Fumikazu Yamazaki

Elevated serum BAFF levels in patients with sarcoidosis: association with disease activity

OBJECTIVE The purpose of this study was to determine serum levels of B-cell-activating factor (BAFF) and its clinical association in patients with sarcoidosis. METHODS; Serum levels of BAFF from 37 patients and 21 healthy subjects were examined by ELISA. Serum angiotensin-converting enzyme (ACE), lysozyme and IFN-γ levels in sarcoidosis patients were also measured. Isolated monocytes cultured with IFN-γ, IL-4 or IL-10 and their expression of membrane and soluble BAFF were analysed by flow cytometry or ELISA. Peripheral B cell subsets were analysed by flow cytometry. BAFF expression in the granuloma of the skin was examined by immunohistochemistry. ANAs were determined by indirect IF using HEp-2 cells as a substrate. RESULTS Serum BAFF levels were significantly elevated in sarcoidosis patients when compared with healthy controls. The frequency of skin and eye involvement was significantly higher in patients with elevated serum BAFF than in patients with normal levels. Serum BAFF levels were correlated with serum levels of ACE, lysozyme and IFN-γ. Immunostaining of anti-BAFF in the skin revealed BAFF expression by epithelioid cells of granuloma. In vitro, IFN-γ induced membrane-bound BAFF expression on monocytes and secretion of soluble BAFF by isolated monocytes. In the peripheral blood, sarcoidosis patients showed increased naïve B cells with a reciprocal decrease in memory B cells and plasmablasts. Seventeen of 26 (65%) sarcoidosis patients exhibited ANA positivity. CONCLUSION Serum BAFF levels can be used as a surrogate marker of disease activity in sarcoidosis patients. Increased BAFF may be related to the pathogenesis of sarcoidosis.

Photobiological Information Obtained from XPA Gene‐deficient Mice†

The XPA gene‐deficient mouse, an animal model of xeroderma pigmentosum (XP), develops enhanced photobiologic reactions including acute inflammation, immunosuppression and skin carcinogenesis, because of the defect in the excision repair of ultraviolet‐induced DNA lesions. The results strongly suggest that nuclear DNA is an important chromophore to initiate acute and chronic skin damages. The model mouse is a useful experimental animal not only to investigate the mechanisms of photosensitivity in XP, but also to study physiological photobiology in humans, because photobiologic reactions are greatly intensified in this mouse.

Maintenance of sweat glands by stem cells located in the acral epithelium

The skin is responsible for a variety of physiological functions and is critical for wound healing and repair. Therefore, the regenerative capacity of the skin is important. However, stem cells responsible for maintaining the acral epithelium had not previously been identified. In this study, we identified the specific stem cells in the acral epithelium that participate in the long-term maintenance of sweat glands, ducts, and interadnexal epidermis and that facilitate the regeneration of these structures following injury. Lgr6-positive cells and Bmi1-positive cells were found to function as long-term multipotent stem cells that maintained the entire eccrine unit and the interadnexal epidermis. However, while Lgr6-positive cells were rapidly cycled and constantly supplied differentiated cells, Bmi1-positive cells were slow to cycle and occasionally entered the cell cycle under physiological conditions. Upon irradiation-induced injury, Bmi1-positive cells rapidly proliferated and regenerated injured epithelial tissue. Therefore, Bmi1-positive stem cells served as reservoir stem cells. Lgr5-positive cells were rapidly cycled and maintained only sweat glands; therefore, we concluded that these cells functioned as lineage-restricted progenitors. Taken together, our data demonstrated the identification of stem cells that maintained the entire acral epithelium and supported the different roles of three cellular classes.

Case of acquired idiopathic cold-induced hyperhidrosis

We report the case of a 76‐year‐old man with a 10‐year history of cold‐induced sweating. He noticed excessive sweating in winter starting at the age of 66 years. The sweat appeared shortly after exposure to a cold environment, and was limited to his neck, chest and arms. Piloerection was also noticed in the sweating areas. The results from a heat‐induced sweating test and axon reflex sweating test, as well as the histology of his sweat glands, were normal. The heart/mediastinum ratio of 123I‐metaiodobenzylguanidine uptake was reduced, suggesting underlying pathomechanisms of incidental Lewy body disease. The cold‐induced sweating and elevation of plasma noradrenaline were inhibited by clonidine and amitriptyline. These results suggest the possibility of misconnection of afferent inputs under a cold environment to efferent pathways of heat‐induced sweating.

Case of childhood polymorphous light eruption provoked by overlap exposure to ultraviolet A and B radiation

day) on days 1, 4, 8 and 11. He also received radiotherapy to the thoracic spine, lumbar spine and pelvis. On day 16 of the second cycle of chemotherapy, he was admitted to our hospital for fever and skin eruptions. Upon admission, he had a fever (>38°C) and a sense of fatigue. He had no gastrointestinal symptoms, and computed tomographic images showed no signs of pneumonia. Skin examination revealed multiple bullae on the lower legs and multiple erythemas on the extremities (Fig. 1a,b). Laboratory tests demonstrated mild liver dysfunction, anemia and thrombocytopenia. Enzyme-linked immunosorbent assay (ELISA) for antidesmoglein 1, anti-desmoglein 3 and anti-BP180 (type XVII collagen) antibodies was negative. pp65 antigenemia assay for circulating CMV antigen was positive (53 positive cells per 50 000 total cells), which suggested systemic active CMV infection. A biopsy specimen from the left leg showed intraepidermal blister formation. In the blister, ballooning degeneration and intranuclear inclusion bodies were observed (Fig. 1c–e). Southern blotting of polymerase chain reaction (PCR) products from biopsy specimens confirmed both CMV and VZV infection. By immunohistological staining, VZV was positive in the blister while CMV was negative (Fig. 1f,g). Therefore, wemade the diagnosis of CMV reactivation accompanied by VZV reactivation or reinfection. After the administration of i.v. ganciclovir (5 mg/kg twice a day for 13 days), the general symptoms and the bullous lesions improved significantly, and the CMV pp65 antigenemia disappeared. Recurrence has not been observed during the 1-year follow-up period. Bortezomib has been widely used for patients with multiple myeloma. A previous study reported that bortezomib treatment significantly reduced VZV-specific cell-mediated immunity. Furthermore, multiple myeloma patients treated with bortezomib are at higher risk of CMV reactivation. To our knowledge, this is the second clinical case report of simultaneous CMV reactivation and VZV reactivation or reinfection presenting with varicella. In the previous case, the VZV was detected only by PCR analysis of the fluid from vesicles. In our case, the CMV and VZV were positive by PCR analysis and immunohistological staining with anti-VZV monoclonal antibodies was positive in biopsy specimens. From the present findings, we assume that the vesiculobullous eruptions were caused by VZV reactivation/reinfection in the present case. Bortezomib therapy strongly suppresses CMVand VZVspecific immunity. Moreover, CMV infection modulates the host immunity, and CMV-infected patients become more susceptible to VZV infection. We conclude that when we follow CMV reactivation of multiple myeloma patients during bortezomib therapy, we must pay attention to VZV reactivation/reinfection, and clinicians must consider prophylactic antiviral medication according to the patient’s condition.

Adalimumab treatment in Japanese patients with generalized pustular psoriasis: Results of an open-label phase 3 study

A phase 3, multicenter, open‐label, 52‐week study investigated the efficacy and safety of adalimumab 80 mg at week 0 followed by adalimumab 40 mg every other week (option to escalate to 80 mg when necessary) in Japanese patients with generalized pustular psoriasis (GPP). Adults (aged 15–75 years) with GPP, total skin score (overall erythema area, erythema area with pustules, and edema area) of 3 or more, and erythema with pustules (skin score, ≥1) based on the 2014 Japanese Dermatological Association severity index of GPP were enrolled. The primary efficacy end‐point was clinical response at week 16 (non‐responder imputation), defined as achieving remission (total skin score, 0) or improvement from baseline (reduction of ≥1 point from a baseline total skin score of 3 or ≥2 points from a baseline total skin score of ≥4). Of 10 enrolled patients (mean disease duration, 10.6 years), seven patients, including three with the dose escalated to 80 mg every other week before week 15, achieved clinical response at week 16, and five achieved clinical response at week 52. Mean change from baseline total GPP score was −4.6 at week 16 (n = 8) and −6.0 at week 52 (n = 5); change in total skin score was −3.1 (n = 8) and −4.2 (n = 5), respectively. Nine patients experienced one or more adverse events and three experienced serious adverse events. The most common adverse events were nasopharyngitis, pruritus and hypoalbuminemia. In conclusion, adalimumab was effective and well tolerated for up to 52 weeks in the treatment of Japanese patients with GPP.

Extraocular sebaceous carcinoma accompanied by invasive squamous cell carcinoma: The first case report and consideration of histogenesis

A 61‐year‐old man presented with a dome‐shaped nodule, 1.2 cm in size, with a central crater covered by keratinous material near the left lateral malleolus. Histological findings demonstrated a basophilic circular cone in the center, surrounded and sharply demarcated by a broad eosinophilic area. The central conical mass was composed mainly of atypical basaloid cells intermingled with scattered atypical sebaceous cells with scalloped nuclei and microvesicular cytoplasms, suggesting sebaceous carcinoma. The peripheral area consisted of atypical keratinizing squamoid cells without sebaceous cells, suggesting invasive squamous cell carcinoma. Atypical sebaceous cells were positive for adipophilin. Atypical basaloid cells were positive for 34βE12 and CAM5.2. Peripheral squamoid cells were positive for 34βB4 and 34βE12 throughout, and were positive for LHP1 in the superficial layer. We herein describe the first case of extraocular sebaceous carcinoma accompanied by invasive squamous cell carcinoma, which might have arisen from biphasic differentiation of cancer stem cells.

Up-regulated expression of CD86 on circulating intermediate monocytes correlated with disease severity in psoriasis

BACKGROUND The number of intermediate monocytes (CD14++CD16+) increases in many inflammatory conditions. However, it is not yet known which functional markers expressed by these populations are linked to the pathogenesis of psoriasis. OBJECTIVES We evaluated the expression of functional markers on circulating intermediate monocytes. Our goal was to correlate specific populations and their markers with the clinical severity of psoriasis. METHODS A cohort of 43 psoriatic patients was subjected to analysis. The proportion of intermediate monocytes with CD86 expression was evaluated by flow cytometry. Serum beta defensin-2 levels were measured by ELISA. Immunofluorescent staining was performed in order to identify the presence of CD14+CD16+ cells that co-expressed CD86 in affected skin tissues. RESULTS Upregulated expression of CD86 on the intermediate subset (but not the number of intermediate monocytes) correlated with clinical severity as measured by PASI scores and serum beta defensin-2 levels. Immunostaining also showed the presence of CD86+CD14+CD16+ cells in the epidermis and dermis of psoriatic plaques, which was associated with increased epidermal proliferation. CONCLUSION These results suggest that the expression of CD86 on circulating intermediate monocytes could be used as an index in clinical practice and provide novel insights into how these cells join a complex immune network under the pathological conditions of psoriasis.