Atsuko Ibusuki

Role for E-Cadherin as an Inhibitory Receptor on Epidermal γδ T Cells

E-cadherin is a homophilic adhesion molecule that maintains homotypic intercellular adhesion between epithelial cells such as epidermal keratinocytes. E-cadherin is also expressed on resident murine epidermal γδ T cells, known as dendritic epidermal T cells (DETCs), but they express another receptor for E-cadherin, αE(CD103)β7 integrin, as well. In this study, we analyzed functional differences between E-cadherin–mediated homophilic binding and heterophilic binding of αEβ7 integrin to E-cadherin in heterotypic intercellular adhesion of DETCs to keratinocytes. E-cadherin, but not αEβ7 integrin, was downregulated on activation of DETCs in vivo and in vitro. Short-term (1-h) adhesion of DETCs to keratinocytes in vitro was primarily mediated by αEβ7 integrin, and blocking of the binding of αEβ7 integrin to E-cadherin inhibited the lysis of keratinocytes by DETCs. Stable binding of E-cadherin on DETCs to plate-bound recombinant E-cadherin was observed only after 24-h culture in vitro. Cytokine production and degranulation by DETCs in response to suboptimal TCR cross-linking and mitogen stimulation were augmented by coligation of αEβ7 integrin. In contrast, engagement of E-cadherin on DETCs with immobilized anti–E-cadherin Ab, plate-bound recombinant E-cadherin, and E-cadherin on keratinocytes inhibited DETC activation. Therefore, E-cadherin acts as an inhibitory receptor on DETCs, whereas αEβ7 integrin acts as a costimulatory receptor. Differential expression of E-cadherin and αEβ7 integrin on resting and activated DETCs, as well as their opposite functions in DETC activation, suggests that E-cadherin and αEβ7 integrin on DETCs regulate their activation threshold through binding to E-cadherin on keratinocytes.

NKG2D Triggers Cytotoxicity in Murine Epidermal γδ T Cells via PI3K-Dependent, Syk/ZAP70-Independent Signaling Pathway

Murine epidermal γδ T cells, known as dendritic epidermal T cells (DETCs), survey tissue stress through the invariant T-cell receptor (TCR) and non-clonotypic receptors such as NKG2D. NKG2D signaling via the DAP10-phosphatidylinositol 3-kinase (PI3K) pathway directly stimulates cytotoxicity in natural killer (NK) cells and costimulates CD8(+) T cells to augment TCR signals. In activated murine NK cells, NKG2D signals also via the DAP12-Syk/ZAP70 pathway that triggers both cytotoxicity and cytokine production. It remains controversial whether NKG2D on DETCs is a primary activating receptor or functions only as a costimulatory receptor, and signaling pathways initiated by NKG2D ligation in DETCs have not been analyzed. We show that stimulation of short-term DETC lines with recombinant NKG2D ligands triggers degranulation (exocytosis of cytotoxic granules) via the PI3K-dependent signaling pathway, but does not induce cytokine production or Syk/ZAP70 activation. Coengagement of TCR or Syk/ZAP70 signaling was not crucial for DETC-mediated killing of NKG2D ligand-expressing target cells. Thus, NKG2D can function as a coactivating stress receptor that directly triggers cytotoxicity in DETCs, at least after priming, via the PI3K-dependent, Syk/ZAP70-independent signaling pathway.

Metastatic cutaneous squamous cell carcinoma treated successfully with surgery, radiotherapy and S-1/cisplatin chemotherapy

Primary cutaneous squamous cell carcinoma (SCC) is a malignant tumor that arises from keratinizing cells of the epidermis or its appendages. We present a patient with cutaneous SCC on the left instep with metastases to multiple lymph nodes in the para‐aortic, iliac and groin region. We chose a combination of surgery and concurrent chemoradiotherapy. The chemotherapeutic agent S‐1/cisplatin was selected based on results of the histoculture drug response assay. The patient responded dramatically to this multidisciplinary treatment and complete remission was achieved.

Granulocyte and monocyte adsorption apheresis as an effective treatment for Reiter disease

Reiter disease (RD) is characterized by a triad of sterile arthritis, urethritis and conjunctivitis. The conditions occur concomitantly or sequentially, and are associated with mucocutaneous features such as circinate balanitis and stomatitis. Arthritis usually occurs in attacks followed by recovery, but it sometimes progresses to permanent damage of the affected joints. Because the symptoms of this disorder are attributable to activated neutrophils, we assessed the efficacy of granulocyte and monocyte adsorption apheresis (GCAP) in a 73‐year‐old man with RD who had skin rashes on his penis, scrotum and right hand, with severe arthralgia. The patient’s skin rash and joint pain responded dramatically to five sessions of GCAP delivered at intervals of 5 days. We present a detailed description of the patient and discuss the mechanisms of GCAP, and suggest that GCAP may be useful for treating RD.

Increased glucose uptake by seborrheic keratosis detected by positoron emission tomography

Figure 2. A dark brown nodule, 17 mm in diameter, on the right lower abdomen. Dear Editor, Seborrheic keratosis (SK) is a common benign epidermal neoplasm in middle-aged and elderly people. Although there is a predilection for the forehead, chest, interscapular region, and waistline, SK may occur on any part of the body except the palms and soles. Positron emission tomography (PET) using the radio labeled glucose derivative 18-fluoro-2-deoxyglucose (FDG) depicts tissue glucose avidity and is widely used for the assessment of neoplastic lesions. Patients with SK are not usually subjected to PET study; our review of the literature found no PET reports on SK. Here we present incidentally detected SK in a patient who underwent PET scanning for the evaluation of lung cancer. This 59-year-old man received a diagnosis of lung cancer in his right lung; a PET scan revealed elevated FDG uptake by the skin of his right lower abdomen as well as the lung lesion (Fig. 1). The standardized uptake value (SUV) of the skin lesion was higher than of the lung cancer (SUVmax: 5.3 vs 3.4) and he was referred to our dermatology department for evaluation of the skin lesion. On physical examination the lesion, which had appeared 10 years earlier and had increased gradually, was a dark brown nodule 17 mm in diameter (Fig. 2). Its location coincided with the PET signal. A total excisional biopsy identified an epidermal tumor composed of basaloid cells with acanthosis, papillomatosis, and marked hyperkeratosis. There were many pseudohorn cysts. Based on these clinical and histopathological findings a diagnosis of seborrheic keratosis was made. The radiotracer FDG used in PET studies is a glucose analog taken up by glucose-consuming cells; it is phosphorylated by hexokinase whose mitochondrial form is greatly increased in rapidly-growing malignant cells. Therefore, PET is used mainly in the imaging of and the search for metastases or systemic

Granulocyte and monocyte adsorption apheresis for palmoplantar pustulosis with extra-palmoplantar lesions and pustulotic arthro-osteitis

Dear Editor, Palmoplantar pustulosis (PPP) is a chronic inflammatory disorder characterized by sterile pustules on the palms and soles. In rare cases, extra-palmoplantar lesions and arthro-osteitis are seen. It is treated with topical or systemic anti-inflammatory and other drugs and ultraviolet therapy. Tumor necrosis factor-a (TNF-a) is involved in its pathogenesis. We reported the effectiveness of granulocyte and monocyte adsorption apheresis (GMA) for intractable skin diseases in whose development myeloid lineage cell-derived TNF-a plays a pivotal role. Here, we present a patient with PPP with extra-palmoplantar lesions and pustulotic arthro-osteitis treated successfully with GMA. A 47-year-old man with a 6-month history of pustules on his soles was given a diagnosis of PPP elsewhere. Treatment with oral minocycline, 200 mg daily for 14 days, and topical corticosteroid, betamethasone butyrate, was not effective and sharp pain developed on his chest and shoulders around the scapulae. Physical examination at our department revealed pustules on his arm (Fig. 1a) and soles (Fig. 1b) and acneiform

High-fat diet exacerbates imiquimod-induced psoriasis-like dermatitis in mice

Psoriasis, a chronic inflammatory skin disease, is closely related to systemic metabolism. An elevated body mass index (BMI) is a risk factor for psoriasis; inflammasomes are activated by adipose tissue macrophages in obese subjects. We hypothesized that hyperlipidaemia is involved in the pathogenesis of psoriasis and examined the role of a high‐fat diet (HFD) in the development of psoriasis in imiquimod (IMQ)‐treated mice. The body weight and serum level of cholesterol were significantly higher in mice fed an HFD than in a regular diet (RD). HFD mice had higher psoriasis skin scores, and the number of neutrophils infiltrating into the lesional skin was elevated. IL‐17A mRNA expression was significantly increased in the skin of IMQ‐treated HFD mice; the expression of IL‐22, IL‐23 and TNF‐α mRNA was not enhanced. Caspase‐1 and IL‐1β were activated in the skin of IMQ‐treated HFD mice, and their serum level of IL‐17A, TNF‐α and IL‐1β was significantly upregulated. Our findings strongly suggest that hyperlipidaemia is involved in the development and progression of psoriasis via systemic inflammation and inflammasome activation.

Anti‐laminin‐332‐type mucous membrane pemphigoid in a patient with adult T‐cell leukemia/lymphoma and graft‐versus‐host disease

Dear Editor, Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive neoplasm involving post-thymic pleomorphic activated T lymphocytes. We report a 63-year-old Japanese man with ATLL, who developed chronic graft-versus-host disease (GVHD) and subsequently anti-laminin-332-type mucous membrane pemphigoid (MMP). Multiple lymphadenopathy and circulating abnormal lymphocytes had resulted in a diagnosis of acute type ATLL. He underwent combined chemotherapy and allogeneic peripheral blood stem cell transplantation from a human leukocyte antigen-matched donor in March 2013. Erythema appeared on his trunk 1 month after transplantation. Oral prednisolone (PSL) 10 mg daily and tacrolimus 1.2 mg daily were started to suppress GVHD. In June 2013, ATLL relapsed with bone marrow involvement. PSL was discontinued expecting the induction of graft-versus-leukemia effect. In February 2014, blisters and erosions developed in his oral mucosa and on his trunk. PSL was increased to 20 mg daily considering that the lesions elicited by chronic GVHD. In October 2015, he presented with nephelopsia and blurred vision due to ocular infiltration by leukemia cells and underwent radiation therapy for ocular symptoms. At the same time, he presented with multiple mucosal ulcers on his lips and palate, and blisters on his scalp, trunk and lower legs (Fig. 1a,b). Histopathologically, the blisters showed subepidermal bullae. Direct immunofluorescence (IF) study revealed linear deposits of immunoglobulin (Ig)G and C3 along the dermoepidermal junction. Indirect IF using 1 mol/L NaClsplit skin showed IgG reactivity on the dermal side of the split (Fig. 1c). On immunoblots of purified human laminin-332, IgG antibodies reacted with the 165and 145-kDa a3 subunits and the 140-kDa b3 subunit of laminin-332 (Fig. 1d), leading to a diagnosis of anti-laminin-332-type MMP. PSL was increased from 2 mg to 20 mg daily and his symptoms gradually improved. Longitudinal studies on patients with anti-laminin-332-type MMP revealed that the disorder is associated with a relatively higher risk for solid cancer than hematopoietic disorders. Only two patients with hematological tumors have been reported; one case with diffuse, large B-cell non-Hodgkin’s lymphoma, and the other case with cutaneous T-cell lymphoma. Our review of the published work found no case of antilaminin-332-type MMP associated with ATLL. Patients with autoimmune bullous diseases and GVHD have been reported. Most patients presented with bullous pemphigoid, and four had anti-laminin-332-type MMP; three of four had the b3 subunit and one had c2. Our patient reacted with both a3 and b3 subunits. However, characteristic clinical features for autoantibodies to different subunits of laminin-332 are still unclear. The previous MMP developed 6 months to 8 years after transplantation. Hofmann et al. detected circulating basement membrane zone (BMZ) antibodies in 24% of GVHD patients. They suggested that damage of keratinocytes, the subsequent release of antigens by GVHD, and reduced self-tolerance induce the

Secondary skin involvement by systemic de novo CD5-positive diffuse large B-cell lymphoma

Dear Editor, An 88-year-old woman presented with a 1-month history of a cutaneous tumor on her right cheek (Fig. 1a) with nasal obstruction. She had no history of lymphoproliferative disorders and did not have B symptoms. Physical examination revealed a 25 mm 9 12 mm, dark red colored plaques at the nasojugal fold without tenderness. Skin biopsy showed diffuse infiltration of large atypical lymphoid cells throughout the dermis and at the bottom marginal edge of the specimen (Fig. 1b, c). Immunohistochemically, the tumor cells expressed CD20, CD79a, BCL2 and BCL6. They were also positive for CD5 (Fig. 1d–h). CD10, CD56, MUM1 and cyclin D1 were negative, as was Epstein–Barr virus-encoded sRNA in situ hybridization. Many small lymphocytes were also seen and these cells were CD3 positive (Fig. 1i), and histiocytes were also observed. Southern blot analysis failed to detect monoclonal rearrangement of the IgH gene. Karyotype analysis of the biopsy specimen revealed the deletion of chromosomes 11 and 14 and two marker chromosomes (46,XX,-11,-14,+2 mar). Peripheral blood analysis did not identify significant anomalies; serum chemistry including lactate dehydrogenase was within normal limits. Serum soluble interleukin-2 receptor was 6792 U/mL (range,