Interpretation of histiocytic/dendritic cell neoplasms and stromal-derived neoplasms of lymphoid tissues in the 5th edition of WHO classification of haematolymphoid tumors / 中华病理学杂志

The 5th edition of the World Health Organization classification of hematolymphoid tumors (WHO Blue Book) is soon to be published. Significant revisions have been made in the chapters on histiocytic/dendritic cell neoplasms and stroma-derived neoplasms of lymphoid tissues, leading to the reclassification and renaming of specific diseases. This article provides a concise interpretation and summary of these updates, highlighting the differences from the fourth edition. Pertinent changes from clinical pathological diagnosis to treatment and prognosis are explored, with an emphasis on recent advancements in molecular genetics. Newly introduced disease classifications are discussed, and the section on follicular dendritic cell sarcoma contributed by the author is detailed to assist readers in quickly understanding and assimilating the new classification standards.

Diacerein mitigates renal ischemia/reperfusion injury via inhibition of renal inflammation, dendritic cells maturation and apoptosis: the role of TLR4/NF-kB/NLRP3/IL-1beta signaling pathway / La diacereína mitiga la lesión por isquemia/reperfusión renal a través de la inhibición de la inflamación renal, la maduración de las células dendríticas y la apoptosis: el papel de la vía de señalización TLR4/NF-kB/NLRP3/IL-1beta

SUMMARY: One of the reasons for acute kidney damage is renal ischemia. Nevertheless, there are limited protective and therapeutic approaches for this problem. Diacerein is an anti-inflammatory drug characterized by numerous biological activities. We aimed to determine the ameliorative impact of diacerein on renal ischemia/reperfusion injury (I/R) condition, exploring the underlying mechanisms. Twenty-four male rats were allotted into four groups (n= 6): sham group; Diacerein (DIA) group; I/R group, in which a non-crushing clamp occluded the left renal pedicle for 45 min, and the right kidney was nephrectomized for 5 min before the reperfusion process; I/R + diacerein group, injected intraperitoneally with 50 mg diacerein/kg i.m 30 minutes prior to I/R operation. Ischemia/ reperfusion was found to affect renal function and induce histopathological alterations. The flow cytometry analysis demonstrated an elevated expression of innate and mature dendritic cells in I/R renal tissues. Moreover, upregulation in the expression of the inflammatory genes (TLR4, Myd88, and NLRP3), and overexpression of the pro-inflammatory cytokines (IL-1β), apoptotic (caspase-3) and pyroptotic (caspase-1) markers were observed in I/R-experienced animals. The aforementioned deteriorations were mitigated by pre-I/R diacerein treatment. Diacerein alleviated I/R-induced inflammation and apoptosis. Thus, it could be a promising protective agent against I/R.

La isquemia renal es una de los motivos del daño renal agudo. Sin embargo, los enfoques protectores y terapéuticos para este problema son limitados. La diacereína es un fármaco antiinflamatorio caracterizado por numerosas actividades biológicas. Nuestro objetivo fue determinar el impacto de mejora de la diacereína en la condición de lesión por isquemia/ reperfusión renal (I/R), explorando los mecanismos subyacentes. Veinticuatro ratas macho se distribuyeron en cuatro grupos (n= 6): grupo simulado; grupo de diacereína (DIA); grupo I/R, en el que una pinza no aplastante ocluyó el pedículo renal izquierdo durante 45 min, y el riñón derecho fue nefrectomizado durante 5 min antes del proceso de reperfusión; Grupo I/R + diacereína, inyectado por vía intraperitoneal con 50 mg de diacereína/kg i.m. 30 min antes de la operación I/R. Se encontró que la isquemia/ reperfusión afecta la función renal e induce alteraciones histopatológicas. El análisis de citometría de flujo demostró una expresión elevada de células dendríticas innatas y maduras en tejidos renales I/R. Además, se observó una regulación positiva en la expresión de los genes inflamatorios (TLR4, Myd88 y NLRP3) y una sobreexpresión de las citoquinas proinflamatorias (IL-1β), marcadores apoptóticos (caspasa-3) y piroptóticos (caspasa-1) en animales con experiencia en I/R. Los deterioros antes mencionados fueron mitigados por el tratamiento previo a la diacereína I/R. La diacereína alivió la inflamación y la apoptosis inducidas por I/R. Por lo tanto, podría ser un agente protector prometedor contra I/R.

Effect of Plasmacytoid Dendritic Cell Dose in Grafts on CMV Infection after Allogeneic Hematopoietic Stem Cell Transplantation / 中国实验血液学杂志

OBJECTIVE@#To investigate the correlation between plasmacytoid dendritic cell (pDC) dose in grafts and the occurrence of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT).@*METHODS@#The clinical data of 80 children who received allo-HSCT in Children's Hospital of Soochow University from August 20, 2020 to June 11, 2021 were retrospectively analyzed. Proportions of DC subsets and T-cell subsets in grafts were detected by flow cytometry in order to calculate infused cell dose of each cell. Weekly monitoring of CMV-DNA copies in peripheral blood for each child were performed after transplantation. The last follow-up date was December 31, 2021.@*RESULTS@#All the children gained hematopoietic reconstitution. CMV infection was observed in 51 children (63.8%±5.4%) within the first 100 days after transplantation, including 2 cases developing CMV disease. Univariate analysis indicated that infused doses of DC and pDC were significantly associated with CMV infection within 100 days after allo-HSCT (P <0.05). Multivariate analysis indicated that a high dose infusion of pDC was an independent protective factor for CMV infection within 100 days after allo-HSCT (P <0.05). By the end of follow-up, 7 children died of transplantation-related complications, including 2 deaths from CMV disease, 2 deaths from extensive chronic graft-versus-host disease, and 3 deaths from capillary leak syndrome. The overall survival rate was 91.2%.@*CONCLUSION@#The pDC in grafts may be associated with early infection of CMV after allo-HSCT, while a high infused pDC dose may serve as a protective factor for CMV infection after transplantation.

Control of lupus activity during pregnancy via the engagement of IgG sialylation: novel crosstalk between IgG sialylation and pDC functions / 医学前沿

Immunoglobulin (IgG) glycosylation affects the effector functions of IgG in a myriad of biological processes and has been closely associated with numerous autoimmune diseases, including systemic lupus erythematosus (SLE), thus underlining the pathogenic role of glycosylation aberration in autoimmunity. This study aims to explore the relationship between IgG sialylation patterns and lupus pregnancy. Relative to that in serum samples from the control cohort, IgG sialylation level was aberrantly downregulated in serum samples from the SLE cohort at four stages (from preconception to the third trimester of pregnancy) and was significantly associated with lupus activity and fetal loss during lupus pregnancy. The type I interferon signature of pregnant patients with SLE was negatively correlated with the level of IgG sialylation. The lack of sialylation dampened the ability of IgG to suppress the functions of plasmacytoid dendritic cells (pDCs). RNA-seq analysis further revealed that the expression of genes associated with the spleen tyrosine kinase (SYK) signaling pathway significantly differed between IgG- and deSia-IgG-treated pDCs. This finding was confirmed by the attenuation of the ability to phosphorylate SYK and BLNK in deSia-IgG. Finally, the coculture of pDCs isolated from pregnant patients with SLE with IgG/deSia-IgG demonstrated the sialylation-dependent anti-inflammatory function of IgG. Our findings suggested that IgG influences lupus activity through regulating pDCs function via the modulation of the SYK pathway in a sialic acid-dependent manner.

Clinical Analysis of Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm / 中国实验血液学杂志

OBJECTIVE@#To explore the clinical characteristics, treatment, and prognosis of patients with blastic plasmacytoid dendritic cell neoplasm(BPDCN).@*METHODS@#Clinical data of 5 patients diagnosed with BPDCN in Wuhan First Hospital and Wuhan Tongji Hospital from June 2016 to November 2021 were retrospectively analyzed.@*RESULTS@#Among the 5 patients, 3 were male and 2 were female, with a median age of 28(10-52) years old. Four patients showed obvious skin damage at the initial diagnosis; the other one showed clinical manifestations of acute leukemia rather than obvious skin damage at the initial diagnosis, but infiltrated skin when the disease relapsed after treatment. Other infiltration sites of lesions included bone marrow (2/5), peripheral blood (2/5), lymph nodes (3/5), liver and spleen (2/5). All patients had no clinical manifestation of central nervous system infiltration. Tumor cell specific immune markers CD4, CD56, CD123 were all positive, and the median Ki-67 index was 70%. TET2, ASXL1 and NRAS gene mutations were found respectively in 3 patients by next-generation sequencing technique (NGS). ALL-like, AML-like and invasive NK/T cell lymphoma-like first-line induction chemotherapy regimens were used for the patients. One patient died of severe complications during the early stage of chemotherapy, 3 patients were evaluated as CR, and 1 patient was evaluated as PR. 2 patients were recurred and progressed after induction of chemotherapy, and one of them was evaluated as CR after re-treatment. One patient received autologous hematopoietic stem cell transplantation (auto-HSCT) and got long-term survival (OS 87 months). 3 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), of which one died of transplantation related complications, and 2 cases survived. The median follow-up time of 4 patients with evaluable efficacy was 28.5(9-84) months, the median OS time was 31.5(10-87) months.@*CONCLUSION@#BPDCN is a highly heterogeneous malignant tumor with a poor prognosis. HSCT, especially allo-HSCT can significantly improve the prognosis of BPDCN patients.

Tumor cell lysate with low content of HMGB1 enhances immune response of dendritic cells against lung cancer in mice / 南方医科大学学报

OBJECTIVE@#To assess the effect of tumor cell lysate (TCL) with low high-mobility group B1 (HMGB1) content for enhancing immune responses of dendritic cells (DCs) against lung cancer.@*METHODS@#TCLs with low HMGB1 content (LH-TCL) and normal HMGB1 content (NH-TCL) were prepared using Lewis lung cancer (LLC) cells in which HMGB1 was inhibited with 30 nmol/L glycyrrhizic acid (GA) and using LLC cells without GA treatment, respectively. Cultured mouse DCs were exposed to different doses of NH-TCL and LH-TCL, using PBS as the control. Flow cytometry was used to detect the expressions of CD11b, CD11c and CD86 and apoptosis of the stimulated DCs, and IL-12 levels in the cell cultures were detected by ELISA. Mouse spleen cells were co-cultured with the stimulated DCs, and the activation of the spleen cells was assessed by detecting CD69 expression using flow cytometry; TNF-β production in the spleen cells was detected with ELISA. The spleen cells were then co-cultured with LLC cells at the effector: target ratios of 5:1, 10:1 and 20:1 to observe the tumor cell killing. In the animal experiment, C57/BL6 mouse models bearing subcutaneous LLC xenograft received multiple injections with the stimulated DCs, and the tumor growth was observed.@*RESULTS@#The content of HMGB1 in the TCL prepared using GA-treated LLC cells was significantly reduced (P < 0.01). Compared with NH-TCL, LH-TCL showed a stronger ability to reduce apoptosis (P < 0.001) and promote activation and IL- 12 production in the DCs. Compared with those with NH-TCL stimulation, the DCs stimulated with LH-TCL more effectively induced activation of splenic lymphocytes and enhanced their anti-tumor immunity (P < 0.05). In the cell co-cultures, the spleen lymphocytes activated by LH-TCL-stimulated DCs showed significantly enhanced LLC cell killing activity (P < 0.01). In the tumor-bearing mice, injections of LH-TCL-stimulated DCs effectively activated host anti-tumor immunity and inhibited the growth of the tumor xenografts (P < 0.05).@*CONCLUSION@#Stimulation of the DCs with LH-TCL enhances the anti-tumor immune activity of the DCs and improve the efficacy of DCbased immunotherapy for LLC in mice.

Blastic plasmacytoid dendritic cell neoplasm: A clinico-pathological retrospective analysis of thirteen cases / 北京大学学报(医学版)

OBJECTIVE@#To investigate the clinicopathological features of blastic plasmacytoid dendritic cell neoplasm (BPDCN).@*METHODS@#A total of 13 cases of BPDCN diagnosed in Peking University First Hospital from January 2013 to March 2022 were collected. The clinical features, histopathological characteristics, immunophenotypes and prognosis of the patients were analyzed retrospectively, and the related literatures was reviewed as well.@*RESULTS@#Among the 13 patients, 11 were male and 2 were female, with a median age of 62 years (ranging from 5 to 78 years). Among them, single organ involvement occurred in 5 cases, all of which presented with skin lesions. Two or more organs were involved in other 8 cases (single organ with bone marrow involved in 3 cases; skin, bone marrow and lymph node involved simultaneously in 3 cases; skin, bone marrow, lymph node and spleen involved simultaneously in 2 cases). Histopathologically, it was characterized by the proliferation of medium to large atypical blastic cells, which infiltrated the whole thickness of dermis. When involved, the bone marrow lesions mainly appeared in a diffuse pattern, while the lymph node structure was usually destroyed, and the red pulp of the affected spleen was diffusely invaded. Immunohistochemical staining showed that all the 13 cases were positive for CD4, CD56, and CD123 (13/13) in varying degrees. All the 9 cases expressed TCL1 (9/9). Variable expression of CD68 (KP1) (8/13), TdT (7/12), CD117 (2/6), and high Ki-67 proliferation index (40%~80%) were showed. The neoplastic cells lacked expressions of CD20, CD3, MPO, CD34, or CD30; EBER in situ hybridization were negative (0/9). After definite diagnosis, 6 cases received chemotherapy, among which 1 received adjuvant radiotherapy, and 2 received subsequent bone marrow transplantation. Another 2 cases only received maintenance treatment. The median follow-up time was 14 months (ranging from 6 to 36 months), 5 patients died of the disease (6 to 18 months), 3 patients survived (7 to 36 months up to now), and the remaining 5 patients lost follow-up.@*CONCLUSION@#BPDCN is a rare type of malignant lymphohematopoietic tumor with aggressive behavior and poor prognosis. The diagnosis should be made combining clinical features, histopathology, and immunohistochemical phenotype. Attention should be paid to differentiating BPDCN from other neoplasms with blastoid morphology or CD4+CD56+ tumors.

Chemotherapy Combined with Venetoclax Followed by Allo-Hematopoietic Stem Cell Transplantation for Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy and safety of chemotherapy combined with venetoclax followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).@*METHODS@#The clinical data of 3 patients with BPDCN undergoing allo-HSCT in Department of Hematology, Wuhan First Hospital from July 2017 to November 2021 were collected and retrospectively analyzed.@*RESULTS@#Among the 3 patients, there were 1 male and 2 females, aged 27-52 years old. Skin lesions were observed during initial diagnosis, and it could also be characterized by acute leukemia. Characteristic molecular markers of tumor cells, such as CD4, CD56, CD123, and CD303 were positive. In addition, the expression detection of Bcl-2 in 3 patients were positive. Chemotherapy combined with venetoclax in the initial induction of chemotherapy (1 case) or disease recurrence and progress (2 cases) was performed. There were 2 cases evaluated as complete remission (CR) and 1 case as partial remission (PR) before allo-HSCT. The patients all received a nonmyeloablative conditioning without total body irradiation (TBI). The prevention programme of graft-versus-host disease (GVHD) was antithymocyte globulin + mycophenolate mofetil + cyclosporin A/FK506 ± methotrexate. The number of mononuclear cell (MNC) count was (16.73-18.35)×108/kg, and CD34+ cell count was (3.57-4.65)×106/kg. The 3 patients were evaluated as CR after allo-HSCT (+21 to +28 d), the donor-recipient chimerism rate was 100%, and Ⅲ-Ⅳ GVHD was not observed. One patient died at +50 d after transplantation, two patients were followed up for 28 months and 15 months, respectively, and achieved disease-free survival (DFS).@*CONCLUSIONS@#BPDCN is a highly aggressive malignant tumor with poor prognosis. Chemotherapy combined with venetoclax followed by allo-HSCT may lead to long-term DFS or even cure. Post-transplant maintenance is still unclear.

Role of dendritic cells in MYD88-mediated immune recognition and osteoinduction initiated by the implantation of biomaterials / 国际口腔科学杂志·英文版

Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects. Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials. Previous studies have mainly focused on innate immune cells such as macrophages. In our previous work, we found that T lymphocytes, as adaptive immune cells, are also essential in the osteoinduction procedure. As the most important antigen-presenting cell, whether dendritic cells (DCs) can recognize non-antigen biomaterials and participate in osteoinduction was still unclear. In this study, we found that surgical trauma associated with materials implantation induces necrocytosis, and this causes the release of high mobility group protein-1 (HMGB1), which is adsorbed on the surface of bone substitute materials. Subsequently, HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells, and the inflammatory response was activated. Finally, activated DCs release regeneration-related chemokines, recruit mesenchymal stem cells, and initiate the osteoinduction process. This study sheds light on the immune-regeneration process after bone substitute materials implantation, points out a potential direction for the development of bone substitute materials, and provides guidance for the development of clinical surgical methods.

Tumor antigen-loaded dendritic cells combined with cytokine-induced killer (CIK) enhance the killing activity of human esophageal cancer cells by promoting ASK1 activation / 细胞与分子免疫学杂志

Objective To clarify the effect and mechanism of tumor antigen-loaded dendritic cells (Ag-DCs) combined with cytokine-induced killers (CIKs) on the killing of esophageal cancer tumor cells. Methods Peripheral blood DCs and CIKs were induced and cultured, and the DCs were loaded with tumor antigen to obtain Ag-DCs, and Ag-DCs were co-cultured with CIKs. The experiment was divided into CIK group, DC combined with CIK group, Ag-DC combined with CIK group. Flow cytometry was used to detect the phenotype of cells. MTT assay was employed to determine the killing activity against EC9706 cells. Annexin V-FITC/PI double staining was used to detect the apoptosis rate of cells, immunofluorescence staining to detect the expression of phosphorylated apoptotic signal-regulated kinase 1 (p-ASK1) and Western blot analysis to detect the expression of ASK1 pathway related proteins. A nude mouse model of esophageal cancer transplantation tumor was constructed and divided into control group, DC combined with CIK group and Ag-DC combined with CIK group. The corresponding immune cells were injected into the tail vein for treatment and the tumor volume was measured every 2 days. After 21 days, all nude mice were sacrificed with the tumors taken out. HE staining was used to observe the tumor pathological changes and immunohistochemical staining was performed to detect the expression of ki67 and ASK1 in the tumor tissue. Results Comparedwith the CIK group alone and the DC combined with CIK group, the ratio of CD3+ CD8+ and CD3+ CD56+ in the cells significantly increased after Ag-DCs and CIKs co-culture, along with the increased killing rate of EC9706 cells, increased apoptosis rate of EC9706 cells, and the improved activation level of ASK1. Compared with the CIK group and the DC combined with CIK group, the growth of the transplanted tumor in nude mice treated with Ag-DCs combined with CIKs was significantly inhibited, and after 21 days, it was observed that the tumor tissue mass in this group was relatively smaller, with sparsely arranged cells in the tumor tissue and a decline in the positive rate of ki67 in tumor tissue, while the positive rate of ASK1 was significantly increased. Conclusion Co-cultivation of tumor antigen-loaded DCs with CIKs can significantly increase the killing activity of esophageal cancer tumor cells. The mechanism of action may be related to the activation of the ASK1 pathway.

Clinical Characteristics and Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm / 中国实验血液学杂志

OBJECTIVE@#To explore the clinical manifestations, diagnosis, treatment and prognosis of blastic plasmacytoid dendritic cell neoplasm(BPDCN).@*METHODS@#The clinical features, bone marrow morphology and immunophenotyping, treatment and prognosis of 4 patients with BPDCN were analyzed retrospectively.@*RESULTS@#4 patients had bone marrow， spleen and lymph nodes involvement， 2 patients had skin lesions， and 3 patients had central nervous system infiltration． Tailing phenomenon of abnormally cells could be seen in bone marrow. The immunophenotyping showed that CD56, CD4 and CD123 expression was observed in 4 patients， and CD304 in 3 patients． One patient refused chemotherapy and died early. Both patients achieved complete remission after the initial treatment with DA+VP regimen, 1 of them achieved complete remission after recurrence by using the same regimen again． One patient failed to respond to reduced dose of DA+VP chemotherapy, and then achieved complete remission with venetoclax+azacitidine.@*CONCLUSION@#The malignant cells in BPDCN patients often infiltrate bone marrow, spleen and lymph nodes, and have specical phenotypes, with poor prognosis. The treatment should take into account both myeloid and lymphatic systems. The treatment containing new drugs such as BCL-2 inhibitors combined with demethylation drugs is worth trying.

Leucemia aguda de fenotipo mixto: presentación de un caso pediátrico de Perú / Acute leukemia of mixed phenotype: presentation of a pediatric case from Peru

Introducción: Las leucemias agudas de linaje ambiguo representan un grupo heterogéneo de leucemias sin una clara diferenciación del linaje celular. Constituyen alrededor de 2 a 5 por ciento del total de leucemias agudas. Objetivo: Describir un caso de leucemia aguda de fenotipo mixto (LAFM) en un paciente pediátrico de 4 años de Lambayeque, Perú. Presentación del caso: Se evaluó una muestra de sangre periférica de un niño de 4 años de edad, cuyo inmunofenotipo por citometría de flujo evidenció una población, correspondiente al 94 por ciento de la celularidad total, de linajes mieloide compatible con diferenciación a linaje neutrófilo y en menor medida a monocítica/célula dendrítica (CD123 intenso), con expresión de mieloperoxidasa (MPO) y CD33 intensos; CD13, CD64 y CD66c parcial; y expresión de marcadores de linaje linfoide B (CD19 y CD22 intensos). Este fenotipo obliga a descartar la t(8;21), y anomalías del gen MLL. Por los mencionados hallazgos, la presente leucemia fue clasificada como leucemia aguda de fenotipo mixto, B/Mieloide. Conclusiones: Se concluyó como una leucemia aguda de fenotipo mixto B/Mieloide, con la peculiar inclinación del linaje mieloide hacia neutrófilos y en menor medida hacia monocítica/célula dendrítica(AU)

Introduction: Acute leukemias of ambiguous lineage represent a heterogeneous group of leukemias without a clear differentiation of the cell lineage. They constitute about 2 to 5 percent of all acute leukemias. Objective: To describe a case of acute leukemia of mixed phenotype (LAFM) in a 4-year-old pediatric patient from Lambayeque, Peru. Case presentation: A peripheral blood sample from a 4-year-old boy was evaluated, whose immunophenotype by flow cytometry showed a population, corresponding to 94 percent of total cellularity, of myeloid lineages compatible with differentiation to neutrophil lineage and in less to monocytic/dendritic cell (CD123 high), with expression of myeloperoxidase (MPO) and CD33 high; CD13, CD64 and CD66c partial; and expression of B lymphoid lineage markers (CD19 and CD22 high). This phenotype requires ruling out the t (8; 21), and abnormalities of the MLL gene. Due to the aforementioned findings, the present leukemia was classified as acute leukemia of mixed phenotype, B/Myeloid. Conclusions: It was concluded as an acute leukemia of mixed phenotype B/Myeloid, with the peculiar inclination of the myeloid lineage towards neutrophils and to a lesser extent towards monocytic/dendritic cell(AU)

Effects of Dasatinib on the Maturation of Monocyte-Derived Dendritic Cells Derived from Healthy Donors and Chronic Myelogenous Leukemia Patients / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of dasatinib on the maturation of monocyte-derived dendritic cells (moDCs) derived from healthy donors (HDs) and chronic myelogenous leukemia (CML) patients.@*METHODS@#Peripheral blood mononuclear cells (PBMCs) were isolated from HDs (n=10) and CML patients (n=10) who had got the remission of MR4.5 with imatinib treatment. The generation of moDCs from PBMCs was completed after 7 days of incubation in DC I culture medium, and another 3 days of incubation in DC II culture medium with or without 25 nmol/L dasatinib. On the 10th day, cells were harvested and expression of molecules of maturation related marker were assessed by flow cytometry. The CD80+CD86+ cell population in total cells was gated as DCs in the fluorescence-activated cell storting (FACS) analyzing system, then the expression of CD83, CD40 or HLA-DR in this population was analyzed respectively.@*RESULTS@#The proportion of CD80+CD86+ cells in total cells didn't show a statistical difference between HD group and patient group (89.46%±9.70% vs 87.39%±9.34%, P=0.690). Dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.008) and HLA-DR (P=0.028) on moDCs derived from HDs compared with the control group, while the expression of CD83 on moDCs didn't show a significant difference between dasatinib group and the control group (P=0.428). Meanwhile, dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.023), CD83 (P=0.038) and HLA-DR (P=0.001) on moDCs derived from patients compared with the control group.@*CONCLUSION@#For CML patients, the same high proportion of moDCs as HDs can be induced in vitro, which provides a basis for the application of DC-based immunotherapy strategy. Dasatinib at the concentration of 25 nmol/L can efficiently promote the maturation of moDCs derived from HDs and CML patients in vitro. Dasatinib shows potential as a DC adjuvant to be applied in DC-based immunotherapy strategies, such as DC vaccine and DC cell-therapy.

Participação dos neutrófilos durante a implantação embrionária no desenvolvimento da placenta em camundongos / Participation of neutrophils during embryonic implantation in the placental development in mice

A implantação do embrião na parede uterina é um processo complexo que consiste na interação do blastocisto com as células epiteliais do útero, e depende de diferentes tipos celulares do microambiente uterino. Embora a literatura mostre a participação de neutrófilos neste processo, os dados ainda são incipientes para proposição da função exata destas células nos períodos iniciais da gestação. Dados do nosso grupo de pesquisa mostraram que neutrófilos pró-angiogênicos induzem a tolerância gestacional, e que a depleção de neutrófilos durante as fases iniciais da gestação prejudica a implantação do blastocisto e a progressão da gestação. Com base nestes resultados, o presente estudo visou investigar se a depleção de neutrófilos na fase pré-receptiva da janela de implantação do blastocisto altera a morfologia placentária. Para tanto, foi utilizado o modelo de gestação alogênica, onde camundongos fêmeas C57BL/6, após cruzamento com machos Balb/C foram tratadas com anticorpo anti-Ly6G ou isotipo no dia 1,5 da gestação (24 horas após a detecção do plug vaginal) em dose suficiente para manter a depleção de neutrófilos circulantes por 48 horas (200µg/ 500µL; i.p). No final da gestação (dia 18,5), o sangue periférico foi coletado e, em seguida, os animais foram submetidos a laparotomia para retirada da placenta, a qual foi submetida à análise histológica. As análises dos leucócitos circulantes evidenciaram a efetividade do tratamento para depleção de neutrófilos periféricos. A análise histológica mostrou alterações significativas na morfologia da placenta nos animais tratados com anti-Ly6G. Foram detectadas a redução da zona juncional, de células trofoblásticas e de fatores angiogênicos, como fator de crescimento do endotélio vascular (VEGF), e das moléculas de adesão intracelular-1 (ICAM-1) e de plaqueta e endotélio (PECAM-1). Esses dados evidenciam a importância dos neutrófilos nos primeiros dias de gestação para o desenvolvimento da placenta

Blastocyst implantation is a complex process, consisting of the interaction between blastocyst and uterine epithelial cells. Also, it is well known that the implantation site resembles an inflammatory response, with a profusion of recruited immune cells into the endometrial stroma and lumen from the blood. The role of macrophages, natural killers, and dendritic cells have been extensively studied, however, the participation of neutrophils in this process remains unclear. Data from our research group showed that pro-angiogenic neutrophils induced gestation tolerance, also peripheral neutrophils depletion at the time of active placental development led to smaller embryo sizes and abnormal placentation in mice. In this context, the present study aimed to investigate whether pharmacological depletion of neutrophils in mice in the blastocyst implantation phase alters placental morphology. Therefore, C7/BL/6 female mice, after mating with Balb/C males, were treated with an anti-Ly6G antibody or isotype on day 1 of gestation (after detection of the vaginal plug) at a dose sufficient to maintain the depletion of circulating neutrophils for 48 hours (200 µg/500µL; i.p). At the end of the gestational day (day 18), peripheral blood was collected, and then the animals were submitted to laparotomy for the placenta removal and subsequent histological analysis. The analysis of circulating leukocytes from neutrophils depleted mice showed a reduction of peripheral neutrophils up to 48 hours after antibody injection. The histological analysis showed significant alterations in the placenta morphology of the animals treated with anti-Ly6G. The morphometric analyses showed a reduction in the size of neutrophils depleted placenta due to diminished junctional zone and reduction of trophoblast cells. Also, it was observed a reduction of vascular endothelial growth factors (VEGF), reduction of adhesion molecules intracell-1 (ICAM-1), and platelets and endothelium (PECAM-1) positive cells in the junctional zone. In conclusion, these data show the importance of neutrophils on the first days of pregnancy for the development of the placenta

Neoplasia de células dendríticas plasmocitoides blásticas, un reporte de caso / Blast plasmacytoid dendritic cell neoplasia, a case report

Introducción: La neoplasia de células dendríticas plasmocitoides blásticas (NCDPB) es una patología agresiva y representa menos del 1% de neoplasias hematológicas, se caracteriza por lesiones cutáneas nodulares violáceas sin evidencia de adenopatías en la mayoría de casos. Estudios observacionales demuestran que el Protocolo de quimioterapia Hyper-CVAD y la consolidación con tras-plante de células progenitoras hematopoyéticas se han asociado con una mayor supervivencia general. Caso Clínico: mujer de 82 años con antecedentes de Diabetes Mellitus tipo con cinco meses de lesiones hiperpigmentadas, elevadas, induradas, violáceas no dolorosas en mejilla, brazos, tórax anterior y posterior y piernas. Evolución: En citometría de flujo se determinó un fenotipo compatible con células patológicas (5.86%) con CD123++, HLADR+++, NG2++, CD56+++, CD4++, que sugiere una NCDPB. La biopsia de médula ósea presentó infiltración. PET CT posterior a terapia corticoide: no evidencia enfermedad tumoral macroscópica metabólicamente activa. Se inicia tratamiento con Dexametasona, con lo que las lesiones cutáneas disminuyeron en un 80%. Se inició Quimioterapia Protocolo CHOP like, ha recibido 6 ciclos hasta octubre del 2021, actualmente en remisión completa. Conclusión: En el presente caso el curso clínico de la NCDPB no fue agresivo hasta el momento del cierre del caso presentando disminución del 80% de las lesiones.

Introduction: blast plasmacytoid dendritic cell neoplasia (BPDCN) is an aggressive pathology and represents less than 1% of hematological neoplasms, it is characterized by violaceous nodular skin lesions without evidence of adenopathy in most cases. Observational studies show that the Hyper-CVAD chemotherapy protocol and consolidation with transplantation of hematopoietic progenitor cells have been associated with greater overall survival. Clinical case: a 82-year-old woman with a history of type Diabetes Mellitus with five months of hyperpigmented, raised, indurated, non-painful violaceous lesions on the cheek, arms, anterior and posterior thorax and legs. Evolution: Flow cytometry determined a phenotype compatible with pathological cells (5.86%) with CD123 ++, HLADR +++, NG2 ++, CD56 +++, CD4 ++, which suggests a BPDCN. The bone marrow biopsy showed infiltration. PET CT after corticosteroid therapy: there is no evidence of metabolically active macroscopic tumor disease. Dexamethasone treatment was started, with which skin lesions decreased by 80%. The CHOP-like Chemotherapy Protocol was started, she has received 6 cycles until October 2021, currently in complete remission. Conclusion: In the present case, the clinical course of NCDPB was not aggressive until the moment of closure of the case, presenting a decrease of 80% of the lesions.

Relação entre exercício físico e sistema imunológico / Relationship between exercise and the immune system

O corpo humano tende sempre a procurar um estado de homeostase, buscando o equilíbrio entre todos os sistemas. O exercício físico está presente na rotina diária de indivíduos, mesmo com objetivos diferentes, porém a influência no sistema imunológico não é muitas vezes abordada como fator relevante. O sistema imune é responsável por proteger o organismo contra infecções e doenças, podendo ser modulado perante a resposta de exercícios físicos regulares. Tendo em vista que, atualmente, existe uma preocupação maior em tornar e manter a imunidade eficiente, a prática regular e moderada do exercício pode contribuir para uma maior eficácia desse sistema, dessa forma, podendo ser considerada uma proteção ao corpo humano. O objetivo dessa revisão foi sintetizar os dados de estudos presentes na literatura que demonstram a influência do exercício físico na resposta do sistema imunológico, tornando possível compreender as alterações moleculares, fisiológicas, metabólicas e celulares que levam a um tipo específico de resposta do organismo humano.

The human body always tends to seek a homeostasis state, trying to balance all systems. Physical exercise is present in the routine of individuals even with different goals, but the influence in the immune system isnt a relevant factor. The immune system is responsible for protecting the human body against some infections and diseases, and could be modulated in response by some regular physical exercise. At the moment there is a greater concern to keep efficient immunity, a practice of regular and moderate exercise can contribute to a better effectiveness of this system, thus, it can be considered a form of protection to the human body. The objective of this review was to synthesize some data from any studies presented in the literature that demonstrate the influence of physical exercise on the immune system response. Making it possible to understand the molecular mechanisms, physiological, metabolic and cellular changes that turn to a specific type of response in the human body.

Plasmacytoid dendritic cells in dermatology

Abstract Plasmacytoid dendritic cells are part of the dendritic cells family and are a relevant link between innate and adaptive immunity. They are the most potent producers of type 1 interferon, generating antiviral response, stimulating macrophages and dendritic cells and inducing activation and migration of natural killer cells. Plasmacytoid dendritic cells also exert a role as antigen-presenting cells, promote T-lymphocyte responses, immunoregulation, plasma cells differentiation and antibody secretion. Even though plasmacytoid dendritic cells are not usually present in normal skin, their presence is detected in healing processes, viral infections, and inflammatory, autoimmune, and neoplastic diseases. In recent years, the presence of plasmacytoid dendritic cells in several dermatological diseases has been described, enhancing their potential role in the pathogenesis of such conditions. Future studies on the role of plasmacytoid dendritic cells in dermatology may lead to new therapeutic targets.

Histiocitosis de células de Langerhans: seguimiento de 5 años del caso y revisión sistemática de literatura / Histiocitose de células de Langerhans: acompanhamento de 5 anos e revisão sistemática da literatura / Langerhans cell histiocytosis: 5-year follow-up and systematic literature review

La Histiocitosis de células de Langerhans (HCL), es una enfermedad rara, caracterizada por la proliferación clonal agresiva de células de Langerhans dendríticas de la médula ósea. La enfermedad crea lesiones osteolíticas en donde las manifestaciones orales usualmente están presentes. El objetivo de este reporte de caso es, presentar el seguimiento de cinco años de un caso diagnosticado en el 2014 y una revisión sistemática de literatura de las manifestaciones orales de HCL. Para la revisión sistemática, el argumento de búsqueda con palabras claves como HCL, histiocitosis X y manifestaciones orales, fueron conducidas en cinco bases de datos como PUBMED, LILACS, EBSCO, OVID y SCOPUS. Las manifestaciones orales más comunes son inflamación, enrojecimiento y pérdida de hueso en las áreas afectadas. Es importante mantener un seguimiento periódico en el consultorio dental de los casos de HCL en la población pediátrica. La HCL usualmente presenta manifestaciones orales que pueden ser un signo de diagnóstico temprano de esta condición, especialmente en la población pediátrica.

A histiocitose de células de Langerhans (HCL) é uma doença rara caracterizada pela proliferação clonal agressiva de células dendríticas de Langerhans da medula óssea. A doença cria lesões osteolíticas onde as manifestações orais geralmente estão presentes. O objetivo deste relato de caso é apresentar o seguimento de cinco anos de um caso diagnosticado em 2014 e uma revisão sistemática da literatura sobre as manifestações orais da HCL. Para a revisão sistemática, a busca de argumento com palavras-chave como LCH, histiocytosis X e oral manifestations, foi realizada em cinco bases de dados como PUBMED, LILACS, EBSCO, OVID e SCOPUS. As manifestações orais mais comuns são inflamação, vermelhidão e perda óssea nas áreas afetadas. É importante monitorar regularmente os casos de HCL na população pediátrica no consultório odontológico. A HCL geralmente apresenta manifestações orais que podem ser um sinal diagnóstico precoce dessa condição, principalmente na população pediátrica

Langerhans cell histiocytosis (LCH) is a rare disease characterized by aggressive clonal proliferation of dendritic Langerhans cells from the bone marrow. The disease creates osteolytic lesions where oral manifestations are usually present. The objective of this case report is to present the five-year follow-up of a case diagnosed in 2014 and a systematic review of the literature on the oral manifestations of LCH. For the systematic review, the search argument with keywords such as LCH, histiocytosis X and oral manifestations, were conducted in five databases such as PUBMED, LILACS, EBSCO, OVID and SCOPUS. The most common oral manifestations are inflammation, redness, and bone loss in the affected areas. It is important to regularly monitor LCH cases in the pediatric population in the dental office. LCH usually presents oral manifestations that can be an early diagnostic sign of this condition, especially in the pediatric population

Oxidized low-density lipoprotein stimulates dendritic cells maturation via LOX-1-mediated MAPK/NF-κB pathway

Dendritic cells (DCs) play a crucial role as central orchestrators of immune system response in atherosclerosis initiation and progression. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in the immune maturation of DCs, but the underlying mechanisms remain unclear. We isolated mouse bone marrow progenitors and stimulated them with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4 to induce immature DCs. We then treated DCs with oxidized low-density lipoprotein (oxLDL) to induce maturation. LOX-1 siRNA was used to investigate the modulation of LOX-1 on the development of DCs and the underlying signal pathways. CD11c-positive DCs were successfully derived from mouse bone marrow progenitors. OxLDL promoted the expressions of DCs maturation markers and pro-inflammatory cytokines. OxLDL also upregulated LOX-1 expression and activated MAPK/NF-κB pathways. LOX-1 siRNA could attenuate the expression of MAPK/NF-κB pathways and inflammatory cytokines. In conclusion, oxLDL induced the maturation of DCs via LOX-1-mediated MAPK/NF-κB pathway, which contributed to the initiation and progression of atherosclerosis.

Impacto funcional de la inhibición farmacológica de Tmem176b en diferentes subpoblaciones de células dendríticas / Functional impact of pharmacological inhibition of Tmem176b on different subpopulations of dendritic cells

Nuestro grupo ha reportado que la proteína Tmem176b es un canal/transportador iónico intracelular fuertemente expresado en células dendríticas (DCs), que bloquea la respuesta inmune anti-tumoral. Identificamos al compuesto BayK8644 como un inhibidor de Tmem176b. BayK8644 promueve el control tumoral en protocolos profilácticos, pero no en tumores establecidos a través de la activación del inflamasoma y células T CD8+. Entendimos que era necesario profundizar en los mecanismos inmunológicos implicados, con el fin de obtener información que nos permitiera mejorar la respuesta terapéutica. Dada la relevancia de las DCs en la respuesta anti-tumoral y la fuerte expresión de Tmem176b en esos leucocitos, nos planteamos como objetivo general estudiar el impacto de la inhibición de Tmem176b en diferentes sub-poblaciones de DCs (cDC1 y cDC2). Aquí hemos demostrado que la inhibición de Tmem176b con BayK8644 resulta en el bloqueo de una de las funciones más específicas de las cDC1, la presentación cruzada de antígenos. Mostramos que la encapsulación de BayK8644 en NP (NP-BayK8644) previene la inhibición de la presentación cruzada de antígenos mientras mantiene la capacidad de activación del inflamasoma. El tratamiento con NP-BayK8644 de animales que poseen tumores establecidos controló el crecimiento tumoral de una manera dependiente de Tmem176b. El control tumoral se asoció con una mayor infiltración tumoral por células T CD8+ totales y específicas de tumor. Por tanto, la formulación de BayK8644 en NP mejoró la eficacia antitumoral del compuesto libre al evitar la inhibición de la presentación cruzada de antígenos al tiempo que desencadena la activación del inflamasoma. Por otra parte, caracterizamos mecanismos inmunológicos desencadenados por cDC2 luego de la deleción génica y el bloqueo farmacológico de Tmem176b. Mostramos en un modelo in vitro y ex vivo que las DC2 de animales portadores de tumores Tmem176b-/- o WT tratados con BayK8644 promovió la diferenciación de células Th17 de una manera dependiente del inflamasoma. Experimentos de transferencia celular adoptiva mostraron que las células Th17 mejoran los efectos anti-tumorales del bloqueo de PD-1, sugiriendo que el eje cDC2/Th17 podría jugar un papel relevante en la terapia anti-PD1. En suma, caracterizamos el impacto de la inhibición de Tmem176b en diferentes subpoblaciones de DCs. Ese conocimiento aportó elementos para desarrollar formulaciones que mejoren el efecto anti-tumoral del BayK8644. Además describimos mecanismos desencadenados al inhibir a Tmem176b que potenciarían respuestas inmunes durante la terapia oncológica basada en el bloqueo de PD-1