Megumi Nishioka

Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans

Significance Regulatory T (Treg) cells expressing the transcription factor FOXP3 play a critical role in suppressing antitumor immune responses. Here we found that, compared with peripheral blood T cells, tumor-infiltrating T cells contained a higher frequency of effector Tregs, which are defined as FOXP3hi and CD45RA−, terminally differentiated, and most suppressive. Effector Treg cells, but not FOXP3lo and CD45RA+ naïve Treg cells, predominantly expressed C-C chemokine receptor 4 (CCR4) in both cancer tissues and peripheral blood. In vivo or in vitro anti-CCR4 mAb treatment selectively depleted effector Treg cells and efficiently induced tumor-antigen-specific CD4+ and CD8+ T cells. Thus, cell-depleting anti-CCR4 mAb therapy is instrumental for evoking and enhancing tumor immunity in humans via selectively removing effector-type FOXP3+ Treg cells. CD4+ Treg cells expressing the transcription factor FOXP3 (forkhead box P3) are abundant in tumor tissues and appear to hinder the induction of effective antitumor immunity. A substantial number of T cells, including Treg cells, in tumor tissues and peripheral blood express C-C chemokine receptor 4 (CCR4). Here we show that CCR4 was specifically expressed by a subset of terminally differentiated and most suppressive CD45RA−FOXP3hiCD4+ Treg cells [designated effector Treg (eTreg) cells], but not by CD45RA+FOXP3loCD4+ naive Treg cells, in peripheral blood of healthy individuals and cancer patients. In melanoma tissues, CCR4+ eTreg cells were predominant among tumor-infiltrating FOXP3+ T cells and much higher in frequency compared with those in peripheral blood. With peripheral blood lymphocytes from healthy individuals and melanoma patients, ex vivo depletion of CCR4+ T cells and subsequent in vitro stimulation of the depleted cell population with the cancer/testis antigen NY-ESO-1 efficiently induced NY-ESO-1–specific CD4+ T cells. Nondepletion failed in the induction. The magnitude of the responses was comparable with total removal of FOXP3+ Treg cells by CD25+ T-cell depletion. CCR4+ T-cell depletion also augmented in vitro induction of NY-ESO-1–specific CD8+ T cells in melanoma patients. Furthermore, in vivo administration of anti-CCR4 mAb markedly reduced the eTreg-cell fraction and augmented NY-ESO-1–specific CD8+ T-cell responses in an adult T-cell leukemia-lymphoma patient whose leukemic cells expressed NY-ESO-1. Collectively, these findings indicate that anti-CCR4 mAb treatment is instrumental for evoking and augmenting antitumor immunity in cancer patients by selectively depleting eTreg cells.

Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals

Immunological tolerance to self requires naturally occurring regulatory T (Treg) cells. Yet how they stably control autoimmune T cells remains obscure. Here, we show that Treg cells can render self-reactive human CD8+ T cells anergic (i.e., hypoproliferative and cytokine hypoproducing upon antigen restimulation) in vitro, likely by controlling the costimulatory function of antigen-presenting cells. Anergic T cells were naïve in phenotype, lower than activated T cells in T cell receptor affinity for cognate antigen, and expressed several coinhibitory molecules, including cytotoxic T lymphocyte–associated antigen-4 (CTLA-4). Using these criteria, we detected in healthy individuals anergic T cells reactive with a skin antigen targeted in the autoimmune disease vitiligo. Collectively, our results suggest that Treg cell–mediated induction of anergy in autoimmune T cells is important for maintaining self-tolerance. Healthy individuals harbor “silenced” self-reactive T cells. For the immune system, silence is golden For the immune system, balance is key. Immune cells must learn to eliminate invading pathogens but tolerate self. A cell type called regulatory T cells (Tregs) help to maintain this balance, but how they do so, particularly in humans, is unclear. Maeda et al. now report that Tregs “silence” T cells with modest reactivity to self. After culture with Tregs, the silenced T cells proliferated very little and produced almost no cytokines in response to antigen. The authors then examined T cells from healthy donors and from people with an autoimmune disease. Only healthy donors harbored silenced T cells, suggesting that if silencing goes awry, autoimmunity may result. Science, this issue p. 1536

Pilomatrix carcinoma arising from pilomatricoma after 10-year senescent period : Immunohistochemical analysis

Pilomatrix carcinoma is a rare malignant counterpart of pilomatricoma. To our knowledge, only approximately 90 cases have been published in English literature. Pilomatrix carcinoma is locally aggressive and occasionally shows rapid progression infiltrating to the muscle, bone and vessels. We report a case of pilomatrix carcinoma that developed in a 38‐year‐old man and started to grow after a long stable period, relapsed for a short time and infiltrated into the muscle underneath. While the initial skin biopsy showed histopathological findings consistent with pilomatricoma, the recurrent tumor contained marked cellular atypia and an aggressive growth pattern. Although it is still controversial whether pilomatrix carcinoma arises de novo or through malignant transformation of a pilomatricoma, the present case might be caused by the latter process considering the patient’s clinical course. β‐catenin is a downstream effecter in the canonical pathway of Wnt, acting as a signal for cell differentiation and proliferation. The characteristic nuclear staining pattern of β‐catenin in the basaloid tumor cells, which is usually observed in pilomatrix carcinoma, supported the diagnosis of pilomatrix carcinoma in the present case.

Four Cases of Atopic Dermatitis Complicated by Sjögren's Syndrome: Link between Dry Skin and Autoimmune Anhidrosis

We report four adult cases of atopic dermatitis (AD) complicated by Sjögrens syndrome (SS). The patients fulfilled diagnostic criteria for AD and SS. All cases showed persistent itchy dry skin and eczematous lesions complicated by sicca symptoms including dry eyes and dry mouth with moderate joint pain. One case manifested annular erythema and another manifested widespread discoid erythema. To investigate the underlying cause of dry skin in these cases, sweating function was evaluated using a quantitative sudomotor axon reflex test (QSART) in which the axon reflex is stimulated by acetylcholine iontophoresis. The sweating latency time was significantly prolonged in eczematous skin of AD and AD/SS compared to normal controls. Axon reflex (AXR) sweat volume was also significantly reduced in AD (normal and eczematous skin) and AD/SS (normal and eczema) compared to normal control. In contrast, the direct sweat volume of lesional or non-lesional AD skin induced by direct stimulation with acetylcholine was only slightly reduced compared to that in normal controls, but not in SS and lesional skin of AD/SS patients. These results suggest that the impaired sweat response in AD is attributable to an abnormal sudomotor axon reflex, which is accelerated and modulated when complicated by SS resulting in dry skin in the present cases.We report four adult cases of atopic dermatitis (AD) complicated by Sjogrens syndrome (SS). The patients fulfilled diagnostic criteria for AD and SS. All cases showed persistent itchy dry skin and eczematous lesions complicated by sicca symptoms including dry eyes and dry mouth with moderate joint pain. One case manifested annular erythema and another manifested widespread discoid erythema. To investigate the underlying cause of dry skin in these cases, sweating function was evaluated using a quantitative sudomotor axon reflex test (QSART) in which the axon reflex is stimulated by acetylcholine iontophoresis. The sweating latency time was significantly prolonged in eczematous skin of AD and AD/SS compared to normal controls. Axon reflex (AXR) sweat volume was also significantly reduced in AD (normal and eczematous skin) and AD/SS (normal and eczema) compared to normal control. In contrast, the direct sweat volume of lesional or non-lesional AD skin induced by direct stimulation with acetylcholine was only slightly reduced compared to that in normal controls, but not in SS and lesional skin of AD/SS patients. These results suggest that the impaired sweat response in AD is attributable to an abnormal sudomotor axon reflex, which is accelerated and modulated when complicated by SS resulting in dry skin in the present cases.

Prevalence and Impact of Past History of Food Allergy in Atopic Dermatitis

BACKGROUND Increases in allergic diseases have been reported from various epidemiological surveys. However, a few reports demonstrate the comorbidity of food allergy (FA) and allergic march. The aim of this study was to assess the prevalence and comorbidity of allergic diseases in Japanese students. METHODS First-year students (n = 3,321; 2,209 male and 1,112 female) at Osaka University were asked about allergic diseases using postal interview sheets. Personal and family histories of doctor-diagnosed allergic diseases, clinical courses, and aggravating factors were included in the questionnaires. RESULTS The lifetime prevalence of allergic rhinitis (AR), atopic dermatitis (AD), bronchial asthma (BA), and FA was 35.7%, 16.5%, 9.9%, and 7.0%, respectively. Disease-specific family histories existed for AR, AD, and BA. There was a positive correlation between the number of family histories of allergic disease and comorbidity (R = 0.370, P <0.001). Comorbidity with AD significantly lowered the onset age of both BA (P = 0.010) and AR (P <0.001). In addition, the onset age of AD was remarkably lowered by comorbidity with FA (P <0.001). Comorbidity with FA was the highest risk factor for the progression of allergic march. Although most students showed improvement in AD, BA, and AR over time, the peak recurrence period was observed in adolescence. CONCLUSIONS These findings indicate that AD associated with FA accelerates the subsequent progression of allergic march. Early appropriate management for genetically high-risk groups is important for the prevention of allergic march.BACKGROUND Increases in allergic diseases have been reported from various epidemiological surveys. However, a few reports demonstrate the comorbidity of food allergy (FA) and allergic march. The aim of this study was to assess the prevalence and comorbidity of allergic diseases in Japanese students. METHODS First-year students (n = 3,321; 2,209 male and 1,112 female) at Osaka University were asked about allergic diseases using postal interview sheets. Personal and family histories of doctor-diagnosed allergic diseases, clinical courses, and aggravating factors were included in the questionnaires. RESULTS The lifetime prevalence of allergic rhinitis (AR), atopic dermatitis (AD), bronchial asthma (BA), and FA was 35.7%, 16.5%, 9.9%, and 7.0%, respectively. Disease-specific family histories existed for AR, AD, and BA. There was a positive correlation between the number of family histories of allergic disease and comorbidity (R = 0.370, P < 0.001). Comorbidity with AD significantly lowered the onset age of both BA (P = 0.010) and AR (P < 0.001). In addition, the onset age of AD was remarkably lowered by comorbidity with FA (P < 0.001). Comorbidity with FA was the highest risk factor for the progression of allergic march. Although most students showed improvement in AD, BA, and AR over time, the peak recurrence period was observed in adolescence. CONCLUSIONS These findings indicate that AD associated with FA accelerates the subsequent progression of allergic march. Early appropriate management for genetically high-risk groups is important for the prevention of allergic march.

Systemic sclerosis with sarcoidosis: case report and review of the published work.

Sarcoidosis and systemic sclerosis (SSc) rarely coexist. Here, we report a Japanese female SSc patient who developed systemic sarcoidosis. Her SSc was a limited type negative for anti‐Scl‐70 antibody and positive for anticentromere antibody (ACA). Moreover, we performed a review of the English‐language published work that described cases of concurrent SSc and sarcoidosis. Then, we found that most SSc and sarcoidosis concurrent patients positive for anti‐Scl‐70 antibody were male (77.8%). On the other hand, most patients positive for ACA were female (87.5%). These results suggest some relationships between autoantibody profiles and sex in SSc and sarcoidosis concurrence.

Vaccination with WT-1 (Wilms’ Tumor gene-1) peptide and BCG-CWS in melanoma

ejd.2011.1619 Auteur(s) : Megumi Nishioka1,a, Atsushi Tanemura1,a tanemura@derma.med.osaka-u.ac.jp, Sumiyuki Nishida3,a, Akiko Nakano2, Akihiro Tsuboi3, Yusuke Oji4, Yoshihiro Oka5, Ichiro Azuma6, Haruo Sugiyama2, Ichiro Katayama1 1 Department of Dermatology, 2 Department of functional Diagnostic Science, 3 Department of Cancer Immunotherapy, 4 Department of Cancer Stem Cell Biology 5 Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2, [...]

Simultaneous occurrence of dermatomyositis and systemic sarcoidosis with recurrent breast cancer

Dear Editor Internal malignancy is one of the precipitating factors for both systemic sarcoidosis and dermatomyositis. Herein, we report a recurrence case of breast cancer who developed both diseases simultaneously. Of interest, treatment of the recurrent breast cancer reinforced the improvement of both disease manifestations. A 79-year-old woman was referred to our hospital for her facial and upper trunk erythema which were resistant to a conventional therapy including topical or oral steroid (prednisolone [PSL], 30 mg daily). Notably, at this time, the oral steroid was effective but it was not possible to reduce or quit PSL. These lesions had gradually become obvious after her breast cancer had recurred. As shown in Figure 1(a), there were diffuse indurated placoid erythemas on her face and ear lobes, and edematous eyelids. Palm-sized scaly erythema was observed on her back (Fig. 1b). Although signs of myopathy were absent, clinically, we suspected her skin manifestations as those of dermatomyositis. Histological examination of the biopsied specimens from erythema of face and trunk revealed damage of the basement membrane and extensive mucin deposition in the upper dermis. Moreover, there were also non-caseating epithelioid granulomas in the dermis and subcutaneous tissue (Fig. 1c–e). Abnormal laboratory data were: lactic dehydrogenase 225 mg ⁄ dL (normal range 90–200 mg ⁄ dL), angiotensin-converting enzyme (ACE) 33.7 IU ⁄ L (7.7–29.4 IU ⁄ L) and serum lysozyme 13.1 lg ⁄ mL (5.0–10.2 lg ⁄ mL). A deviation of sarcoplasmic enzyme was absent. To exclude the possibility of tuberculosis, tuberculin reaction and QuantiFERON-TB Gold (Cellestis, Carnegie, Vic., Australia) tests were performed and both were negative. Chest radiography did not show bilateral hilar lymphadenopathy. Chest computed tomography (CT) revealed small nodular lesions in both lungs, which were not observed when CT had been performed 5 months earlier. No particular findings were evident by electrocardiogram, echocardiography and ophthalmological examination. Thus, she was diagnosed as having amyopathic dermatomyositis and systemic sarcoidosis in addition to the recurrent breast cancer. The surgeons and patient discussed her treatment and it was decided that the planned treatment for the recurrent breast cancer was to be performed after the skin conditions were controlled. Topical potent steroid did not show any efficacy for her erythema and an oral steroid (PSL, 30 mg daily) was started. Two weeks after, her skin lesions showed remarkable improvement and the values of ACE and serum lysozyme were normalized. The numbers of small nodular lesions in both lungs were also improved with oral steroid only which was confirmed by chest CT scan and finally considered as lung lesions of systemic sarcoidosis but not metastasis of breast cancer, although a biopsy was not performed. For the recurrent breast cancer, total excision with the combination of postoperative irradiation (50 Gy) and sequential chemotherapy (consisting of methotrexate, 5-fluorouracil and cyclophosphamide) were performed. Along with these therapies for the breast cancer, PSL as therapy for the skin conditions was successfully able to be tapered to 3 mg without any exacerbation of the manifestations of either sarcoidosis or dermatomyositis. A relationship between dermatomyositis and internal malignancies is well documented, and there can be a close relationship between dermatomyositis and breast cancer as in our present case. As mentioned in many previous reports, the association between sarcoidosis and malignancies can be also obvious. Le Jeune et al. found 56 patients with malignancy among 1153 sarcoidosis cases with a rate ratio estimated to be 1.65 (95% confidence interval = 1.22–2.24). However, sarcoidosis is rarely associated with dermatomyositis, thus, our present case is a relatively rare case, in

T helper 2 polarization in senile erythroderma with elevated levels of TARC and IgE.

Background: Some cases of senile erythroderma tend to be diagnosed as senile atopic dermatitis (AD) based on elevated levels of immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC). However, there are few studies that describe the detailed characteristics of senile erythroderma and senile AD. Objective: We examined the association of erythroderma with AD. Methods: In this retrospective observational study, 68 patients over 65 years of age who presented with erythroderma at Osaka University Hospital were enrolled. Patient data were collected through medical records and descriptive statistics. Results: 47% of the patients were classified as having idiopathic erythroderma and 53% as having secondary erythroderma. In both idiopathic and secondary senile erythroderma patients, serum IgE and TARC levels were elevated. 84% of idiopathic erythroderma patients fulfilled the Japanese Dermatological Associations criteria for AD; however, only 4 patients were finally definitely diagnosed with senile AD. Conclusion: Many senile erythroderma patients showed AD-like symptoms due to T helper 2 polarization.

Seven cases of vitiligo complicated by atopic dermatitis: suggestive new spectrum of autoimmune vitiligo.

ejd.2012.1656 Auteur(s) : Atsushi Tanemura1 tanemura@derma.med.osaka-u.ac.jp, Tomoko Yajima1, Mayuko Nakano1, Megumi Nishioka1, Saori Itoi1, Yorihisa Kotobuki1, Mari Higashiyama2, Ichiro Katayama1 1 Department of Dermatology, Osaka University School of Medicine, 2-2 Yamadaoka Suita, Osaka 565-0871, Japan 2 Department of Dermatology, Nissei Hospital, Osaka, Japan A recent report strongly suggests that genetic polymorphisms such as the NALP1 gene are closely associated with generalized vitiligo, especially [...]