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.     

Cutaneous presentation preceding acute myeloid leukemia with CD4+/CD56+ expression misdiagnosed as a blastic plasmocytoid dendritic cell neoplasm: A case report

Acute myeloid leukemia (AML) may initially present as cutaneous lesions corresponding to blasts involving the skin as the first clinical manifestation prior to blood and bone marrow (BM) infiltration. Such presentation is known as myeloid leukemia cutis (LC). Blastic plasmocytoid dendritic cell neoplasm (BPDCN) is an aggressive tumor derived from the precursors of plasmocytoid dendritic cells with cutaneous and BM involvement and leukemic dissemination. Myeloid LC and BPDCN may be difficult to distinguish as they share similar clinical and histopathological features, in particular AML with monocytic differentiation. Nevertheless, the correct diagnosis has to be made to determine adequate and effective therapy. Here, we report the case of a 61‐year‐old woman who presented with an AML with MLL rearrangement and CD4+/CD56+ expression presenting as LC and that was misdiagnosed as BPDCN. We emphasize that careful and exhaustive analyses should be performed to make the correct diagnosis.     

In utero presentation of aggressive systemic mastocytosis in a neonate

Mastocytosis is a clinically heterogenous disease characterized by mast cell hyperplasia in skin, bone marrow and/or visceral organs. Cutaneous mastocytosis is more frequently observed in children, whereas indolent systemic mastocytosis is more commonly observed in adults. Aggressive systemic presentation, particularly of the neonate, is exceptionally rare. We present a rare case of congenital aggressive systemic mastocytosis. The patient was a 37‐week‐old male, born by caesarean section owing to hepatosplenomegaly and ascites diagnosed in utero, who exhibited extensive cutaneous and systemic manifestations of mastocytosis at birth. Mutation analysis of c‐KIT identified D816V mutation in exon 17. Although initial bilateral bone marrow aspirates demonstrated no mast‐cell infiltrates or haematological neoplasm, subsequent bone‐marrow biopsies postmortem exhibited multifocal mast‐cell aggregates. Clinical course was complicated by bacteraemia and cardiorespiratory failure, leading to death at 10 weeks.     

Immunostimulatory activity of murine keratinocyte‐derived exosomes

It has long been known that keratinocytes influence cutaneous immunity through secretion of soluble factors. Exosomes, small membrane vesicles of endocytotic origin, have been implicated in intercellular communication processes such as the transfer of tumor cell antigens and the activation of recipient dendritic cells (DC). However, little is known about immunomodulatory functions of keratinocyte‐derived exosomes. To address this question, we analysed exosome secretion of the murine keratinocyte cell line MPEK under steady state as well as inflammatory conditions (+/? IFNγ). These exosomes were readily taken up by bone marrow‐derived DC (BMDC) in vitro resulting in a matured phenotype, as evidenced by increased CD40 expression as well as by the production of large amounts of IL‐6, IL‐10 and IL‐12. When the transfer of antigen‐specific information through exosomes was investigated, it was found that keratinocytes took up antigen (ovalbumin) and transferred it to their exosomes. However, these antigen‐harbouring exosomes failed to induce antigen‐specific T cell responses via BMDC. Together, this novel biological function suggests that keratinocytes are able to direct unspecific immune processes but do not elicit specific immune responses.     

Cold subcutaneous abscesses as the first manifestation of disseminated coccidioidomycosis in an immunocompromised host

Coccidioidomycosis is an endemic fungal infection in the southwestern USA and northern Mexico. It is caused by Coccidioides immitis and C. posadasii. This infection occurs due to the inhalation of airborne arthroconidia, causing a mild pulmonary infection, but most cases are asymptomatic. Disseminated coccidioidomycosis (DC) is a rare entity occurring in less than 1% of all cases, usually in immunocompromised patients, and it carries high risks of morbidity and mortality. The skin is one of the most frequently affected organs and in some cases cutaneous lesions may be the first or only sign of infection. A wide spectrum of clinical lesions may develop, including cold abscess. In immunocompromised hosts, DC represents a diagnostic and therapeutic challenge. Treatment is based on antifungal drugs, such as amphotericin B and azoles, administered for long periods of time and under close follow up to monitor the treatment response and to detect relapse. In the following case report, we present a 35‐year‐old male patient with systemic lupus erythematosus under immunosuppressive therapy who presented with cold subcutaneous abscesses as the first sign of DC.     

Dyskeratosis congenita: a literature review

Dyskeratosis congenita is a rare hereditary disease that occurs predominantly in males and manifests clinically as the classic triad of reticulate hyperpigmentation, nail dystrophy and leukoplakia. It increases the risk of malignancy and other potentially lethal complications such as bone marrow failure, lung and liver diseases. Mutations in 19 genes are associated with dyskeratosis congenita, and a fifth of the pathogenic mutations are found in DKC1, the gene coding for dyskerin. This review aims to address the clinical and genetic aspects of the disease.     

Cytokines and their effects on maturation,differentiation and migration of dendritic cells

In this review the role of cytokines in the maturation and migration of phenotypically and functionally diverse dendritic cell (DC) subpopulations is discussed and their role in the progress of differentiation from bone marrow progenitors to lymphoid DC is described. GM-CSF is the most important cytokine for the development of functional DC and acts in concert with a varying mixture of other cytokines such as IL-4, IL-1 and TNF-α to direct the development of individual DC subpopulations. Received: 18 July 1996     

DC–T cell virological synapses and the skin: novel perspectives in dermatology

Virological synapses (VS) increase cell‐to‐cell viral transmission and facilitate propagation of human immunodeficiency virus type 1 (HIV‐1) and human T‐cell leukaemia virus type 1 (HTLV‐1). VS formation also plays a more general role in viral replication and dissemination. VS have been observed in vitro and ex vivo between uninfected T cells and T cells infected with HIV‐1 or HTLV‐1. In addition, dendritic cells (DC) infected with HIV‐1 also play an important role in viral transmission to uninfected CD4⁺ T cells via VS formation. Recent studies revealed that several DC subsets are also infected with HTLV‐1. These findings may help explain the rapid dissemination of both viruses within secondary lymphoid tissues in vivo. VS also explain, at least in part, why HIV‐1 can propagate in the mucosal sites during sexual transmission. Furthermore, in the case of HTLV‐1, VS can potentially explain some of the features of HTLV‐1‐associated dermatitis as infected T cells in the skin contribute to the pathogenesis of this condition.     

A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis–ichthyosis–deafness (KID) syndrome

Background. Keratitis–ichthyosis–deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. Aim. To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. Methods. Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. Results. The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa‐like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket‐weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended‐spectrum beta‐lactamase‐producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). Conclusions. This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome.     

Aleukemia cutis: Clinicopathological and molecular investigation of two cases

We describe two cases of acute myeloid leukemia (AML) who presented with cutaneous manifestations. Leukemia cutis (LC) is the cutaneous presentation of any type of leukemia and occurs in 10% to 15% of patients with AML, but cutaneous infiltration of AML rarely precedes the involvement of the bone marrow or peripheral blood and is called “aleukemia cutis.” Our first case presented with facial skin thickening, a manifestation which is known as lionization and his initial clinical diagnosis was nonspecific allergic reaction. Our second case presented with urticaria-like lesions with the initial clinical and histomorphologic diagnoses of leukocytoclastic vasculitis. Histopathologic examination of skin biopsy specimens in both patients showed diffuse infiltration of the dermis with a monotonous population of intermediate-sized mononuclear cells by open chromatin and promonocytic features. Bone marrow aspiration leukocyte karyotyping showed normal cytogenetics, and molecular investigation revealed mutations of NPM1 and FLT3 genes. Somatic CEBPA gene mutation was negative in both patients. LC as the first manifestation of leukemia is very rare and could result in delayed diagnosis and affect patient prognosis.     

Animal-type melanoma: a clinical and histopathological study of 22 cases from a single institution

Background Animal‐type melanoma is a rare distinct melanoma subtype, characterized by proliferation of heavily pigmented epithelioid and spindled melanocytes that resembles the heavily pigmented melanomas seen in grey horses. While animal‐type melanoma is generally considered to be more indolent than conventional melanoma, only a limited number of cases have been reported and, as such, the clinical characteristics of animal‐type melanoma are incompletely understood. Objectives To characterize the clinical and histopathological features of animal‐type melanoma, and determine any features that may predict outcome. Patients/Methods Data was extracted from a prospectively collected melanoma database (1994–2008), and a retrospective pathology database (1991–2008) for all patients with a diagnosis of both equivocal (8) and unequivocal (14) malignant animal‐type melanoma. We reviewed the clinical and histopathological features, including the sentinel lymph node biopsy (SLNB) status. Results A total of 22 patients were identified, with a median age of 35 years. The median Breslow depth was 2·22 mm. A SLNB was performed in 17 patients, eight (47%) were positive. Younger age was associated with: (i) animal‐type melanoma with features equivocal for malignancy (median age of 7 vs. 48 years, P = 0·01), and (ii) a negative SLNB (median age 12 vs. 53 years, P = 0·03). Four patients with unequivocal animal‐type melanoma developed recurrent metastatic disease, with one patient death. No patient with an equivocal animal‐type melanoma or negative SLNB developed recurrent disease; however, this did not reach statistical significance (P = 0·13 and P = 0·09, respectively). Conclusions Animal‐type melanoma has a propensity for regional lymphatic metastasis and is rarely capable of disseminated metastatic disease and death. Animal‐type melanoma appears to exhibit a spectrum of biological behaviour, with young patient age associated with more indolent disease.     

Cutaneous manifestations in relation to immunologic parameters in a cohort of primary myelodysplastic syndrome patients

Background Cutaneous lesions in myelodysplastic syndrome (MDS) may be specific or not and may reveal bone marrow transformation. Our purpose was to investigate in a cohort of 84 MDS patients the correlation of cutaneous findings with immunologic parameters and prognostic features of MDS in order to clarify their potential clinical significance. Materials and methods We studied a cohort of 84 newly diagnosed MDS patients in order to assess the cutaneous findings present at the time of diagnosis and during 1 to 3 years of follow‐up. We described the clinical variety of cutaneous findings ascertained by histology. We also looked for any association between the group of MDS patients with skin manifestations and MDS subtype, immunologic and prognostic features highlighting transformation to acute leukaemia. Results Twenty‐one patients presented cutaneous manifestations: 1 patient developed leukaemia cutis, 6 patients photosensitivity not associated with autoimmune disease, 3 prurigo nodularis, 2 Sweet's syndrome, 6 leucocytoclastic vasculitis, 2 ecchymoses and purpura associated with preexisting relapsing polychondritis, 1 patient subcutaneous nodules associated with Wegener's granulomatosis and 1 patient with malar rash and oral ulcers associated with preexisting systemic lupus erythematosus. Adjusted for age and gender, the presence of skin findings constitutes a significant predictor of the high‐risk MDS subgroup (odds ratio, 3.59; 95% confidence interval, 1.18–10.92). Hypergammaglobulinemia was significantly higher in the MDS subgroup with skin manifestations (P = 0.03). Conclusion Most MDS patients with cutaneous manifestations belong to the high‐risk MDS subgroup and present hypergammaglobulinemia. Early biopsy of skin lesions in myelodysplasia is indicated.     

Lichen planus and lichenoid drug-induced eruption: a histological and immunohistochemical study

Introduction Lichenoid drug eruption (LDE) shares similar features with lichen planus (LP), that could reflect the same pathogenesis. In LP, an autoimmune attack is accepted and cytotoxic T‐lymphocytes (CD8+) predominate, especially in late lesions. Apoptosis of keratinocytes may be mediated by CD8+ T and NK cells in two distinct ways: by the release of cytotoxic molecules such as perforin and granzyme B or by the Fas/FasL system. The immunological mechanisms involved in LDE are not yet fully established. Objectives Investigate immunohistological features in LP and LDE to add clues to better understand their pathogenesis. Material and methods Twenty‐two patients fulfilled all clinical, laboratory, histopathological, and follow‐up features of lichen planus (n = 16) and lichenoid drug eruption (n = 6). Classic histological features favoring LP or LDE were evaluated by two observers. HAM56, MAC387, UCHL‐1, OPD4, CD8, Granzyme B, Perforin, and ICAM‐1 antibodies were used to decorate the immune infiltrate. Results were analyzed through Pearson correlation, Student’s t‐test, and linear discriminant analysis. Results A higher number of necrotic keratinocytes as well as plasma cells and eosinophils within inflammatory cells were associated with LDE diagnosis. Only in LDE, a correlation was found between the number of T and CD8+ cells and between the number of granzyme B+ cells and apoptotic keratinocytes. Conclusion Our findings suggest a more important role of CD8+ granzyme B‐containing cells in LDE group, being its synthesis associated with more intense apoptosis. So, LP and LDE may have a somewhat distinct pathogenesis.     

Injection lipolysis for reduction of saddlebag trochanteric bulges ‐ half‐side controlled pilot study

Background: Phosphatidylcholine, a lecithin extracted from soybeans can reduce serum cholesterol to some extent. Intravenous use may prevent fat embolism in polytrauma patients. When injected intralesionally in a formulation containing also deoxycholate and ethanol it is supposed to act as “fat burner” to reduce undesired fat deposits; there is little evidence‐based scientific support for this indictaion. Objective: To evaluate the capability of phosphatidylcholin + deoxycholate + ethanol (PPC/DC/E) to reduce body fat with a half‐side pilot study for the reduction of saddlebag trochanteric bulges. Methods: PPC/DC/E was injected into the right posterior trochanteric areas three times at weeks 0, 3 and 6. Treatment areas and the same regions of the contralateral side as a control were evaluated by sonography. Tape measurements were taken and the thickness of the subcutaneous adipose tissue (SAT) was measured with an optical device (Lipometer^®) at baseline and at week 8 and week 20 (2 and 14 weeks after completign therapy). Results: In this half‐side trial, no significant reduction of subcutaneous fat was achieved after three treatments with PPC/DC/E when compared to the untreated side.Transient inflammatory reactions occurred in all patients. Limitations: Only the commercially available formulation containing the three components was tested. Conclusion: The off‐label use of PPC/DC/E as a “fat burner” did not produce measurable reduction of undesired trochanteric fat deposits.     

先天性角化不良与端粒酶、端粒相关基因的研究进展

先天性角化不良是一种具有遗传异质性的皮肤遗传病,其临床特征为黏膜白斑、甲营养不良、皮肤异色症、骨髓衰竭、肿瘤易感性以及其他系统损害.目前研究表明,其发病与端粒的长度缩短相关.端粒酶组分的基因突变可导致端粒酶活性的降低,使端粒缩短.概述引起端粒酶活性降低、端粒缩短的端粒酶组分的多个相关基因的研究进展,进一步阐明先天性角化不良的发病机制.

Abstract：

Dyskeratosis congenita (DC) is a rare skin disorder with heterogeneity, which is characterized by mucosal leukoplakia, nail dystrophy, abnormal skin pigmentation, bone marrow failure, cancer predisposition and other system damage. Currently, it is revealed that the pathogenesis of DC is related to the shortening of telomere length. Gene mutation of telomerase complex may result in a decline in telomerase activity and shortening of telomere length. This paper presents the advances in researches of telomerase complex genes responsible for reduction in telomerase activity and shortening of telomerase length, which may facilitate further elucidation of DC pathogenesis.     

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.     

Neutrophilic Panniculitis in a child with MYSM1 deficiency

Neutrophilic panniculitis (NP) with myelodysplasia has been described in adults but not in children. We report a case of NP associated with myelodysplasia in a child with MYSM1 deficiency, a newly described syndrome with primary immunodeficiency (PI), bone marrow failure, and developmental aberrations.     

Retrospective analysis of 12 Korean patients with paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP) is a rare, life‐threatening, autoimmune, mucocutaneous blistering disease associated with neoplasia. Both humoral and cellular immunity are involved in the pathogenesis of PNP. Characteristically, PNP has a diverse spectrum of clinical and immunopathological features. We retrospectively analyzed 12 Korean patients with PNP who were diagnosed between 1993 and 2011. We performed analysis of the clinical features, clinical outcomes, underlying neoplasia, histological features and laboratory findings. All of the patients except one had severe mucosal involvement. Two patients had only mucosal lesions but no cutaneous involvement was observed. Erythema multiforme or lichen planus‐like eruptions rather than bullous lesions were more commonly observed skin rashes. The most common histological features were interface dermatitis and apoptotic keratinocytes. There were associated hematological‐related neoplasms in 11 patients, with Castleman's disease (n = 4) as the most frequent. Twelve patients were followed for 5–148 months (mean, 43.0). The prognosis depended on the nature of the underlying neoplasm. Six patients died due to respiratory failure (n = 3), postoperative septicemia (n = 1), lymphoma (n = 1) and sarcomatosis (n = 1). The 2‐year survival rate was 50.0%, and the median survival period after diagnosis was 21.0 months. Immunoblotting was performed in 12 patients and autoantibodies to plakins were detected in 11 patients. The results of this study demonstrated the clinical, histological and immunological diversity of PNP. Widely accepted diagnostic criteria that account for the diversity of PNP are needed.