Impaired intratumoral dendritic cell function and potential predictive value of dendritic cells markers for metastasis in malignant salivary gland tumors

Background: The differentiation between primary and metastatic salivary gland neoplasms (SGNs) helps in determining appropriate management strategies, including the need for additional diagnostic tests, surveillance, or aggressive treatment. The purpose of this study was to identify and quantify the immature and mature dendritic cells (DCs) in metastatic and no metastatic SGNs and determine its association with clinicopathological findings. Material and Methods: Cross-sectional, observational, and descriptive study that includes 33 malignant salivary gland neoplasms [MSGN (6, 18.1% metastatic)], and 22 pleomorphic adenomas (PA), as a control group. Clinical and histopathological characteristics were obtained. Immunohistochemistry for human leukocyte antigen Drelated (HLA-DR), CD1a, CD83, and Ki-67 proteins was done. Positive intra- and peritumoral DCs were counted. Results: Individuals with MSGN had a lower density of intratumoral HLA-DR+ cells than those with PA (p=0.001), Ki-67 immunostaining was significantly higher in MSGN than in PA (6% vs. 1.4%, p<0.001). Metastatic MSGN showed less intratumoral CD1a+ than non-metastatic (3.2 vs. 165.1, p=0.001). No differences in intra- and peritumoral CD83+ cells were found between benign and malignant SGN. Conclusions: These results suggest that the immune-protective function of intratumoral DCs is compromised in MSGNs. DCs markers may represent useful prediction tools for metastases in salivary gland malignancies, with crucial implications in the implementation of appropriate disease management strategies. (AU)

Diagnóstico clínico-patológico de la neoplasia de células dendríticas plasmocitoides blásticas: reporte de 3 casos / Clinicopathological diagnosis of blastic plasmacytoid dendritic cell neoplasm: Report of three cases

La neoplasia de células dendríticas plasmocitoides blásticas (NCDPB) es una enfermedad de baja incidencia y muy mal pronóstico, que con gran frecuencia afecta a la piel, pudiendo ser el primer signo clínico de la enfermedad. Se presentan 3 casos en los que la primera manifestación de la enfermedad fueron lesiones cutáneas. Se describe el cuadro clínico, los hallazgos histopatológicos e inmunohistoquímicos, así como los estudios de extensión y las características moleculares de las 3 neoplasias. Uno de los pacientes permanece en un ensayo clínico con IMGN632, una molécula dirigida contra CD123, mientras que los otros 2 pacientes fallecieron tras distintos regímenes terapéuticos. La NCDPB es una entidad de diagnóstico complejo. Esto, unido a su mal pronóstico, obligan a una comunicación clínico-patológica estrecha que acelere su diagnóstico y ofrezca alternativas terapéuticas precoces con fármacos dirigidos contra dianas moleculares específicas de esta entidad. (AU)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease with a poor prognosis. It frequently affects the skin; indeed, dermal lesions may be the first clinical manifestation. We report three cases of BPDCN where the patients presented with skin lesions and describe the clinical, histopathological and immunohistochemical findings, its molecular characteristics and metastatic work-up. One of the patients remains in a clinical trial with IMGN632, a molecule directed against CD123, while the other two patients died after different therapeutic regimens. BPDCN is a complex diagnostic challenge which, together with its poor prognosis, requires close clinical-pathological cooperation in order to accelerate its diagnosis and offer early therapeutic alternatives with drugs directed against specific molecular targets. (AU)

Diagnóstico clínico-patológico de la neoplasia de células dendríticas plasmocitoides blásticas: reporte de 3 casos / Clinicopathological diagnosis of blastic plasmacytoid dendritic cell neoplasm: Report of three cases

La neoplasia de células dendríticas plasmocitoides blásticas (NCDPB) es una enfermedad de baja incidencia y muy mal pronóstico, que con gran frecuencia afecta a la piel, pudiendo ser el primer signo clínico de la enfermedad. Se presentan 3 casos en los que la primera manifestación de la enfermedad fueron lesiones cutáneas. Se describe el cuadro clínico, los hallazgos histopatológicos e inmunohistoquímicos, así como los estudios de extensión y las características moleculares de las 3 neoplasias. Uno de los pacientes permanece en un ensayo clínico con IMGN632, una molécula dirigida contra CD123, mientras que los otros 2 pacientes fallecieron tras distintos regímenes terapéuticos. La NCDPB es una entidad de diagnóstico complejo. Esto, unido a su mal pronóstico, obligan a una comunicación clínico-patológica estrecha que acelere su diagnóstico y ofrezca alternativas terapéuticas precoces con fármacos dirigidos contra dianas moleculares específicas de esta entidad. (AU)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease with a poor prognosis. It frequently affects the skin; indeed, dermal lesions may be the first clinical manifestation. We report three cases of BPDCN where the patients presented with skin lesions and describe the clinical, histopathological and immunohistochemical findings, its molecular characteristics and metastatic work-up. One of the patients remains in a clinical trial with IMGN632, a molecule directed against CD123, while the other two patients died after different therapeutic regimens. BPDCN is a complex diagnostic challenge which, together with its poor prognosis, requires close clinical-pathological cooperation in order to accelerate its diagnosis and offer early therapeutic alternatives with drugs directed against specific molecular targets. (AU)

El uso de un anticuerpo biespecífico neutralizante frente a SARS-CoV-2 y dirigido hacia DNGR-1 potencia la respuesta de las células T citotóxicas, mediante su acción a través de células dendríticas c1, protegiendo eficazmente frente a la infección / [The use of a bispecific neutralizing antibody against SARS-CoV-2 and directed towards DNGR-1 enhances the response of cytotoxic T cells, through its action through c1 dendritic cells, effectively protecting against infection]

En este trabajo, recientemente publicado en la prestigiosa revista Advanced Science (Adv Sci; Weinheim, Baden-Württemberg, Germany), se ha diseñado y estudiado a nivel preclínico un anticuerpo biespecífico neutralizante (nAbs) frente al virus SARS-CoV-2 y dirigido específicamente a un receptor de células dendríticas convencionales de tipo 1 (cDC1s) para estimular específicamente la respuesta de linfocitos T citotóxicos. El trabajo surge de la colaboración de un consorcio muy amplio de grupos de investigación expertos en distintas áreas de la inmunología, biología celular, virología, biología estructural, química de proteínas y partículas, que han logrado generar un anticuerpo trimérico biespecífico, TNTDNGR-1. TNT se corresponde con las siglas en inglés para anticuerpo neutralizante en tándem trimérico, mientras que DNGR-1 es la molécula inmuno-reguladora “dendritic cell natural killer group receptor-1”, también conocida como CLEC9A. TNTDNGR-1 presenta una gran avidez frente a la región RBD (“receptor binding domain”) del virus SARS-CoV-2 y también frente al receptor DNGR-1, una lectina tipo C expresada por cDC1s. Se trata, además de una colaboración público-privada, con la participación de una compañía de biotecnología española, otorgando valor añadido al trabajo de investigación, por su potencial traslación a la clínica a corto o medio plazo. Mediante el uso de técnicas de crio-microscopía electrónica se ha comprobado que la estructura TNT , backbone de TNTDNGR-1, permite la unión simultánea a sus seis epítopos en la proteína S (del inglés spike) del SARS-CoV-2, dos por cada RBD, dotándola de una interacción neutralizante de alta afinidad frente al virus. ... (AU)

Análisis inmunohistológico de las células dendríticas dérmicas positivas para CD34 y de la densidad de microvasos en el liquen escleroso genital y extragenital / Immunohistological Analysis of CD34-Positive Dermal Dendritic Cells and Microvessel Density in the Genital and Extragenital Lichen Sclerosus

Introducción El liquen escleroso (LiE) es una enfermedad crónica escleroatrófica que afectará generalmente el área anogenital y ocasionalmente a localizaciones extragenitales. Las células dendríticas dérmicas CD34 positivas (DDC) contribuyen al mantenimiento de la microarquitectura dérmica y a la modulación de la respuesta inmunitaria. El p53 es un gen supresor de tumores importante para la regulación del ciclo celular y de la apoptosis. De manera similar a lo que ocurre en la morfea (una condición escleroatrófica estrechamente relacionada con el LiE), la esclerosis dérmica, las alteraciones de las DDC y de la microvasculatura dérmica pueden ser mecanismos patogénicos subyacentes importantes en el LiE. Objetivos Examinar el perfil de las DDC positivas para el CD34, la densidad de microvasos (MVD) y la proteína p53 en el LiE. Materiales y métodos Se evaluaron los perfiles inmunohistológicos de las DDC, de la MVD y del p53 en 19 casos de LiE y en la piel normal de pacientes emparejados por edad y sexo (10 muestras), utilizando los anticuerpos contra el CD34 y el p53. Resultados Hubo una marcada disminución de los recuentos (1,7±0,5/mm2) o pérdida completa de DDC CD34+en el LiE en comparación con su elevada expresión en la piel normal (23,4±2,1/mm2, p =0,000). La MVD estaba notablemente aumentada en las lesiones de LiE (20±0,47) en comparación con la de la piel normal (5,50±0,20, p =0,000). Se observó una tinción nuclear discontinua, de células aisladas, débilmente positiva para el p53, localizada en los queratinocitos de las capas basales epidérmicas de la piel sana y de la piel afectada por el LiE. Conclusiones Hasta donde tenemos conocimiento, este es el primer estudio que analiza los perfiles de las DDC, de la MVD y del p53 de manera simultánea en el LiE. Los hallazgos sugirieron que las alteraciones de las DDC y de la MVD tienen papeles en la patogénesis del LiE (AU)

Background Lichen sclerosus (LiS) is a chronic scleroatrophic condition that usually affects the anogenital area and occasionally the extragenital sites. CD34-positive dermal dendritic cells (DDCs) contribute to the maintenance of the dermal microarchitecture and modulation of the immune response. p53 is a tumor suppressor gene important for the regulation of the cell cycle and apoptosis. Similar to morphea (a LiS-closely related scleroatrophic condition), dermal sclerosis, alterations of DDCs, and dermal microvasculature may be important underlying pathogenetic mechanisms in LiS. Objectives To examine the profile of CD34-positive DDCs, microvessel density (MVD), and p53 protein in LiS. Materials and methods The immunohistological profiles of DDCs, MVD, and p53 were examined in 19 cases of LiS and their age- and sex-matched normal skin (10 specimens), using antibodies against CD34 and p53. Results There was a markedly decreased counts (1.7±0.5/mm2) or complete loss of CD34-positive DDCs in LiS against their abundance in the normal skin (23.4±2.1/mm2, p=0.000). MVD was markedly increased in LiS lesions (20±0.47) as compared to normal skin (5.50±0.20, p=0.000). Discontinuous single-cell p53 weakly positive nuclear staining was seen in the epidermal basal cell keratinocytes in normal skin and LiS lesions. Conclusions To the best of this author's knowledge, this is the first study analyzing DDCs, MVD, and p53 profiles together in LiS. The findings suggest that alterations of DDCs and MVD have roles in the pathogenesis of LiS (AU)

Associations of PD-L1, PD-L2, and HLA class I expression with responses to immunotherapy in patients with advanced sarcoma: post hoc analysis of a phase 1/2 trial

Background Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma. Methods This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated. Results Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (−). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (−) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (−) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (−). No associations of HLA class I expression with the immune response or oncological outcomes were observed. Conclusions This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy (AU)

Long-chain non-coding RNA n337374 relieves symptoms of respiratory syncytial virus-induced asthma by inhibiting dendritic cell maturation via the CD86 and the ERK pathway

Background: In this study, we investigated the relationship between long-chain non-coding RNAs (lncRNAs) and respiratory syncytial virus (RSV)-exacerbated asthma. Methods: Transcriptome microarray was used to detect differentially expressed lncRNAs in dendritic cells (DCs) co-cultured with RSV-infected human airway epithelial cells and DCs infected with RSV. The identified downregulation of lncRNA n337374 was validated using fluorescence RT-qPCR. LncRNA n337374-overexpressing DCs and RSV-exacerbated asthmatic mouse models were established. Airway hyper-reactivity and bronchoalveolar lavage fluid (BALF) were examined, and pathological changes in lung tissues were observed in mice. Surface molecules in DCs were detected by flow cytometry and RT-qPCR and the expression of CD86 and mitogen-activated protein kinases was determined by western blot. Results: In an RSV-exacerbated asthmatic mouse model, the airway wall was thickened, luminal stenosis was observed, a large number of inflammatory cells were infiltrated in the lung tissue, lung function was impaired, and counts of inflammatory cells in the BALF were increased. The overexpression of lncRNA n337374 ameliorated these pathological changes and improved impaired lung function and inflammation in an asthmatic mouse model. In DCs co-cultured with RSV-infected human airway epithelial cells, CD86 expression was promoted and ERK was markedly phosphorylated. When lncRNA n337374-overexpressing DCs were used in the co-cultures, the expression of CD86 and phosphorylated ERK was decreased. Conclusion: The results suggest that lncRNA n337374 overexpression may suppress DC maturation by downregulating the CD86 and ERK pathway, subsequently relieving the symptoms of RSV-induced asthma. LncRNA n337374 may be a promising target in the treatment of RSV infection-induced asthma (AU)

El aprendizaje motor induce cambios plásticos en las espinas dendríticas de las células de Purkinje del cerebelo de ratas / No disponible

INTRODUCCIÓN: El lóbulo paramediano del cerebelo está involucrado en el desempeño correcto de las habilidades motoras a través de la práctica. Las espinas dendríticas son estructuras dinámicas que regulan la estimulación sináptica excitadora. En este trabajo se estudiaron los posibles cambios plásticos en espinas de células de Purkinje del lóbulo paramediano cerebelar de ratas, durante el aprendizaje motor. MÉTODOS: Se entrenaron a ratas macho adultas durante un período de seis días, en un paradigma de aprendizaje motor acrobático y se cuantificó tanto la densidad como los tipos de espinas dendríticas en cada uno de los seis días de estudio, mediante una modificación al método de Golgi. RESULTADOS: La curva de aprendizaje reflejó una disminución consistente de los errores cometidos en el transcurso de los días de entrenamiento. Así mismo, se observaron más espinas dendríticas en los días 2 y 6 y, en particular, más espinas delgadas en los días 1, 3 y 6, menos espinas en hongo el día 3, menos espinas gordas el día 1 y más espinas anchas los días 4 y 6. CONCLUSIÓN: El período inicial de aprendizaje motor podría estar asociado con el procesamiento rápido de la información sináptica subyacente y con un aparente «silenciamiento» de los procesos de consolidación mnémica, en una base de regulación de la excitabilidad neuronal

INTRODUCTION: The paramedian lobule of the cerebellum is involved in learning to correctly perform motor skills through practice. Dendritic spines are dynamic structures that regulate excitatory synaptic stimulation. We studied plastic changes occurring in the dendritic spines of Purkinje cells from the paramedian lobule of rats during motor learning. METHODS: Adult male rats were trained over a 6-day period using an acrobatic motor learning paradigm; the density and type of dendritic spines were determined every day during the study period using a modified version of the Golgi method. RESULTS: The learning curve reflected a considerable decrease in the number of errors made by rats as the training period progressed. We observed more dendritic spines on days 2 and 6, particularly more thin spines on days 1, 3, and 6, fewer mushroom spines on day 3, fewer stubby spines on day 1, and more thick spines on days 4 and 6. CONCLUSION: The initial stage of motor learning may be associated with fast processing of the underlying synaptic information combined with an apparent "silencing" of memory consolidation processes, based on the regulation of the neuronal excitability

Neoplasia de células dendríticas blásticas plasmacitoides. Estudio de tres casos / Blastic plasmacytoid dendritic cell neoplasm. A study of three cases

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Different methods of cell quantification can lead to different results: a comparison of digital methods using a pilot study of dendritic cells in HIV-positive patients

BACKGROUND: Although new digital pathology tools have improved the positive cell quantification, there is a heterogeneity of the quantification methods in the literature. The aim of this study was to evaluate and propose a novel dendritic cells quantification method in squamous cell carcinoma comparing it with a conventional quantification method. MATERIAL AND METHODS: Twenty-six squamous cell carcinomas HIV-positive cases affecting the oropharynx, lips and oral cavity were selected. Immunohistochemistry for CD1a, CD83, and CD207 was performed. The immunohistochemical stains were evaluated by automated examination using a positive pixel count algorithm. A conventional quantification method (unspecific area method; UA) and a novel method (specific area method; SA) were performed obtaining the corresponding density of positive dendritic cells for the intratumoral and peritumoral regions. The Mann-Whitney U test was used to verify the influence of the quantification methods on the positive cell counting according to the evaluated regions. Data were subjected to the ANOVA and Student's t-test to verify the influence of the tumour location, stage, histological grade, and amount of inflammation on the dendritic cells density counting. RESULTS: The cell quantification method affected the dendritic cells counting independently of the evaluated region (P-value < 0.05). Significant differences between methods were also observed according to the tumour features evaluations. CONCLUSIONS: The positive cell quantification method influences the dendritic cells density results. Unlike the conventional method (UA method), the novel SA method avoids non-target areas included in the hotspots improving the reliability and reproducibility of the density cell quantification

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CD1a+ and CD207+ cells are reduced in oral submucous fibrosis and oral squamous cell carcinoma

BACKGROUND: The objective of this study investigated the distribution of immature dendritic cells (DCs), Langer-hans cells and plasmacytoid DCs in oral submucous fibrosis (OSMF), OSMF associated with oral squamous cell carcinoma (OSMF-OSCC), oral leukoplakia (OL), and oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: Fourteen cases of OSMF, 9 of OSMF-OSCC, 8 of OL ̧ 45 of OSCC and 8 of normal epi-thelium were retrospectively retrieved and their diagnoses confirmed. Immunoreactions against CD1a, CD207 e CD303 were performed and the number of positive cells quantified. RESULTS: A significant decrease of CD1a+ was found in OSMF (p≤0.05), OSMF-OSCC (p ≤ 0.01), and OSCC (p ≤ 0.001) when compared to normal epithelium. For CD207+ the significance decrease was observed in OSMF-OSCC (p ≤ 0.05), and OSCC (p ≤ 0.01) when compared with normal epithelium, and in OSMF when compared with OL (p ≤ 0.05). There was no significant difference for CD303, but increased in CD303+ was observed in OSCC when compared with normal epithelium. CONCLUSION: The decrease in the number of CD1a+ and CD207+ cells may be associate to the development of oral OSCC, and in OPMDs they might be indicators of malignant transformation

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Histiocitosis de células de Langerhans multisistémica asociada con papulosis linfomatoide: ¿solo un hallazgo accidental? Presentación de un caso y revisión de la literatura / Multisystem histiocytosis of Langerhans cells associated with Lymphomatoid papulosis: An accidental finding? Case report and literature review

La histiocitosis de células de Langerhans (HCL) es una enfermedad caracterizada por la proliferación de células dendríticas CD1a+con compromiso orgánico único o difuso. La identificación de mutaciones génicas recurrentes ha confirmado la hipótesis de HCL como una verdadera neoplasia. La papulosis linfomatoide (PL) pertenece al espectro de los linfomas cutáneos primarios CD30+. La HCL ha sido descrita en asociación con otros trastornos linfoproliferativos, pero hasta la fecha, las lesiones constituidas por células de Langerhans (CL) han sido consideradas de carácter reactivo, relacionada con citocinas producidas por la interacción linfoma microambiente. Algunos autores designan estas lesiones «Langerhans cells like lesions». Presentamos el caso de una mujer de 28 años con HCL multisistémica y presencia simultánea de lesiones de PL con hiperplasia reactiva de CL

Langerhans cell histiocytosis (LCH) is a disease characterized by proliferation of CD1a+dendritic cells with local or diffuse organ compromise. The identification of recurrent gene mutations has confirmed the hypothesis of LCH as a true neoplasm. Lymphomatoid papulosis (LyP) belongs to the spectrum of CD30+primary cutaneous lymphomas. LCH has been described in association with other lymphoproliferative disorders. However, lesions constituted by Langerhans cells (LC) have been commonly considered reactive, related to cytokines produced by the lymphoma-microenvironment interaction. Some authors designate these lesions as "Langerhans cells-like lesions". We present the case of a 28-years-old woman with multisystem LCH and simultaneous PyL lesions with reactive LC hyperplasia

Osteoprotegerin mediate RANK/RANKL signaling inhibition eases asthma inflammatory reaction by affecting the survival and function of dendritic cells

Introduction: Asthma is a chronic inflammatory, heterogeneous airway disease affecting millions of people around the world. Dendritic cells (DCs) are considered the most important antigen-presenting cell in asthma airway inflammatory reaction. But whether osteoprotegerin (OPG) mediate RANK/RANKL signaling inhibition influences asthma development by affecting the survival and function of DCs remains unclear. In this study, we assessed the effects of OPG on DCs and asthma. Material and methods: BALB/c mice immunized with ovalbumin (OVA) were challenged thrice with an aerosol of OVA every second day for eight days. Dexamethasone (1.0mg/kg) or OPG (50 mig/kg) was administered intraperitoneally to OVA-immunized BALB/c mice on day 24 once a day for nine days. Mice were analyzed for effects of OPG on asthma, inflammatory cell infiltration and cytokine levels in lung tissue. The expression of RANK and β-actin was detected by Western Blot. DCs were isolated from mouse bone morrow. Cell survival was assessed by cell counting. The content of IL-12 was detected by ELISA. Results: Results showed that OVA increased the number of inflammatory factors in BALF, elevated lung inflammation scores in mice. OPG reversed the alterations induced by OVA in the asthmatic mice. OPG inhibited the survival and function of DC via inhibition of RANK/RANKL signaling. Conclusions: This research proved inhibition of RANK/RANKL signaling by OPG could ease the inflammatory reaction in asthma, providing new evidence for the application of OPG on asthma

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Tumoración de rápido crecimiento en la zona anterior del tórax / Rapidly Growing Lesion on the Chest

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Neoplasias de células histiocitarias y dendríticas: revisión de la literatura / Histiocytic and dendritic cell neoplasms: Review of the literature

Las neoplasias de células histiocitarias y dendríticas (NHD) son poco frecuentes y su biología, pronóstico, tratamiento y terminología están aún en estudio. Son lesiones constituidas por células derivadas de células dendríticas o macrófagos y presentan un amplio rango de características clínicas, morfológicas y pronósticas. Su diagnóstico es complejo y requiere la integración de datos clínicos y morfológicos y la realización de un amplio panel inmunohistoquímico. Tras la detección de mutaciones de BRAF en las histiocitosis de células de Langerhans, se están realizando estudios para determinar el significado de otras alteraciones moleculares en las NHD. Realizamos una revisión de la bibliografía publicada sobre las NHD en los últimos 10 años, con especial énfasis en la patología molecular de estas lesiones

Histiocytic and dendritic cell neoplasms (HDN) are rare and their biology, prognosis, treatment and terminology are still under discussion. They are composed of macrophage and dendritic-derived cells and show a wide range of clinical, morphological and prognostic features. Clinicopathological correlation and a broad immunohistochemical panel are required to establish a correct diagnosis. After the detection of BRAF mutations in Langerhans cell histiocytosis, the potential role of other molecular alterations is being studied. We have reviewed the literature published in the last 10 years to provide an overview of NHD, with particular emphasis their molecular features

¿Cómo pueden las células del sistema inmunitario contribuir a los infartos e ictus? / No disponible

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