Oligosaccharide modification by N‐acetylglucosaminyltransferase‐V in macrophages are involved in pathogenesis of bleomycin‐induced scleroderma

Oligosaccharide modification by N‐acetylglucosaminyltransferase‐V (GnT‐V), which catalyses the formation of β1,6 GlcNAc (N‐acetylglucosamine) branches on N‐glycans, is associated with various pathologies, such as cancer metastasis, multiple sclerosis and liver fibrosis. In this study, we demonstrated the involvement of GnT‐V in the pathophysiology of scleroderma. High expression of GnT‐V was observed in infiltrating cells in skin section samples from systemic and localized patients with scleroderma. Most of the infiltrating cells were T cells and macrophages, most of which were CD163⁺ M2 macrophages. To determine the role of GnT‐V in scleroderma, we next investigated skin sclerosis in GnT‐V knockout (MGAT5^?/?) mice. Expression of GnT‐V was also elevated in bleomycin (BLM)‐injected sclerotic skin, and MGAT5^?/? mice were resistant to BLM‐induced skin sclerosis with reduced collagen type 1 α1 content, suggesting the biological significance of GnT‐V in skin sclerosis. Furthermore, the number of CD163⁺ M2 macrophages and CD3‐positive T cells in BLM‐induced skin sclerosis was significantly fewer in MGAT5^?/? mice. In bone marrow‐derived macrophages (BMDMs), IL‐4‐induced expressions of Fizz1 and Ym1 were significantly reduced in MGAT5^?/? mice‐derived BMDMs. Taken together, these results suggest the induction of GnT‐V in skin sclerosis progression is possibly dependent on increased numbers of M2 macrophages in the skin, which are important for tissue fibrosis and remodelling.     

Papuloerythroderma‐like cutaneous involvement of a CD62L− subclone of T‐cell prolymphocytic leukemia

We report the case of an 88‐year‐old Japanese man with erythrodermic involvement of T‐cell prolymphocytic leukemia (T‐PLL). He had a history of pharyngeal diffuse large B‐cell lymphoma successfully treated with polychemotherapy including cyclophosphamide and epirubicin, 6 years before the current illness. He presented with numerous reddish, coalescing, flat‐topped papules on the trunk and extremities, sparing the skin folds of the abdomen, the features of which mimicked those of papuloerythroderma. Immunohistochemistry showed perivascular and epidermotropic infiltration of CD3⁺ CD4⁺ T cells in the cutaneous lesion. However, flow cytometric analysis revealed that the skin infiltrating T cells were negative for surface CD4, and that CD3⁺ CD4^? CD8^? cells made up 92% of the T‐cell fraction of peripheral blood. The circulating atypical T cells had a round or oval nucleus and prominent nucleoli, and the deletion of chromosomes 6q, 13 and 17. These cytological profiles were consistent with those of T‐PLL and distinct from those of Sézary cells. The same T‐cell clone was detected in the cutaneous lesion and peripheral blood, but the expression of CD62L was absent in the skin infiltrates and present in the circulating cells. No specific mutation was detected in STAT3 or STAT5B. Although low‐dose oral etoposide had a beneficial effect on the skin rash, a fatal crisis of marked leukocytosis (169 × 10³/μL) occurred 19 months after the illness onset. CD62L‐leukemic cells of T‐PLL may infiltrate the skin to form papuloerythroderma‐like cutaneous lesions.     

A case of S‐100‐negative CD1a‐positive indeterminate cell histiocytosis

Histiocytoses are a group of rare disorders characterized by a proliferation of monocytes/macrophages and dendritic cells. We present a case of a 3‐year‐old girl with a diffuse papular eruption without systemic symptoms demonstrating a proliferation of strongly CD1a⁺ histiocytes, but negative for S‐100 and langerin on histopathology. Systemic work‐up including bone marrow biopsy was unremarkable, and the patient received a diagnosis of CD1a⁺ S^? 100‐indeterminate cell histiocytosis.     

Multiple cutaneous reticulohistiocytosis with T‐cell large granular lymphocyte clonopathy

A 63‐year‐old Caucasian man presented with a 4‐month history of disseminated asymptomatic reddish‐brown papulonodular lesions. A skin biopsy showed dermal infiltration with CD68⁺ histiocytes, predominantly with eosinophilic cytoplasm, some with a ground‐glass cytoplasm, and a small number of giant cells. The diagnosis of multiple cutaneous reticulohistiocytosis was made. Bone marrow immunophenotyping due to peripheral blood lymphocytosis revealed the presence of a monoclonal population of CD3⁺, CD8⁺ CD57⁺ large granular lymphocytes. The present case suggests the coexistence of multiple cutaneous reticulohistiocytosis with an underlying disorder.     

X‐linked dyskeratosis congenita presenting in adulthood with photodamaged skin and epiphora

Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous multisystem bone marrow failure disorder of telomere maintenance, which may present with dermatological features. The main cause of mortality is bone marrow failure, often developing in the second decade of life, although pulmonary disease and malignancies such as squamous cell carcinomas (SCCs) may also prove fatal. We report the case of a 28‐year‐old man with X‐linked DC and confirmed DKC1 gene mutation. In addition to the classic triad of nail dystrophy, hyperpigmentation and oral leucoplakia, the patient had actinic keratosis (AK) and photodamaged skin, hitherto under‐recognized features of this condition. Awareness of the clinical presentation of DC is important, as accurate clinical and molecular diagnosis affords patients and their families genetic counselling, cancer prevention and screening measures, and planning for complications such as bone marrow failure.     

CD4+ T cells producing interleukin (IL)‐17, IL‐22 and interferon‐γ are major effector T cells in nickel allergy

Background It has been suggested that interleukin (IL)‐17 and IL‐22 play important roles in the elicitation of human allergic contact dermatitis; however, the frequencies of T cell subtypes producing IL‐17 and IL‐22 in human allergic contact dermatitis are unknown. Objectives To determine the frequencies of CD4⁺, CD8⁺ and γδ T cells producing IL‐17, IL‐22 and interferon (IFN)‐γ in the blood and skin from nickel‐allergic patients. Patients/materials/methods Blood samples were collected from 14 patients and 17 controls, and analysed by flow cytometry. Biopsies were taken from 5 patients and 6 controls, and analysed by immunohistochemistry and flow cytometry of skin lymphocytes. Results We found an increased frequency of γδ T cells in the blood, but no differences in the distribution of cytokine‐producing CLA⁺ T cell subtypes in nickel‐allergic patients as compared with controls. In nickel‐allergic patients, there was massive cellular infiltration dominated by CD4⁺ T cells producing IL‐17, IL‐22 and IFN‐γ in nickel‐challenged skin but not in vehicle‐challenged skin. Conclusion CD4⁺ T cells producing IL‐17, IL‐22 and IFN‐γ are important effector cells in the eczematous reactions of nickel‐induced allergic contact dermatitis in humans.     

Keratotic vascular papules over the feet: a case of Waldenström’s macroglobulinaemia‐associated cutaneous macroglobulinosis

Waldenström’s macroglobulinaemia (WM) is a plasma‐cell dyscrasia characterized by the monoclonal proliferation of lymphoplasmacytes. A 48‐year‐old man presented with a 4‐year history of multiple painful, hyperkeratotic deep‐seated papules over the pressure areas of both soles. He had a 1‐year history of Raynaud’s phenomenon, intermittent epistaxis, recurrent vomiting, tingling and numbness, and visual disturbances. Histological examination of a skin biopsy found amyloid‐like deposits in the upper and mid dermis involving dermal blood vessels, but apart from periodic‐acid–Schiff, various stains gave negative results for amyloid. Direct immunofluorescence was positive for IgM antibody. Hence, a diagnosis of WM with cutaneous macroglobulinosis was made. Immunoelectrophoresis found monoclonal IgM kappa antibody, and bone‐marrow examination revealed a lymphoplasmacytoid malignancy. The patient’s systemic systems were attributed to hyperviscosity syndrome associated with WM and the cutaneous papules were identified as deposits of excess IgM antibodies. The patient received five cycles of chemotherapy, resulting in nearly complete resolution of the skin lesions and systemic symptoms.     

Mechanism of pathogenesis of imiquimod‐induced skin inflammation in the mouse: A role for interferon‐alpha in dendritic cell activation by imiquimod

Topical application of imiquimod (IMQ), a Toll‐like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ‐induced psoriasis‐like skin inflammation, T‐helper (Th)17 cells and interleukin (IL)‐17/IL‐22‐producing γδ‐T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis‐like skin inflammation by IMQ treatment remain unclear. In this study, we investigated pathogenic mechanisms of IMQ‐induced psoriasis‐like skin inflammation in mice. We first confirmed that, together with an increase in IL‐17 and IL‐22 production, application of IMQ to mouse skin induced the expression of cytokines required for activation of the Th17 pathway, and pro‐inflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7^?/? mice demonstrated that most of the in vivo effects of IMQ were mediated via TLR7. In an in vitro study using plasmacytoid dendritic cells (DCs), IMQ induced production of interferon (IFN)‐α, IL‐23, IL‐6 and tumor necrosis factor (TNF)‐α. Furthermore, when we analyzed in vitro‐generated bone marrow‐derived DCs with features similar to TNF‐α and inducible nitric oxide synthase (iNOS)‐producing DCs, IL‐23, IL‐6, IL‐1β, TNF‐α and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co‐stimulation with IMQ and IFN‐α. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN‐α was suggested to be caused by upregulation of TLR7 expression by IFN‐α. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasis‐like skin inflammation are induced by IMQ and IFN‐α in a mouse model.     

Narrowband ultraviolet B phototherapy in the treatment of cutaneous graft‐versus‐host disease in oncohaematological paediatric patients

Background Graft‐versus‐host disease (GVHD) represents an important complication following allogeneic bone marrow transplantation. In recent years, narrowband ultraviolet B (NB‐UVB, 311–313 nm) has been found to be a beneficial adjuvant treatment in patients refractory to first‐line immunosuppressive drugs. Objectives The aim of this study is to analyse retrospectively the clinical outcome of 10 GVHD paediatric patients treated with NB‐UVB therapy. Patients and methods Ten paediatric patients (six girls and four boys: median age 12·5 years, range 4–20) with cutaneous GVHD were enrolled in the study: five patients with chronic GVHD and five patients with an overlap syndrome GVHD. All patients had already been shown to be resistant to first‐choice immunosuppressive protocols, and were treated with NB‐UVB phototherapy until a clinical remission of skin lesions occurred. Results A complete response (absence of lesions) was achieved in 80% of the cases (eight patients) after a median number of 29 treatments, corresponding to a median of 7·5 weeks (52 days) of treatment (range 3–13 weeks), with an average cumulative dose of 28·71 J cm^?2 (range 1·02–70·38 J cm^?2). Only two patients reported a partial remission (< 18% of body surface area involved). During the follow‐up period, a complete remission after 1 year was observed in 75% of patients and after 2 years in 71% of the evaluable patients. Conclusions This study provides evidence that NB‐UVB phototherapy represents a valid second‐line treatment in paediatric patients affected by GVHD and refractory to immunosuppressive first‐line treatment.     

Epstein–Barr virus‐associated T‐cell lymphoproliferative disorder affecting skin and lung in an elderly patient

A 70‐year‐old man presented with papular skin lesions and was diagnosed with Epstein–Barr virus (EBV)‐associated T‐cell lymphoproliferative disorder (T‐LPD). The patient showed infiltration of a large number of EBV‐encoded RNA‐positive T cells in the skin and lung, presence of EBV load in the peripheral blood, and expansion of clonal EBV‐infected γδ T cells and CD8⁺ T cells in the blood and skin, as assessed by EBV‐terminal repeat Southern blot, T‐cell receptor polymerase chain reaction and flow cytometric analyses. In the Japanese or East Asian fatal cases of EBV‐associated T/natural killer (NK)‐LPD, there are two peaks in age at death, approximately 20 years and 60 years. The former age group is associated with chronic active EBV infection (CAEBV), and the latter group typically suffers from extranodal NK/T‐cell lymphoma. Our case is characterized not only by the unique skin and lung manifestations but also the late onset age of the disease, indicating that the skin manifestation of CAEBV can be seen even in elderly patients.     

Late‐onset cutaneous porphyria in a patient heterozygous for a uroporphyrinogen III synthase gene mutation

Deficiency of uroporphyrinogen III synthase (UROS) causes congenital erythropoietic porphyria (CEP). The disease, originating from the inheritance of mutations within the UROS gene, presents a recessive form of transmission. In a few patients, a late‐onset CEP‐like phenotype without UROS mutations appears to be associated with a myelodysplastic syndrome. We report a 60‐year‐old man with late‐onset signs of cutaneous porphyria and accumulation in urine, plasma and faeces of type I porphyrin isomers characteristic of CEP. Analysis of DNA from peripheral leucocytes, skin and bone marrow aspirate showed that he was a heterozygous carrier of a Cys73Arg (c.217 T>C) mutation within UROS. Sequencing of cDNA from peripheral blood confirmed heterozygosity and expression of the normal allele. Measurement of UROS enzymatic activity in erythrocytes showed values ~70% of normal, indirectly indicating expression of the normal allele. Differently from other cases of late‐onset uroporphyria, the patient did not present thrombocytopenia or any evidence of a myelodysplastic syndrome. Five years of clinical follow‐up showed persistence of skin signs and increased excretion of porphyrins, independently of lifestyle factors or changes in medication regimes. We hypothesize acquired mosaicism (in the bone marrow) affecting the UROS gene. Thus, unstable cellular clones initiated overproduction of isomer I porphyrins leading to a CEP phenotype. This could be explained either by a clonal expansion of the porphyric (Cys73Arg) allele or by loss of function of the normal allele. Cellular turnover would facilitate release of uroporphyrins into circulation and subsequent skin lesions. This is the first case of a CEP heterozygous carrier presenting clinical manifestations.     

Relapsing lymphomatoid papulosis after allogenic bone‐marrow transplant

Lymphomatoid papulosis (LyP) is a rare cutaneous lymphoproliferative disorder in children, which can rarely be associated with a cutaneous or systemic lymphoma. We report a 13‐year‐old girl who presented with typical LyP and pathological features of subtype A. Six months later, the patient presented with rapidly progressive peripheral and systemic lymphadenopathy. On examination of a lymph‐node biopsy, a lymphoid infiltrate negative for anaplastic lymphoma kinase (ALK) and positive for CD30 was found, suggestive of systemic anaplastic large T‐cell lymphoma (S‐ALCL). The patient was treated with chemotherapy, followed by allogeneic bone‐marrow transplant (BMT). Over the following 6 years, she presented with biopsy‐confirmed LyP relapses with complete cutaneous, peripheral‐blood and bone‐marrow chimerism. This is only the third reported paediatric association of S‐ALCL with LyP to our knowledge, and seems to be the first paediatric case of recurrent relapses of LyP after bone‐marrow allograft for S‐ALCL with total (100%) cutaneous and bone‐marrow chimerism. LyP occurring after allogenic BMT does not appear to be donor‐derived.     

Indolent systemic mastocytosis treated with narrow‐band UVB phototherapy: study of five cases

Background Mastocytoses represent a heterogeneous group of stem cell disorders marked by an abnormal hyperplasia and accumulation of mast cells in one or more tissues, including bone marrow, gastrointestinal tract, liver, spleen, lymph nodes and skin. Indolent systemic mastocytosis (ISM) is characterized by red‐brownish and pruriginous maculopapular lesions, a bone marrow infiltration without functional impairment and an indolent clinical course with a good prognosis. In particular, the most common cutaneous symptoms are urticarial rash and mild‐to‐high pruritus. Objectives This study analyses the clinical outcome of patients affected by ISM with prevalent pruriginous cutaneous symptoms and a scarce response to anti‐histamines treated using narrowband ultraviolet B (NB‐UVB) phototherapy. Methods Narrowband ultraviolet B phototherapy was administered in a UV‐irradiation cabin equipped with fluorescent UVB lamps with a peak emission at 311–313 nm. The perception of pruritus severity was assessed using the Visual Analogue Scale (VAS) before starting the treatment and at each control. Results A complete remission of the cutaneous lesions and pruritus was documented in all patients after a median of 40.3 UV treatments and a median cumulative dose of 51.4 J/cm², with a lasting remission over a 6‐month follow‐up. The median VAS score at the beginning of the treatment was 86.6 (SD = 6.64), whereas it decreased to 6.66 (SD = 3.75) after 3 months of therapy. Conclusions Our work provides evidence that NB‐UVB phototherapy is useful for the treatment of the cutaneous symptoms and pruritus in ISM.     

Mouse bone marrow‐derived dendritic cells can phagocytize the Sporothrix schenckii,and mature and activate the immune response by secreting interleukin‐12 and presenting antigens to T lymphocytes

In sporotrichosis, dermal dendritic cells were considered to participate in induction of the immune responses against Sporothrix schenckii infection. However, it is still unclear whether and how dermal dendritic cells were involved in the progress. To clarify the pathogenic role of dermal dendritic cells (DC) in sporotrichosis, we examined the phagocytosis, maturation stages, cytokine production and antigen‐presenting ability of mouse bone marrow‐derived DC after stimulation with S. schenckii. By analysis of flow cytometry, electron microscope and confocal microscope, mouse bone marrow‐derived DC were proved to be able to phagocytize the S. schenckii. The increased expression of CD40, CD80 and CD86 on the surface of S. schenckii‐pulsed mouse bone marrow‐derived DC was detected by flow cytometer, indicating that the S. schenckii‐pulsed mouse bone marrow‐derived DC underwent the maturation program. The secretory enhancement of interleukin (IL)‐12, but not IL‐4, was found in S. schenckii‐pulsed mouse bone marrow‐derived DC, suggesting the possible activation of T‐helper 1 prone immune responses. Furthermore, S. schenckii‐pulsed mouse bone marrow‐derived DC were demonstrated to be capable of inducing the proliferation of T lymphocytes from BALB/c mice that were pre‐sensitized with S. schenckii. Together, all the results implied that dermal DC may participate in the induction of immune responses against S. schenckii infection in sporotrichosis.     

Immature mast cells exhibit rolling and adhesion to endothelial cells and subsequent diapedesis triggered by E‐ and P‐selectin,VCAM‐1 and PECAM‐1

Please cite this paper as: Immature mast cells exhibit rolling and adhesion to endothelial cells and subsequent diapedesis triggered by E‐ and P‐selectin, VCAM‐1 and PECAM‐1. Experimental Dermatology 2010; 19: 424–434. Abstract: Mast cell numbers are markedly increased at sites of chronic inflammation. However, the underlying mechanisms of mast cell accumulation including mast cell progenitor trafficking remain to be identified in detail. Thus, the aim of this study was to identify the adhesion molecules involved in rolling, firm adhesion and transendothelial diapedesis of murine bone marrow‐derived cultured mast cells (BMCMC) as a model for immature mast cells. We could show that BMCMCs exhibit in vivo rolling on skin vessel walls and strong adhesion to skin endothelial cells (ECs) in vitro under static and flow conditions. Interestingly, interaction of BMCMC with the EC adhesion molecules E‐ and P‐selectin, vascular cell adhesion molecule‐1 (VCAM‐1) and platelet endothelial cell adhesion molecule‐1 (PECAM‐1) is required to mediate rolling and firm adhesion to ECs. The adhesion of BMCMCs to skin ECs is further enhanced by TNF, IL‐4, IL‐15 and vascular endothelial cell growth factor. Furthermore, BMCMCs exhibit directed and dose‐dependent transmigration across an endothelial barrier, mediated by a PECAM‐1‐dependent mechanism. Our results demonstrate that BMCMCs can undergo a tightly regulated extravasation cascade consisting of rolling on and adhesion to endothelium and followed by directed diapedesis and reveal selectins, VCAM‐1 and PECAM‐1 as required adhesion molecules. These processes may contribute to mast cell accumulation in chronic inflammatory skin diseases and reveal opportunities to modulate peripheral tissue numbers of mast cells.     

Beneficial effects of the melanocortin analogue Nle4‐D‐Phe7‐α‐MSH in acne vulgaris

Background α‐Melanocyte‐stimulating hormone (α‐MSH) is a melanocortin peptide that increases skin pigmentation during ultraviolet light‐mediated tanning. As α‐MSH has been shown to possess anti‐inflammatory effects, we assessed the clinical potential of a superpotent α‐MSH analogue, afamelanotide (Nle⁴‐d ‐Phe⁷‐α‐MSH), in patients with acne vulgaris, the most common inflammatory skin disorder. Methods Afamelanotide (16 mg) was given in a phase II open‐label pilot study subcutaneously as a sustained‐release resorbable implant formulation to 3 patients with mild‐to‐moderate facial acne vulgaris. Evaluation included lesion count, adverse effects and patient‐reported outcome. Monitoring of laboratory parameters included differential blood counts, electrolytes, urine analysis, and liver and kidney function tests. Skin melanin density was measured by reflectance spectrophotometry. Results The total number as well as the number of inflammatory acne lesions declined in all patients 56 days after the first injection of afamelanotide. Life quality as measured by Dermatology Life Quality Index likewise improved in all 3 patients 56 days after the first injection of afamelanotide. There were no adverse effects except mild and short‐term fatigue in one patient. All patients experienced increased pigmentation especially on the face. Clinically relevant changes in laboratory parameters were not detected. Conclusions Afamelanotide appears to have anti‐inflammatory effects in patients with mild‐to‐moderate acne vulgaris. Future trials are needed to confirm the anti‐inflammatory action of this melanocortin analogue in patients with acne vulgaris.     

Cutaneous presentation of chronic lymphocytic leukemia as unique extramedullar involvement in a patient with normal peripheral blood lymphocyte count (monoclonal B‐cell lymphocytosis)

Skin infiltration by chronic lymphocytic leukemia (CLL) is very rare and almost all reported cases occur in advanced stage. We report a patient with no relevant past medical history who presented with cutaneous erythematous plaques. A punch biopsy showed typical CLL morphologic and immunophenotypic features. Subsequent studies revealed a normal lymphocyte count in peripheral blood, and there was no evidence of lymphadenopathy or organomegaly. Flow cytometry demonstrated a clonal B‐cell population both in the bone marrow and peripheral blood (1.60 × 10⁹/l) with a CLL phenotype, but it did not fulfill required criteria for CLL diagnosis. Without cutaneous involvement, this case should be classified as monoclonal B‐cell lymphocytosis.     

Nodules behind the ears: IgG4‐related skin disease

A 53‐year‐old healthy factory worker consulted our hospital complaining of small nodules of similar size, shape and location on both ears. The nodules revealed focal and massive infiltration of lymphocytes, plasma cells and eosinophils with fibrosis. They had no specific structure on pathological staining with haematoxylin and eosin. Immunostaining for IgG4 revealed that a large majority of the IgG⁺ cells were positive for IgG4. The ratio of IgG4⁺ to IgG⁺ plasma cells was approximately 40%. IgG4⁺ plasma cells were present at approximately 250 per high‐power field. The patient was diagnosed with IgG4‐related skin disease without multiple organ involvement in the systemic syndrome of IgG4‐related diseases. Because the patient was a factory worker and exposed to an environment of metallic dust, a skin patch test that included a metal series was performed. Zinc and manganese produced positive reactions. Because only skin lesions were observed in this case, not multiple organ involvement, tissue infiltration by IgG4⁺ plasma cells might have resulted from continuous sensitization to zinc and/or manganese.     

Coats plus syndrome (cerebroretinal microangiopathy with calcifications and cysts‐1): A case report

We present a 6‐year‐old girl with skin hyperpigmentation, leukoplakia, and onychodystrophy, the classic mucocutaneous triad usually associated with dyskeratosis congenita. The patient also had premature graying of the hair, bone marrow failure, hepatitis, exudative retinopathy, osteopenia with multiple long bone fractures, and intracranial calcifications and brain cysts. Coats plus syndrome is a rare disease with a clinical and genetic overlap with dyskeratosis congenita. This disease is reviewed, with a focus on the pathogenesis of the genetic anomalies and its background as a telomere biology disorder.