleotide deletion/duplication mutations: c.520delC; c.681dupA; c.956delC, three new donor splice site mutations: c.360+1G>C; c.899+1G>T; c.1570+2T>C, as well as a previously described nonsense mutation: p.Arg153X. RT-PCR analysis in the mildest affected patient with a heterozygous c.360+1G>C mutation, demonstrated expression of a short in-frame mutant transcript with exon 5 skipping, which may account for the mild phenotype. CONCLUSIONS The results expand the known mutation spectrum in HHD and show the importance of RNA analysis for understanding the genotype-phenotype correlations more precisely.

Subcutaneous panniculitis by Epstein‐Barr virus‐infected natural killer (NK) cell proliferation terminating in aggressive subcutaneous NK cell lymphoma

We describe here a case involving a patient presenting initially with subcutaneous panniculitis, which developed after 12 years into aggressive subcutaneous natural killer (NK) cell lymphoma with peripheral blood involvement and hemophagocytosis. The surface marker of lymphoid cells in peripheral blood was CD2+3–7+8–16+56+. Skin biopsies were taken in May 1986 and June 1998. The initial biopsy revealed a diffuse proliferation of atypical lymphoid cells in the subcutaneous tissue with panniculitis, while the second biopsy revealed the presence of large lymphoid cells in the subcutaneous tissue with necrotic changes, consistent with a diagnosis of malignant lymphoma (diffuse pleomorphic type). The lymphoid cells from these two specimens were positive for CD56 and such cytotoxic molecules as T‐cell intracellular antigen‐1 (TIA‐1), granzyme B, and, interestingly, also positive for Epstein‐Barr (EB) virus by in situ hybridization. This suggests that chronic EB virus infections play an important role in the early stages of tumorigenesis and in the progression of NK cell lymphoproliferative disorders. Am. J. Hematol. 64:221–225, 2000.

Clinicopathological features and prognostic significance of CXCL12 in blastic plasmacytoid dendritic cell neoplasm

BACKGROUND Blastic plasmacytoid dendritic cell neoplasm (BPDC) is a rare hematologic neoplasm, which almost always involves the skin and shows poor prognosis. OBJECTIVE The aim of our study was to enhance BPDC diagnosis and indications for prognosis. METHODS This study involved 26 patients with BPDC. To investigate the histogenesis of BPDC, we reviewed the clinical features and stained markers of various hematopoietic lineages, chemokines, and their receptors. RESULTS Bone-marrow infiltration was detected in 13 of the 19 cases examined and leukemic changes in 18. Complete remission was achieved in 14 cases, but more than half of the patients showed recurrence within a short time, and 14 patients died of the disease after 1 to 25 months (mean 8.5 months). Positivity for CD123 was detected in 18 of 24 cases and for T-cell leukemia 1 in 18 of 22 cases. Of the chemokines and their receptors, 8 of 15 skin biopsy specimens proved to be positive for CXCL12. Leukemic change subsequent to skin lesions occurred in 7 of 8 CXCL12-positive cases (87.5%) and in 3 of 6 CXCL12-negative cases (50%). Seven of the 8 CXCL12-positive patients (87.5%) and two of the 6 CXCL12-negative patients (33.3%) have died, whereas one of 8 CXCL12-positive patients (12.5%) and 4 of 6 CXCL12-negative patients (66.7%) remain alive. LIMITATIONS The number of patients was limited. CONCLUSIONS We speculate that the presence of CXCL12-positive cells in the skin may be associated with leukemic change and a poor prognosis.

Malignant Granular Cell Tumor

A malignant granular cell tumor (MGCT) appeared on the subungual tissue of the right index finger of a 51‐year‐old woman. Two years after resection of the tumor, it recurred, and the finger finally had to be amputated. Six months later, she noticed multiple cutaneous nodules on her trunk. Despite chemotherapy and X‐ray irradiation, the patient died 18 months after the second operation. Histology of the specimen revealed a proliferation of both polygonal and spindle‐shaped cells with large hyperchromatic nuclei and an eosinophilic granular cytoplasm. Peripheral nerves were encompassed by the tumor cells. Immunohistochemically, the tumor cells were positive for S‐100 protein and Leu 7 (myelin‐associated glycoprotein). These findings support the hypothesis that MGCT cells are of Schwann cell origin.

A clinical study of patients with pemphigus vulgaris and pemphigus foliaceous: an 11‐year retrospective study (1996–2006)

Only a few reports have been published of detailed clinical studies of pemphigus in Japan. The aim of this study was to determine the clinical characteristics of patients with pemphigus vulgaris (PV) and pemphigus foliaceous (PF), who were newly diagnosed in the dermatology department of Kurume University Hospital, Japan, over the past 11 years. The primary site of involvement was the oral mucosa in 21 patients (75%) with PV. At the initial visit, most of the patients with PV had moderate to severe disease. With regard to management, systemic corticosteroids were the mainstay of treatment for patients with PV, and plasmapheresis was the most frequently used adjuvant therapy. Dapsone was the mainstay of treatment for the patients with PF. The patients were investigated for any association with an underlying malignancy; in patients with PV, lung, stomach and uterine cancers (one patient each) were seen.

Case report: Gianotti-Crosti syndrome associated with human herpesvirus-6 infection.

We report a case of Gianotti‐Crosti syndrome associated with human herpesvirus‐6 (HHV‐6) infection. An eight‐month‐old girl developed monomorphous papules on her cheeks, buttocks, and extremities after the subsidence of exanthema subitum. Viral antibody analysis confirmed primary HHV‐6 infection. HHV‐6 may be added to the list of causative agents of Gianotti‐Crosti syndrome.

A case of epidermolysis bullosa acquisita with clinical features of Brunsting-Perry pemphigoid showing an excellent response to colchicine.

BACKGROUND Brunsting-Perry pemphigoid is a rare subepidermal blistering disease characterized by scarring blisters on the head and neck. However, the identity of the responsible autoantigens is still unresolved. METHODS We reported a patient with epidermolysis bullosa acquisita who had clinical features typical of Brunsting-Perry pemphigoid and investigated the involved type VII collagen epitopes. The patient was a 65-year-old Japanese woman with a 20-month history of recurrent subepidermal bullae on her head, face, and neck. RESULTS Immunoblot studies revealed that the serum of this patient reacted with type VII collagen, specifically with the noncollagenous domain 1 and the triple-helical domain. The patient responded completely to colchicine monotherapy. LIMITATIONS This study was performed on only one case. CONCLUSION This study suggests that Brunsting-Perry pemphigoid may be a clinical variant of epidermolysis bullosa acquisita.