Noriko Ando

Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy

Objectives Myositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM. Methods Clinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab. Results Seven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb–IV). Conclusions While less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy.

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.

Allergen-specific basophil reactivity exhibits daily variations in seasonal allergic rhinitis

It remains poorly understood how symptoms in allergic rhinitis are most severe during overnight or early in the morning. The circadian clock consisting of a network of several ‘clock genes’ including Clock drives daily rhythms in physiology. This study showed that allergen‐induced surface CD203c expression on basophils in seasonal allergic rhinitis caused by Japanese cedar pollen exhibited a time‐of‐day‐dependent variation associated with temporal variations in canonical circadian clock gene expression. We also found that bone‐marrow‐derived basophils (BM basophils) generated from wild‐type mice exhibited a time‐of‐day‐dependent variation in IgE‐mediated IL‐4 and histamine production, which was not observed in BM basophils generated from Clock‐mutated mice. Therefore, allergen‐specific basophil reactivity shows daily variations depending on the circadian clock activity in basophils, which could partly explain temporal symptomatic variations in allergic rhinitis. Additionally, circadian variations in CD203c expression should be considered for interpretation of this biomarker in clinical research.

Circadian Gene Clock Regulates Psoriasis-Like Skin Inflammation in Mice

There are several reports suggesting that the pathophysiology of psoriasis may be associated with aberrant circadian rhythms. However, the mechanistic link between psoriasis and the circadian time-keeping system, “the circadian clock,” remains unclear. This study determined whether the core circadian gene, Clock, had a regulatory role in the development of psoriasis. For this purpose, we compared the development of psoriasis-like skin inflammation induced by the Toll-like receptor 7 ligand imiquimod (IMQ) between wild-type mice and mice with a loss-of-function mutation of Clock. We also compared the development of IMQ-induced dermatitis between wild-type mice and mice with a loss-of-function mutation of Period2 (Per2), another key circadian gene that inhibits CLOCK activity. We found that Clock mutation ameliorated IMQ-induced dermatitis, whereas the Per2 mutation exaggerated IMQ-induced dermatitis, when compared with wild-type mice associated with decreased or increased IL-23 receptor (IL-23R) expression in γ/δ+ T cells, respectively. In addition, CLOCK directly bound to the promoter of IL-23R in γ/δ+ T cells, and IL-23R expression in the mouse skin was under circadian control. These findings suggest that Clock is a novel regulator of psoriasis-like skin inflammation in mice via direct modulation of IL-23R expression in γ/δ+ T cells, establishing a mechanistic link between psoriasis and the circadian clock.

Marked response to imatinib mesylate in metastatic acral lentiginous melanoma on the thumb

We report a case of melanoma that had a marked response to treatment with imatinib mesylate (IM). The patient was a 61‐year‐old man who presented with a small red nodule on the thumb and destruction of the nail plate. On histological examination, this lesion was diagnosed as a melanoma, and computed tomography revealed lymph‐node swelling in the left axilla and nodules in both lung fields. Although the patient received intratumoral injections of interferon‐β and systemic administration of dacarbazine, both primary and metastatic lesions increased in size. Immunochemistry detected a KIT mutation, which was confirmed by DNA sequencing analysis, and patient was given IM. Within 2 weeks of starting the IM regimen, the size of the nodule on the nail plate markedly decreased, and the axillary lymph‐node swelling and lung‐nodule formation regressed. This case suggests that IM may be a promising treatment option for KIT mutation‐positive melanoma.

Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock

BACKGROUND The circadian clock temporally gates signaling through the high-affinity IgE receptor (FcεRI) in mast cells, thereby generating a marked day/night variation in allergic reactions. Thus manipulation of the molecular clock in mast cells might have therapeutic potential for IgE-mediated allergic reactions. OBJECTIVE We determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling was reduced (ie, when core circadian protein period 2 [PER2] is upregulated) resulted in suppression of IgE-mediated allergic reactions. METHODS We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase 1δ/ε, or glucocorticoid, both of which upregulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo. RESULTS PF670462 or corticosterone (or dexamethasone) suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils and passive cutaneous anaphylactic reactions in mice in association with increased PER2 levels in mast cells or basophils. PF670462 or dexamethasone also ameliorated allergic symptoms in a mouse model of allergic rhinitis and downregulated allergen-specific basophil reactivity in patients with allergic rhinitis. CONCLUSION Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases. Additionally, this study suggests a novel mechanism underlying the antiallergic actions of glucocorticoids that relies on the circadian clock, which might provide a novel insight into the pharmacology of this drug in allergic patients.

Case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified, with characteristics of follicular helper T cells

We report a case of an 88‐year‐old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium‐to‐large‐sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death‐1 (PD‐1), Bcl‐6 and CXCL13. Flow cytometry analysis showed that CD4+ PD‐1hi T cells also expressed CD10, inducible T‐cell co‐stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T‐cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH)‐cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH‐cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept.

Successful use of etretinate for long‐term management of a patient with cutaneous‐type adult T‐cell leukaemia/lymphoma

SIR, Adult T-cell leukaemia ⁄ lymphoma (ATLL) is a fatal T-cell malignancy caused by human T-cell lymphotropic virus type I (HTLV-I) found mainly in south-western Japan and the Caribbean basin. ATLL has broad diversity in its clinical features, and is frequently accompanied by cutaneous lesions. These may be the only manifestations of the disease (e.g. in cutaneous-type ATLL). Cutaneous-type ATLL requires no aggressive treatment until progression occurs. Prognosis is unpredictable or worse than previously thought. We report a patient with cutaneous-type ATLL in whom skin involvement has been effectively and reproducibly treated with etretinate for 6 years without evidence of progression. A 69-year-old Japanese man was originally hospitalized with a 3-month history of irregularly shaped, indurated erythematous plaques on the trunk and extremities (Fig. 1a), without lymphadenopathy or hepatosplenomegaly. Haematological examination revealed no atypical lymphocytes. Serum lactate dehydrogenase and calcium were normal. Soluble interleukin (IL)-2 receptor level was 1430 U mL (normal 145–519). Serum anti-HTLV-I antibody titre was 8192 (particle agglutination method). Skin biopsy showed a dense infiltration of atypical lymphocytes in the upper dermis with exocytosis of the atypical cells into the epidermis (Fig. 1c). These atypical cells were characterized immunohistochemically as CD3+ ⁄CD4+, CD8– ⁄CD20– ⁄CD56–. Southern blotting of biopsy-obtained DNA and hybridization with an HTLV-I-specific probe showed clonal integration of HTLV-1 provirus (Fig. 1d). Further examination confirmed that the disease was limited to skin. The patient was diagnosed as having smouldering-type ATLL (according to the Japanese Lymphoma Study Group) or cutaneous-type ATLL (according to Johno et al.). The treatment regimen and the patient’s clinical course are illustrated in Figure 2. After 4 weeks of treatment with intravenous interferon (IFN)-c (200 million IU daily) had no

Non‐occlusive mesenteric ischemia after chemotherapy for metastatic melanoma

genetic test and performed a mutation analysis of the NF1 gene. Total RNA was extracted from the peripheral blood and constitutional DNA was synthesized using reverse transcription polymerase chain reaction (PCR). The PCR product was directly sequenced and the base sequence compared against records stored in GenBank (NC_000017.10, NM_000267.3) using GENETYX version 11 software (GENETYX, Tokyo, Japan). The deletion of c.7808_8053del was identified in exon 54 to exon 56, suggesting that this deletion caused truncated neurofibromin molecules due to an in-frame deletion. (Fig. 1b). Only six cases of non-segmental, late-onset NF1, including our patient, have been reported. The onset of the pigment spots and neurofibromas in all of the reported cases occurred in the third decade of life or later, and there was no family history. Most of these cases revealedmild symptomswithout Lisch nodules. Mosaicism may be responsible for the late onset of hereditary diseases. Mosaicism is defined as the presence of two or more populations of cells with different genotypes in one individual. An example of typical mosaicism is segmental NF1, which is caused by a postzygotic mutation of NF1. Later, somatic mutations may cause localized diseases such as the segmental form, while early somatic mutations may give rise to a generalized cutaneous form. A generalized form of mosaicism has been reported to present generalized but milder manifestations such as fewer neurofibromas and/or pigment spots. Other possible causes of mild manifestations may include the benign nature of a leaky NF1-splice mutation. A specific, small mutation, a 3-bp in-frame deletion in exon 17 of the NF1 gene, has been identified in a milder phenotype of NF1. Later onset of the cutaneous manifestations and the absence of ophthalmologic manifestations may arise from mosaicism or specific, small mutations, though we were unable to confirm the presence of them in our case.

Nodular melanoma on the hyponychium: Clinical and dermoscopic features

Dear Editor, Dermoscopy is an essential tool for diagnosis of pigmented skin lesions. Here, we provide a case of nodular melanoma (NM), in which dermoscopy demonstrated rare features of blue-gray globules and nodular melanoma or Spitz nevus was suspected. A 70-year-old man was referred to our clinic with a nodule on the right big toe since 4 months prior. He had experienced no trauma on the toe. His clinical examination revealed a 12 mm 9 7 mm, symmetrical, dome-shaped, well-circumscribed and reddish-brown nodule on the hyponychium of the big toe. The lesion was accompanied by blue to black dots on the surface (Fig. 1a). Dermoscopic examination demonstrated thick negative pigment networks and irregular brown to blue-gray dots/globules (Fig. 1b). The dots/ globules, the size and density of which were varied, were entirely distributed on surface of the nodule and large and dense globules tended to be well recognized at the margin of this lesion. Moreover, the central area of the lesion showed a structureless white area with blue-gray dots. Although Spitz nevus, other mesenchymal or epithelial tumors could be diagnosed from clinical presentation, the dermoscopic findings suggestive of melanoma. Therefore, we performed resection of the nodule. Histopathological examination showed sheet-like proliferation of tumor cells with atypical nuclei from the papillary dermis to subcutaneous tissue, formation of irregular nests of atypical melanocytes in the epidermis and solitary atypical melanocytes throughout the epidermis (Fig. 1c,d). Melanophages, degenerated tumor cells and dermal fibrosis were observed in the central portion of nodule, indicating the regression of melanoma (Fig. 1e). The tumor cells of the nodule were stained positively with HMB45 and S-100 and tumor thickness was 6 mm. Based upon these findings, a diagnosis of NM was established. A computed tomography scan revealed no metastasis but a sentinel lymph node biopsy detected a micrometastasis in an inguinal lymph node, suggesting a tumor grade of pT4a, N1a, M0 (stage IIIA). We additionally performed an amputation of the big toe and a radical dissection of lymph nodes. The pathological sample showed no atypical melanocytes in the nail matrix. Most malignant melanoma on the toe occurs in the nail matrix. The early lesion of nail apparatus melanoma presents as a longitudinal brown lines on the nail. The present case had a dome-shape nodule on the hyponychium of the big toe without melanonychia, suggesting that atypical melanocytes may appear at the distal nail bed or the hyponychium of the big toe. To our knowledge, only three cases of melanoma on the big toe including the present case without melanonychia have been reported from Japan. To date, some dermoscopic findings including blue-white veil, atypical vascular pattern and homogeneous blue pigmentation have been reported to be suggestive for NM. In this case, the dermoscopy demonstrated entirely distributed dots/globules, of which the size and density varied, with thick negativepigment networks. These features corresponded to melanophages in the papillary dermis, sheet-like proliferation of atypical melanocytes and dermal fibrosis (Fig. 1d,e). These dermoscopic findings provide an additional clue in the diagnosis of NM. (a) (b)