Hisayoshi Imanishi

Laminin-332-integrin interaction: a target for cancer therapy?

For many years, extracellular matrix (ECM) was considered to function as a tissue support and filler. However, we now know that ECM proteins control many cellular events through their interaction with cell-surface receptors and cytoplasmic signaling pathways. For example, they regulate cell proliferation, cell division, cell adhesion, cell migration, and apoptosis. We focus in this review on a laminin isoform, laminin-332 (formerly termed laminin-5), a major component of the basement membrane (BM) of skin and other epithelial tissues. It is composed of 3 subunits (alpha3beta3 and gamma3 and interacts with at least two integrin receptors expressed by epithelial cells (alpha3beta1 and alpha6beta4 integrin. Mutations in either laminin-332 or integrin alpha6beta4 result in junctional epidermolysis bullosa, a blistering skin disease, while targeting of laminin-332 by autoantibodies in cicatricial pemphigoid leads to dysadhesion of epithelial cells from their underlying connective tissue. Abnormal expression of laminin-332 and its integrin receptors is also a hallmark of certain tumor types and is believed to promote invasion of colon, breast and skin cancer cells. Moreover, there is emerging evidence that laminin-332 and its protease degradation products are not only found at the leading front of several tumors but also likely induce and/or promote tumor cell migration. Thus, in this review, we focus specifically on the role of laminin-332 and its integrin receptors in adhesion, proliferation, and migration/invasion of cancer cells. Finally, we discuss strategies for the development of laminin-332-based antagonists for the treatment of malignant tumors.

Phylloid Hypermelanosis and Melanocytic Nevi with Aggregated and Disfigured Melanosomes: Causal Relationship between Phylloid Pigment Distribution and Chromosome 13 Abnormalities

The mosaic pattern of phylloid hypomelanosis is mostly associated with chromosome 13 abnormalities. Recently, 1 case of hypermelanosis in a phylloid pattern has been described. We describe a 29-year-old Japanese male with mental retardation, phylloid hypermelanosis and histopathologically and ultrastructurally peculiar melanocytic nevi, which were associated with 3 aberrant chromosome 13 cell lines. The karyotyping of 30 peripheral blood lymphocytes showed 46,XY,r(13)(p11.2q34) in 21 cells, 45,XY,–13 in 7 cells and 46,XY,dic r(13)(p11.2q34) in 2 cells. Immunohistochemical staining with HMB45 showed a positive reaction to basal keratinocytes in phylloid hypermelanosis. HMB45 staining reacted to the nevus cells and keratinocytes in the melanocytic nevi. Electron microscopy of a specimen excised from a melanocytic nevus showed an unusual finding of aggregated and disfigured melanosomes in the keratinocytes. This case suggests that chromosome 13 abnormalities may be related to the development of phylloid hypermelanosis and the bizarre melanosomes in the keratinocytes of melanocytic nevi.

Pemphigoid with antibodies to laminin γ1, BP180 and BP230, associated with psoriasis vulgaris: Successful disease control with cyclosporin

Both anti‐laminin γ1 pemphigoid and bullous pemphigoid are autoimmune subepidermal blistering diseases. The former is rare and characterized by autoantibodies to laminin γ1, a 200‐kDa dermal protein, while the latter is common among the elderly and characterized by autoantibodies to BP180 and BP230, both of which are hemidesmosomal proteins. We experienced a 69‐year‐old Japanese male patient with blister formation secondary to erythrodermic psoriasis, which was successfully treated with cyclosporin. The histopathology of erythema corresponded with psoriasis and that of a blistering lesion showed infiltration of neutrophils and eosinophils in and around the subepidermal blisters. Patient immunoglobulin G antibodies labeled both the epidermal and dermal sides of 1 mol/L NaCl‐split human skin by indirect immunofluorescent microscopy and recognized laminin γ1, BP180 and BP230 by immunoblotting. To the best of our knowledge, this is the first report of coexistence of psoriasis and atypical pemphigoid with these three autoantibodies.

Necrotizing fasciitis caused by Cryptococcus neoformans in a patient with pemphigus vegetans

Cryptococcosis occurs most often in immunocompromised people. The cutaneous features of cryptococcosis include papules, pustules, nodules, subcutaneous swelling, abscesses, molluscum contagiosum‐like or tumour‐like lesions, cellulitis, blisters, ulcers and very rarely, necrotizing fasciitis (NF). NF is a destructive soft‐tissue infection that is most typically caused by group A streptococci or by a combination of facultative and anaerobic bacteria. We present the case of a 55‐year‐old woman with pemphigus vegetans, who developed cryptococcal NF in the legs. She had been treated with immunosuppressants including plasmapheresis and pulse therapy with steroid and cyclophosphamide. Cryptococcal NF localized to the legs is very rare. Because diagnosis and treatment of cryptococcal infection is often delayed, clinicians should be aware of the possibility of cryptococcal infection when antibacterial therapy is not effective in an immunocompromised patient.

Cutaneous polyarteritis nodosa induced by Mycobacterium tuberculosis

condition. In addition to the skin, the lungs and kidneys are often involved in patients with microscopic polyangiitis. Renal involvement, such as necrotizing crescentic glomerulonephritis or hemorrhagic pulmonary capillaritis, is present in 90% of the cases. In our case, hematuria and non-nephritic range proteinuria were observed, but severe renal symptoms and pulmonary alveolar hemorrhage were absent. Discontinuation of PTU at a relatively early stage and systemic, high-dose prednisolone therapy might account for the prevention of damage to the internal organs. Microscopic polyangiitis should be considered in the differential diagnosis of deep skin ulcers resembling PG during the antithyroid therapy using PTU.

Three-base deletion mutation c.120_122delGTT in ATP2A2 leads to the unique phenotype of comedonal Darier disease

Darier disease (DD; Darier―White disease; OMIM 124200) is an autosomal dominant inherited disorder. 1 Clinically, it is characterized by recurrent and multiple hyperkeratotic papules or nodules affecting the trunk and flexural aspects of the extremities. 1 Characteristic histopathological features are dyskeratotic cells in the form of corps ronds and grains, suprabasal acantholysis forming suprabasal lacunae and irregular upward proliferation into the lacunae of papillae lined with a single layer of basal cells, the so-called villi. 2 The causative gene is ATP2A2 (OMIM 108740) on chromosome 12, which encodes the sarco/endoplasmic reticulum calcium pump ATPase (SERCA2). 2 Clinical variants include the hypertrophic, vesiculobullous, hypopigmented, cornifying, zosteriform and linear subtypes, and the rare subtype comedonal Darier disease (CDD). 1,3―6 CDD tends to appear in seborrhoeic areas. The characteristic morphological features are prominent follicular involvement, sometimes associated with keratotic plugs, and the presence of greatly elongated dermal villi and papillary projections. 4 There have been no conclusive reports on the aetiology of CDD and it is still controversial as to whether or not CDD is a variant of DD, and if it is caused by ATP2A2 gene mutations, although a combination of CDD and classic DD was reported in one patient. 7 The present study identifies a previously unreported three-base deletion mutation in ATP2A2 in a patient with CDD.

Case of trichomycosis axillaris caused by Corynebacterium propinquum.

10 mg of prednisolone. Mooren’s ulcer is an intractable sterile ulcer occurring in the periphery of the cornea. The ulcer is deep, and is characterized by presence of gouged, deep tunnels at the progressing edge. Mooren’s ulcer has a risk for significant visual impairment by corneal perforation. However, pathogenesis of Mooren’s ulcer is not clear. The cornea is an avascular organ and isolated from the systemic immune systems. Exposure of the covered specific antigens in the corneal stroma to the immune systems by infection or trauma may trigger the autoreactive immunity. Histopathologically, plasma cells, lymphocytes and neutrophils infiltrate the lesions of Mooren’s ulcers with deposition of complements and immunoglobulins. PG is classified as a neutrophilic dermatosis. Interestingly, the present case simultaneously developed the skin and eye lesions. This implicates the presence of a common pathogenesis of the two diseases. Excessively activated neutrophil function is conceivable as a common pathogenic factor for PG and Mooren’s ulcer in the present case. In addition, both diseases show similar histopathological changes with aseptic neutrophilic inflammation and good responses to systemic immunosuppressants, including corticosteroid, cyclosporin A, tacrolimus and anti-tumor necrosis factor-a anitibodies. Mooren’s ulcer is an extremely rare disease. PG occasionally accompanies some eye involvements. Mooren’s ulcer has a risk for blindness. Ocular examination should be scheduled for diagnosis of potential PG cases.

Laminin-511, inducer of hair growth, is down-regulated and its suppressor in hair growth, laminin-332 up-regulated in chemotherapy-induced alopecia

BACKGROUND Chemotherapy-induced alopecia (CIA) has a devastating cosmetic effect, especially in the young. Recent data indicate that two major basement membrane components (laminin-332 and -511) of the skin have opposing effects on hair growth. OBJECTIVE In this study, we examined the role and localization of laminin-332 and -511 in CIA. METHODS We examined the expression of laminin-332 and -511 during the dystrophic catagen form of CIA induced in C57BL/6 mice by cyclophosphamide (CYP) treatment. RESULTS Our data indicate that both laminin-332 and its receptor alpha 6 beta 4 integrin are up-regulated (both quantitatively and spatially) after mid to late dystrophic catagen around the outer root sheath (ORS) in the lower third of hair follicles in CIA. This up-regulation also occurs at the transcriptional level. In contrast, laminin-511 is down-regulated after mid dystrophic catagen at the protein level, with transcriptional inactivation of laminin-511 occurring transiently at the early dystrophic catagen stage in both epidermal and ORS keratinocytes. Laminin-511 expression correlates with expression of alpha 3 integrin in CIA and we also demonstrate that laminin-511 can up-regulate the activity of the alpha 3 integrin promoter in cultured keratinocytes. Injection of a laminin-511 rich protein extract, but not recombinant laminin-332, in the back skin of mice delays hair loss in CYP-induced CIA. CONCLUSIONS We propose that abrupt hair loss in CIA is, at least in part, caused by down-regulation of laminin-511 and up-regulation of laminin-332 at the transcriptional and translational levels.

Erythema Dyschromicum Perstans in a Japanese Child

Abstract:  Erythema dyschromicum perstans (EDP) is asymptomatic slate‐gray to blue‐brown macules. Idiopathic eruptive macular pigmentation is asymptomatic brown nonconfluent macules. We describe electron microscopic studies of a 9‐year‐old Japanese girl with EDP. The ultrastructural figures indicated that the production of immature, small, irregular‐shaped melanosomes in melanocytes and peripheral localization of melanosomes in keratinocytes caused the clinical appearance of EDP. The ultrastructural evidence distinguishes EDP from idiopathic eruptive macular pigmentation and suggests a distinct pathogenesis of the disease.

Yellow urticaria associated with hepatitis type-C liver cirrhosis

Dear Editor, Urticaria is a common skin disease. The symptoms include circumscribed, raised, erythematous and evanescent plaques with severe itching, stinging or pricking sensations. It results from immunological, inflammatory or idiopathic mechanisms. Yellow urticaria is an unusual variant which has been rarely reported since the initial description by Clarke in 1969. Yellow urticaria was originally reported to occur in hepatitis virus-infected individuals (type of hepatitis was not reported) and might be an early sign of infectious hepatitis. However, it has also occurred in association with end-stage non-viral alcoholic hepatitis. Among only four case reports in which yellow urticaria associated with hepatitis to date, there has been only one case that described the exact type of infectious hepatitis; this was type B. We report here the first case of yellow urticaria occurring in a type-C hepatitis patient. A 58-year-old Japanese man was referred from an orthopedician to our department because of the multiple yellowish plaques that suddenly appeared on almost his entire body. Ten days before this episode, he had undergone orthopedic surgery for a compression fracture resulting from a motorbike accident. He fell into septic shock 5 days after the operation from an infection acquired during the procedure. The lesions were pruritic, edematous, yellowish plaques that were partially surrounded by peripheral erythema (Fig. 1). Compression by a glass plate did not diminish the yellow color of the lesion. Histopathology of a thigh tissue section demonstrated dermal edema and a mild superficial perivascular infiltrate consisting of lymphocytes, neutrophils and eosinophils characteristic of urticaria. We performed a test for the Gmelin reaction for bilirubin. No staining was observed. His body temperature was 39.6°C and he was found to have leukocytosis (17 300 cells/μL; normal, 4300–8000 cells/μL). Clinical laboratory tests showed hyperbilirubinemia (direct bilirubin 3.1 mg/dl; normal, 0–0.2 mg/ dL; total bilirubin 4.1 mg/dl; normal, 0.2–1.0 mg/dL), liver dysfunction (alanine aminotransferase 76 IU/L; normal, 10–45 IU/L; γ-glutamine transpeptidase 137 IU/L; normal, 5–60 IU/L; chorine esterase 52 IU/L; normal, 200–450 IU/L), and kidney dysfunction (blood urea nitrogen 49 mg/dl; normal, 7–18 mg/dL; creatinine 2.45 mg/dl; normal, 0.4–0.9 mg/dL). There was no hyperimmunoglobulinemia for immunoglobulin (Ig)E. He had suffered from type-C liver cirrhosis for 10 years. The lesions gradually faded within 2 h and completely diminished within 4 h with oral administration of chlorpheniramine maleate. From the clinical course, features and the pathological result, we diagnosed this case as yellow urticaria secondary to type-C hepatitis. There has been no recurrence after this episode.