Yuji Horiguchi

A randomized double-blind trial of intravenous immunoglobulin for pemphigus

BACKGROUND Pemphigus is a rare life-threatening intractable autoimmune blistering disease caused by IgG autoantibodies to desmogleins. It has been difficult to conduct a double-blind clinical study for pemphigus partly because, in a placebo group, appropriate treatment often must be provided when the disease flares. OBJECTIVE A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of a single cycle of high-dose intravenous immunoglobulin (400, 200, or 0 mg/kg/d) administered over 5 consecutive days in patients relatively resistant to systemic steroids. METHODS We evaluated efficacy with time to escape from the protocol as a novel primary end point, and pemphigus activity score, antidesmoglein enzyme-linked immunosorbent assay scores, and safety as secondary end points. RESULTS We enrolled 61 patients with pemphigus vulgaris or pemphigus foliaceus who did not respond to prednisolone (> or =20 mg/d). Time to escape from the protocol was significantly prolonged in the 400-mg group compared with the placebo group (P < .001), and a dose-response relationship among the 3 treatment groups was observed (P < .001). Disease activity and enzyme-linked immunosorbent assay scores were significantly lower in the 400-mg group than in the other groups (P < .05 on day 43, P < .01 on day 85). There was no significant difference in the safety end point among the 3 treatment groups. LIMITATION Prednisolone at 20 mg/d or more may not be high enough to define steroid resistance. CONCLUSION Intravenous immunoglobulin (400 mg/kg/d for 5 d) in a single cycle is an effective and safe treatment for patients with pemphigus who are relatively resistant to systemic steroids. Time to escape from the protocol is a useful indicator for evaluation in randomized, placebo-controlled, double-blind studies of rare and serious diseases.

Dermatopathological studies on skin lesions of MRL mice

SummaryThe MRL-lpr/lpr(MRL/l) mouse is a new animal model for human systemic lupus erythematosus (SLE) and skin lesions with hair loss and scab formation are one of the characteristic manifestations in this mouse. We investigated the histopathology of the skin lesions in MRL/l mice and studied the related autoimmune phenomenon. Light microscopical observations revealed hyperkeratosis, acanthosis, hypergranulosis, liquefaction, vasodilation in the dermis and T-cell infiltration into the dermis at the age of 5 months (mo). Immunohistological studies showed the presence of immunoglobulins and/or complement depositions at the dermal-epidermal junction (DEJ). In some mice there was deposition of immunoglobulin at the DEJ at 2 mo and in 90%–100% of MRL/l mice at over 5 mo. Temporal relationship was present among cutaneous immunoglobulin depositions, the occurrence of anti-DNA antibodies and proteinuria. These findings suggest that MRL/l mice might provide a new aid for studying the biological mechanisms of the development of skin lesions in human SLE.

Roles of E- and P-cadherin in the human skin.

The Ca2+‐dependent cell‐cell adhesion molecules, termed cadherins, are subdivided into several subclasses. E (epithelial)‐ and P (placental)‐cadherins are involved in the selective adhesion of epidermal cells.

Kindler syndrome: Report of two cases and review of the literature

Abstract: We evaluated two patients Mrith hereditary bullous polkiloderma. Both had acral buliae, generalized poiidloderma with prominent atrophy, and acral keratoses. One patient, with sporadic disease, hj, in addition, urethral and subgiottic stenoses, weiabing of digits, and poor dentition. Hie other patient, whose disease was dominantiy inherited, had koiionychia. The resuits of cutaneous histopathology, electron microscopy, and immunofiuorescice mapping studies are presented, it is possible that Kindler syndrome and Wearys hereditary acrokeratotic poikiioderma are variants of the same disease.

Expression of cadherin cell adhesion molecules during human skin development: morphogenesis of epidermis, hair follicles and eccrine sweat ducts

SummaryExpression of E (epithelia) and P (placental) cadherin cell adhesion molecules was examined immunohistochemically using human developing skin. In adult skin, E-cadherin was expressed on cell surfaces of whole epidermal layers including skin appendages, whereas P-cadherin was expressed only on those of basal layers and the outer layers of skin appendages, which was consistent with the compartment of proliferating cells. In fetal skin, while the patterns of E- and P-cadherin expression were generally similar to those in the adult, P-cadherin temporarily showed a unique spatiotemporal expression pattern in developing sweat ducts. During this stage, the expression of P-cadherin accumulated in the epidermal ridges and showed a discrepancy with the compartment of proliferating cells. These results suggest that the expression of P-cadherin is spatiotemporally controlled, and may be closely related to the segregation of basal layers as well as to the arrangement of epidermal cells into eccrine sweat ducts, but is not closely related to cell proliferation.

Fulminant clonal expansion of large granular lymphocytes: Characterization of their morphology, phenotype, genotype, and function

A 39‐year‐old woman exhibited abrupt malignant transformation of the large granular lymphocytes (LGL) after a chronic course of Tγ‐lymphoproliferative disease (Tγ7‐LPD). The Tγ‐lymphocytes were CD2+, CD3‐, CD8‐, CD16+, Leu7‐, and Leul9+ with morphologic characteristics of LGL. Newly appearing LGL were much larger and had more prominent azurophilic granules. Although fundamentally they had the same phenotype as the LGL in chronic stage, they showed increased la‐like antigen and decreased CD16 antigen expressions. Immunoglobulin (Ig) G‐kappa type monoclonal component was detected in the patients serum. The LGL showed a germ‐line configuration for T‐cell receptor (TCR) beta and gamma chain genes, whereas the clonal chromosomal abnormalities indicated the neoplastic nature of the LGL. The LGL exhibited competent natural killer (NK), interleukin 2 (IL2) activated killer (AK), and antibody‐dependent cell‐mediated cytotoxicity (ADCC) activities. The LGL may have derived from NK cells at their mature stage with prethymic phenotype and may have influenced the homeostasis of the patients humoral immune response.

Cadherins in Cutaneous Biology

The role of cadherins in cutaneous biology has focused mainly on the classical cadherins, E‐ and P‐cadherin. In this review, roles for cadherins in skin morphogenesis, keratinocyte differentiation, and cancer metastasis are discussed.

Basal cell carcinoma cells resemble follicular matrix cells rather than follicular bulge cells: immunohistochemical and ultrastructural comparative studies.

To detail the histogenetic relationship between basal cell carcinoma (BCC) and hair follicles, we immunohistochemically compared BCC cells to follicular matrix cells and follicular bulge cells using a panel of monoclonal antibodies against melanocytes, cytokeratins, subepidermal extracellular matrix components, and bullous pemphigoid (BP) sera, as well as using electron microscopy. Cytokeratin expression patterns were not consistent with the variety in types of cytokeratins and in cases of BCC. The distribution of some extracellular matrix components was not only linear along the interfaces of BCC tumor nests and stroma, and follicular matrix and follicular papilla; granular deposits were also seen in the stroma and follicular papilla, whereas they were only linearly distributed along the follicular bulge. The BP antigens and integrin alpha 6, which were absent in BCC and follicular matrix, were expressed in the follicular bulge area. Electron microscopically, hemidesmosomes were poorly organized in these three tissues, but the lamina densa was incomplete in BCC and follicular matrix, whereas the lamina densa in the follicular bulge area was continuous. These morphologic similarities between BCC and follicular matrix cells, and coexistence of melanocytes in the BCC tumor nest strongly suggest the differentiation of BCC toward the follicular matrix cells.

Immunoelectron microscopic observations in a case of linear IgA bullous dermatosis of childhood

A 16-month-old boy exhibited vesicobullous skin lesions on the lower part of his abdomen, in his genital region, and on the buttocks and extremities. The eruptions presented small, tense bullae with or without erythematous changes of the surrounding skin, some of which clustered around the resolving lesions. Histologic examination of the eruptions showed subepidermal, ultrastructurally suprabasal laminar blister formation with infiltration of the polymorphonuclear cells and large mononuclear cells in the blister cavity. Immunoelectron microscopy revealed IgA deposits at the basilar surface of the basal keratinocytes of the lesional skin, as well as the presence of circulating IgA-class antibodies reacting to the basilar surface of the hemidesmosomes. The eruptions responded well to a combination therapy of small doses of a corticosteroid agent and a sulfonamide. There were neither clinical nor laboratory findings suggesting dermatitis herpetiformis. This case, diagnosed as linear IgA bullous dermatosis of childhood by immunofluorescence microscopy, ultrastructurally had a pathogenic site close to that observed in bullous pemphigoid.

Linear IgA dermatosis: Report of an infantile case and analysis of 213 cases in Japan

A 3‐year‐old boy presented with multiple vesicles, showing a rosette‐like arrangement around the crusts. Histopathological and immunohistochemical examinations demonstrated subepidermal blistering with neutrophilic infiltration associated with deposition of IgA, but not IgG, linearly distributed along the basement membrane zone (BMZ) of the epidermis. Indirect immunofluorescence revealed circulating antibodies (IgA class, ×160) against the BMZ of guinea pig lip skin. Based on the diagnosis of linear IgA dermatosis (LAD) of childhood, administration of dexamethasone (2 mg/day) was started, and the eruptions diminished immediately. Western blot analysis using extract of the HaCaT cell as a substrate, demonstrated the corresponding antigen at 120‐kDa molecular weight. There have been 213 cases of LAD reported in Japan including conference abstracts and these were studied to determine whether infantile cases differed from adult ones, and whether cases associated with IgG as well as IgA (IgA/G type), differed from the cases associated with IgA only (IgA type). IgG contributed less frequently to the infantile type (age of onset, ≤15 years) than to the adult type (age of onset, ≥16 years). Clinical appearance did not show any obvious difference between the IgA/G type and IgA type. However, three‐quarters of cases showing localization of antigen to the dermal side were the IgA/G type.