Naotaka Shibagaki

Overexpression of CD82 on human T cells enhances LFA-1 / ICAM-1-mediated cell-cell adhesion: functional association between CD82 and LFA-1 in T cell activation.

We previously demonstrated that CD82, expressed on both T cells and antigen‐presenting cells (APC), plays an important role as a co‐stimulatory molecule especially in the early phase of T cell activation. We also showed that the CD82 expression level is up‐regulated on activated T cells and memory T cells. This up‐regulation enhances both T cell‐T cell and T cell‐APC interactions. In this study, we further investigated the mechanism of CD82‐mediated cell‐cell adhesion. The enhanced adhesion between CD82‐overexpressing Jurkat cells was completely blocked by anti‐ICAM‐1 / LFA‐1 monoclonal antibodies. Increased interaction of LFA‐1 with ICAM‐1 was further confirmed by enhanced adhesion of CD82‐overexpressing Jurkat cells to immobilized ICAM‐1‐Ig. CD82 co‐immunoprecipitated with LFA‐1 from Jurkat cells and CD82 and LFA‐1 colocalized at an adhesion foci. These results suggest that the T cell stimulation via anti‐CD3 cross‐linking or phorbol myristate acetate treatment up‐regulates CD82 expression, leading to the colocalization of CD82 and LFA‐1, and results in enhanced interaction between LFA‐1 and ICAM‐1. In addition, a blocking experiment using monoclonal antibodies suggested that CD82 and LFA‐1 molecules on APC are also important for the optimal activation of T cells. This is the first report that describes the enhancement of cell‐cell interaction through LFA‐1 and ICAM‐1 by the overexpression of another cell surface molecule, CD82.

A clinical study of Henoch-Schönlein Purpura associated with malignancy

Background  Malignancy has been reported as a causative factor of cutaneous vasculitis, although only two retrospective epidemiological studies have analysed the association between Henoch‐Schönlein purpura (HSP) and malignancy to date.

CD4+CD25high Regulatory T Cells Are Markedly Decreased in Blood of Patients with Pemphigus Vulgaris

Background: It remains to be determined whether pemphigus vulgaris (PV), an autoimmune blistering disease, has a reduction and/or dysfunction of CD4+CD25high regulatory T (Treg) cells. Objectives: To evaluate the frequency and phenotypes of Treg cells in blood of patients with PV. Methods: Peripheral blood mononuclear cells were prepared from PV patients as well as normal and disease control volunteers, and the frequency and phenotypes of Treg cells were determined by flow cytometry. CD4+CD25+ and CD4+CD25– T cells isolated from peripheral blood mononuclear cells of PV patients and normal controls were subjected to real-time semiquantitative RT-PCR for the expression of Foxp3 gene. Results: The proportion of Treg cells in all PV patients was severely reduced, approximately ten times less than controls. These observations were further confirmed by both diminished gene and protein expression of Foxp3 in the CD4+CD25+ T cell population in PV patients. Conclusions: Numerical impairment of Treg cells may be involved in the pathogenesis of PV.

Functional analysis of CD82 in the early phase of T cell activation: roles in cell adhesion and signal transduction

To define T cell co‐stimulatory molecules that work in the early phase of T cell activation, we established monoclonal antibodies (mAb) that inhibit or enhance T cell activation by the histiocytic leukemia cell line U937. One of the mAb, 53H5, which recognized both T cells and U937, was identified to bind to CD82 by expression cloning. Functional analyses of CD82 revealed that 1) CD82 needs to exist on both T cells and U937 for the full activation of T cells; 2) CD82 expression is up‐regulated on both T cells and U937 by stimulation such as CD3 ligation or treatment with phorbol 12‐myristate 13‐acetate; 3) overexpression of CD82 enhances both homotypic and heterotypic cell adhesion betweenT cells and U937; 4) CD82 signal co‐stimulates T cells and the signal works synergistically with the CD28‐mediated T cell co‐stimulation signal; 5) in mixed leukocyte reactions using U937 as stimulator cells, CD82 overexpression on U937 correlates with the higher allogeneicity of U937 cells. These results indicate that CD82 co‐stimulates T cells not only by sending intra‐T cell signals that work synergistically with CD28 signals but also by inducing enhanced T cell‐antigen‐presenting cell interaction.

Overexpression of GRIM-19 in cancer cells suppresses STAT3-mediated signal transduction and cancer growth.

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is common in many human and murine cancer cells, and its activation leads to cellular transformation. STAT3 pathway inhibitors have been reported to suppress cancer growth. To investigate the antitumor effects of inhibiting the STAT3-mediated signaling cascade in the cancer microenvironment, using a molecular-targeting approach, we focused on the gene associated with retinoid-IFN-induced mortality 19 (GRIM-19). GRIM-19 has been reported to interact physically with STAT3 and inhibit STAT3-dependent signal transduction. We used the nona-arginine (R9)-protein transduction domain (R9-PTD) as a protein carrier to induce high levels of GRIM-19 expression in vitro and in vivo. We generated an R9-PTD–containing GRIM-19 fusion protein (rR9-GRIM19) and successfully induced overexpression in the cytoplasm of cancer cells. Analysis of the expression of downstream molecules of STAT3 confirmed that in vitro rR9-GRIM19 treatment of constitutively activated STAT3 (STAT3c) cancer cells significantly reduced STAT3-dependent transcription. Moreover, intratumoral injections of rR9-GRIM19 in STAT3c cancer-bearing mice significantly suppressed tumor growth. These results suggest that intratumoral injections of rR9-GRIM19 have potential as a novel anticancer therapy in STAT3c cancer due to their ability to inhibit STAT3-mediated signal transduction without major systemic side effects. Mol Cancer Ther; 9(8); 2333–43. ©2010 AACR.

Topical mechlorethamine and clobetasol in multifocal primary cutaneous marginal zone-B cell lymphoma

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A case of lymphoepithelioma-like carcinoma of the skin associated with Epstein-Barr virus infection.

Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare cutaneous neoplasm with histopathologic similarities to nasopharyngeal carcinoma. The association of nasopharyngeal carcinoma with Epstein-Barr virus (EBV) is well documented. EBV has also been reported to be associated with LELC in only four sites (the stomach, salivary glands, lung, and thymus), but not in the skin. We report herein a case of EBV-positive LELCS. An 82-year-old female presented with a red nodule on the right cheek. Histologically, the entire dermis was occupied by atypical tumor cell nests with dense lymphocytic infiltration. Neoplastic cells were strongly positive for cytokeratin 14 but were negative for cytokeratins 19 and 20. EBV genomes in neoplastic cells were detected by polymerase chain reaction analysis and in situ hybridization for EBV-encoded RNA, suggesting an association with EBV.

A Case of Metastatic Extramammary Paget’s Disease Responding to Trastuzumab plus Paclitaxel Combination Therapy

There is no effective treatment for advanced extramammary Paget’s disease (EMPD). The human epidermal growth factor receptor 2 (HER2) protein is often overexpressed in EMPD. Trastuzumab is a humanized monoclonal antibody against HER2 used in the treatment of breast cancers in which HER2 is overexpressed. We report a case of advanced EMPD in which trastuzumab and paclitaxel combination therapy was effective. The patient was a70-year-old Japanese woman who presented with EMPD on the vulva and multiple metastatic lymph nodes. Immunohistochemical staining revealed strong HER2 protein expression in the primary tumor and metastatic lymph nodes. The patient received trastuzumab and paclitaxel. After 4 courses of this regimen, the mass on the vulva and the metastatic lymph nodes regressed. Our findings may imply that trastuzumab plus paclitaxel combination therapy is useful for the treatment of advanced EMPD overexpressing HER2.

A case of endocrine mucin-producing sweat gland carcinoma

Endocrine mucin‐producing sweat gland carcinoma (EMPSGC), which is an uncommon sweat gland tumor with a predilection for the eyelids, is morphologically analogous to solid papillary carcinoma of the breast. We report the case of a 55‐year‐old man with a subcutaneous tumor of the upper cheek. The pathological findings for this patient were compatible with those of reported cases of EMPSGC, and p63 staining revealed partial microinvasion into the dermis. On the basis of these findings, the patient was diagnosed with EMPSGC. It is reported that EMPSGC is a precursor of invasive mucinous carcinoma of the skin. Therefore, this patient was treated and followed up as if he had mucinous carcinoma of the skin. To the best of our knowledge, this is the first report of such a case from Japan.

Psoriasiform eruption associated with alopecia areata during infliximab therapy.

Infliximab, a chimeric monoclonal antibody to tumour necrosis factor (TNF)-a, is used to treat autoimmune diseases. Although this biological agent has also been used to treat psoriasis, paradoxical inductions of psoriasis-like eruptions have been reported in patients treated with infliximab. Some cases of alopecia areata (AA) in patients receiving infliximab have also been described. We report a case of psoriasiform eruption and AA with infliximab therapy that was successfully treated with ciclosporin. A 69-year-old Japanese woman with rheumatoid arthritis (RA) who had been receiving infliximab therapy for 21 months developed a psoriasiform eruption followed by palmoplantar pustulosis. Despite topical treatment, the eruption rapidly disseminated to the limbs and the trunk. Three months later, alopecia started to appear on the patient s scalp. On physical examination, there was an erythematous pustular eruption on the palms and soles and scaly plaques over the trunk and limbs, with clustering over the lower back (Fig. 1a). The most striking cutaneous feature was the presence of multiple patches of hair loss on the scalp (Fig. 1b). Histological examination of a skin-biopsy specimen taken from a lesion on the thigh showed epidermal hyperplasia, parakeratosis, subcorneal pustules with neutrophilic infiltration, and dermal infiltration with lymphocytes, as well as a small number of eosinophils. After infliximab treatment was discontinued, the patient was treated with clobetasol propionate 0.05% ointment. The scaly plaques on the trunk and limbs responded partially to topical steroid therapy, but the hair loss progressed. Therefore, the patient was started on ciclosporin 200 mg ⁄ day (Neoral ; Novartis Pharma, Basel, Switzerland). The psoriasiform eruption disappeared, and the patient s hair started to regrow. The ciclosporin dosage was progressively decreased and eventually stopped without any relapses of either the scaly erythema or the AA. Infliximab is a chimeric monoclonal antibody to TNF-a that acts by binding to the TNF molecule. This monoclonal antibody is used to treat some autoimmune diseases, including RA, ankylosing spondylitis, and Crohn s disease. This biological drug is also regarded as one of the most potent treatments for psoriasis, but paradoxically, psoriasiform eruptions have been reported in patients receiving this medication. Although the mechanism by which antiTNF-a agents induce psoriasis remains to be elucidated, blocking the action of TNF-a may increase the production of interferon-a, a critical cytokine in psoriasis, by plasmacytoid dendritic cells. Some cases of AA induced by infliximab through an unknown mechanism have also (a)