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1.
Am J Forensic Med Pathol ; 41(1): 32-34, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32000220

RESUMEN

Thymus glands from 283 autopsy cases were sampled and evaluated with histochemical and immunohistochemical methods. A subpopulation of 41 intravenous drug addicts were compared with age-matched control cases.It was found that an accelerated involution of the thymus occurred in the 20- to 25-year interval and thereafter with a steady pace of 5% per year. Also the size of Hassall bodies declined successively.In drug addicts, an increased dystrophic calcification of the Hassall bodies and a significant difference in thymus size (atrophy) compared with controls were seen. Moreover, a difference was seen in the relative numbers of CD4 and CD8 lymphocytes where CD4+ cells were reduced in drug addicts.It is hypothesized that signs of hepatitis C virus infection that was found in the majority of drug addicts and the reduced number of functionally intact Hassall corpuscles could explain the reduction of CD4+ lymphocytes and thymic hypotrophy in this population.


Asunto(s)
Consumidores de Drogas , Abuso de Sustancias por Vía Intravenosa , Timo/patología , Adolescente , Adulto , Envejecimiento/patología , Atrofia/patología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Calcinosis/patología , Estudios de Casos y Controles , Femenino , Patologia Forense , Hepatitis C Crónica/patología , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
2.
BMC Infect Dis ; 19(1): 926, 2019 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-31675923

RESUMEN

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play immunosuppressive roles in cancers and some infectious diseases; however, their role in dengue fever (DF) remains unknown. This study evaluated the clinical significance of MDSCs in DF patients. METHODS: This study comprised 178 non-severe DF patients, 20 non-dengue fever (NDF) controls, and 30 healthy donors. The DF patients were divided into the following five groups based on the fever duration from its onset to the day of sample collection: fever duration of 1-2, 3-4, 5-6, 7-8, and > 9 days. Among these DF patients, 14 were monitored for eight days, and their peripheral blood samples were collected every two days. The mononuclear cells were isolated and analyzed using flow cytometry. The correlation between the MDSCs and clinical and immunological indicators of the DF patients was evaluated using Spearman analysis. RESULTS: The count of the peripheral blood MDSCs, especially monocytic MDSCs, of the 178 DF patients were dramatically higher than those of the NDF and healthy controls, and remarkably decreased with the fever duration. Moreover, the MDSC count correlated with some indicators, including the dengue viral load (rho = 0.367, p < .001), body temperature (rho = 0.263, p = .005), prothrombin time (rho = 0.475, p < .001), CD4+ T cell number (rho = - 0.317, p < .001), CD8+ T cell number (rho = - 0.361, p < .001), "programmed cell death protein 1" (PD-1) (rho = - 0.347, p < .001), "T cell immunoglobulin domain and mucin domain-3" (Tim3) (rho = - 0.258, p = .001), interferon-α (IFN-α) (rho = 0.43, p < .001), and "regulated upon activation normal T-cell expressed and secreted" (RANTES) (rho = 0.278, p = .019). Furthermore, the level of arginase-1, but not nitric oxide, was higher in the DF patients than in the healthy controls and was closely related to the number of MDSCs (rho = 0.265, p = .024). CONCLUSIONS: Our study reveals a significant correlation between MDSCs and DF clinical indicators, posing MDSCs as potential target cells for DF treatment.


Asunto(s)
Dengue/etiología , Células Supresoras de Origen Mieloide/patología , Adolescente , Adulto , Arginasa/sangre , Linfocitos T CD4-Positivos/patología , Estudios de Casos y Controles , Estudios Transversales , Dengue/sangre , Femenino , Citometría de Flujo , Humanos , Interferón-alfa/sangre , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Óxido Nítrico/sangre , Pronóstico , Factores de Tiempo , Carga Viral , Adulto Joven
3.
Cancer Immunol Immunother ; 68(12): 1995-2004, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31690954

RESUMEN

Glioblastoma is a highly prevalent and aggressive form of primary brain tumor. It represents approximately 56% of all the newly diagnosed gliomas. Macrophages are one of the major constituents of tumor-infiltrating immune cells in the human gliomas. The role of immunosuppressive macrophages is very well documented in correlation with the poor prognosis of patients suffering from breast, prostate, bladder and cervical cancers. The current study highlights the correlation between the tumor-associated macrophage phenotypes and glioma progression. We observed an increase in the pool of M2 macrophages in high-grade gliomas, as confirmed by their CD68 and CD163 double-positive phenotype. In contrast, less M1 macrophages were noticed in high-grade gliomas, as evidenced by the down-regulation in the expression of CCL3 marker. In addition, we observed that higher gene expression ratio of CD163/CCL3 is associated with glioma progression. The Kaplan-Meier survival plots indicate that glioma patients with lower expression of M2c marker (CD163), and higher expression of M1 marker (CCL3) had better survival. Furthermore, we examined the systemic immune response in the peripheral blood and noted a predominance of M2 macrophages, myeloid-derived suppressor cells and PD-1+ CD4 T cells in glioma patients. Thus, the study indicates a high gene expression ratio of CD163/CCL3 in high-grade gliomas as compared to low-grade gliomas and significantly elevated frequency of M2 macrophages and PD-1+ CD4 T cells in the blood of tumor patients. These parameters could be used as an indicator of the early diagnosis and prognosis of the disease.


Asunto(s)
Neoplasias Encefálicas/inmunología , Linfocitos T CD4-Positivos/patología , Glioblastoma/inmunología , Macrófagos/inmunología , Células Supresoras de Origen Mieloide/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Neoplasias Encefálicas/mortalidad , Carcinogénesis , Quimiocina CCL3/metabolismo , Citocinas/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Glioblastoma/mortalidad , Humanos , Tolerancia Inmunológica , Inmunidad Humoral , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Superficie Celular/metabolismo , Análisis de Supervivencia , Células Th2/inmunología
4.
Medicine (Baltimore) ; 98(39): e17311, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31574860

RESUMEN

Immune infiltration of nasopharyngeal carcinoma (NPC) is closely associated with the patients' prognosis. However, previous studies have not interpreted the difference of infiltrating immune cells in NPC.We comprehensively analyzed the tumor-infiltrating immune cells present in NPC for the first time, which was based on a scientific deconvolution algorithm (CIBERSORT) and the gene expression data of GSE64634. The fractions of 22 immune cells were assessed to reveal the associations between normal samples and NPC samples.Profiles of immune infiltration vary significantly between normal samples and NPC samples, and the variation could characterize the individual differences. NPC samples contained a higher proportion for M1 macrophages, whereas memory B cells and CD4 memory resting T cells were relatively lower.Our data suggest that the differences in the infiltrating immune cells in NPC and these differences would probably facilitate patient consultation and individualized treatment.


Asunto(s)
Linfocitos Infiltrantes de Tumor , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Adulto , Algoritmos , Linfocitos B/inmunología , Linfocitos B/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , China , Correlación de Datos , Femenino , Expresión Génica , Humanos , Memoria Inmunológica , Linfocitos Infiltrantes de Tumor/clasificación , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Macrófagos/inmunología , Macrófagos/patología , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/inmunología , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/patología , Pronóstico , Reproducibilidad de los Resultados
5.
BMC Cancer ; 19(1): 809, 2019 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-31412798

RESUMEN

BACKGROUND: Eradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia. But such deep responses are also associated with severe immuno-depletion, leading to infections and the development of secondary cancers. METHODS: We assessed, blood MRD and normal immune cell levels at the end of treatment, in 162 first-line FCR patients, and analysed survival and adverse event. RESULTS: Multivariate Landmark analysis 3 months after FCR completion identified unmutated IGHV status (HR, 2.03, p = 0.043), the level of MRD reached (intermediate versus low, HR, 2.43, p = 0.002; high versus low, HR, 4.56, p = 0.002) and CD4 > 200/mm3 (HR, 3.30, p <  0.001) as factors independently associated with progression-free survival (PFS); neither CD8 nor NK counts were associated with PFS. The CD4 count was associated with PFS irrespective of IGHV mutational status, but only in patients with detectable MRD (HR, 3.51, p = 0.0004, whereas it had no prognostic impact in MRD < 10- 4 patients: p = 0.6998). We next used a competitive risk model to investigate whether immune cell subsets could be associated with the risk of infection and found no association between CD4, CD8 and NK cells and infection. CONCLUSIONS: Consolidation/maintenance trials based on detectable MRD after FCR should investigate CD4 T-cell numbers both as a selection and a response criterion, and consolidation treatments should target B-cell/T-cell interactions.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos T CD4-Positivos/patología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfocitos T CD4-Positivos/efectos de los fármacos , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Región Variable de Inmunoglobulina/genética , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Mutación , Neoplasia Residual , Pronóstico , Rituximab/efectos adversos , Rituximab/uso terapéutico , Análisis de Supervivencia , Resultado del Tratamiento , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico
6.
Technol Cancer Res Treat ; 18: 1533033819869949, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31451090

RESUMEN

Tumor-infiltrating immune cells are part of a complex microenvironment and associated with improved clinical outcomes in a broad range of tumor types. However, a detailed map for the prognostic landscape of tumor-infiltrating immune cells and immune checkpoint modulators in glioblastoma is still lacking. Here, with the web-accessible resource, The Cancer Immunome Archive, 28 types of both adaptive and innate tumor-infiltrating immune cells were characterized in glioblastoma. Tumors lacking central memory CD4 T cells or natural killer cells were associated with better prognosis in glioblastoma, as verified by immunohistochemical analysis. Moreover, Kaplan-Meier analysis for a total of 71 key immune checkpoint molecules revealed that the expression level of inducible T cell costimulators, tumor necrosis factor superfamily member 14, and UL16 binding protein 1 were negatively correlated with the clinical outcome of patients with glioblastoma. In addition, there was a significant difference between nontumor and glioblastoma samples of several immune checkpoint modulators based on the expression level of their corresponding gene. Collectively, the annotation of tumor-infiltrating immune cells and immune checkpoint modulators in glioblastoma provides a valuable resource for identifying their involvement in tumor escape mechanisms and response to therapy.


Asunto(s)
Glioblastoma/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas de Neoplasias/inmunología , Pronóstico , Adolescente , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Niño , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Glioblastoma/genética , Glioblastoma/patología , Humanos , Estimación de Kaplan-Meier , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Adulto Joven
7.
PLoS Pathog ; 15(6): e1007868, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31220191

RESUMEN

We previously reported the presence of memory CD4+ T cells that express low levels of SAMHD1 (SAMHD1low) in peripheral blood and lymph nodes from both HIV-1 infected and uninfected individuals. These cells are enriched in Th17 and Tfh subsets, two populations known to be preferentially targeted by HIV-1. Here we investigated whether SAMHD1low CD4+ T-cells harbour replication-competent virus and compartimentalized HIV-1 genomes. We sorted memory CD4+CD45RO+SAMHD1low, CD4+CD45RO+SAMHD1+ and naive CD4+CD45RO-SAMHD1+ cells from HIV-1-infected patients on anti-retroviral therapy (c-ART) and performed HIV-1 DNA quantification, ultra-deep-sequencing of partial env (C2/V3) sequences and phenotypic characterization of the cells. We show that SAMHD1low cells include novel Th17 CCR6+ subsets that lack CXCR3 and CCR4 (CCR6+DN). There is a decrease of the % of Th17 in SAMHD1low compartment in infected compared to uninfected individuals (41% vs 55%, p<0.05), whereas the % of CCR6+DN increases (7.95% vs 3.8%, p<0.05). Moreover, in HIV-1 infected patients, memory SAMHD1low cells harbour high levels of HIV-1 DNA compared to memory SAMHD1+ cells (4.5 vs 3.8 log/106cells, respectively, p<0.001), while naïve SAMHD1+ showed significantly lower levels (3.1 log/106cells, p<0.0001). Importantly, we show that SAMHD1low cells contain p24-producing cells. Moreover, phylogenetic analyses revealed well-segregated HIV-1 DNA populations with compartmentalization between SAMHD1low and SAMHD1+ memory cells, and limited viral exchange. As expected, the % of Ki67+ cells was significantly higher in SAMHD1low compared to SAMHD1+ cells. There was positive association between levels of HIV-1 DNA and Ki67+ in memory SAMHD1low cells, but not in memory and naïve SAMHD1+ CD4+ T-cells. Altogether, these data suggest that proliferative memory SAMHD1low cells contribute to viral persistence.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Memoria Inmunológica , Proteína 1 que Contiene Dominios SAM y HD/inmunología , Adulto , Anciano , Antirretrovirales/administración & dosificación , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Humanos , Masculino , Persona de Mediana Edad
8.
Int J Mol Sci ; 20(11)2019 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-31151151

RESUMEN

Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor infiltrating lymphocytes (TILs) was shown to have a better prognosis, opposite to the trend seen with ER-negative BC. We hypothesized that ER-positive BC with high expression of AR will have fewer TILs and an inferior response to NAC, but with a better prognosis. In both TCGA and METABRIC cohorts, AR expression was significantly higher in ER-positive BCs compared to ER-negatives (p < 0.001, p < 0.001, respectively) and it correlated with ER expression (R = 0.630, R = 0.509, respectively). In ER-positive tumors, AR high tumors enriched UV response down (NES = 2.01, p < 0.001), and AR low tumors enriched DNA repair (NES = -2.02, p < 0.001). AR high tumors were significantly associated with procancer regulatory T-cells, and AR low tumors were associated with anticancer immune cells, such as CD4, CD8, and Gamma-Delta T-cells and memory B-cells in ER-positive BC (p < 0.01). Further, cytolytic activity was significantly lower in AR high BC in both cohorts. Finally, AR high tumors had a significantly lower rate of attaining pathological complete response to NAC (GSE22358), but better survival. In conclusion, our results demonstrated that high AR has fewer tumor infiltrating lymphocytes as well as cytolytic activity and an inferior response to NAC, but better survival in ER-positive BC.


Asunto(s)
Neoplasias de la Mama/etiología , Neoplasias de la Mama/metabolismo , Citotoxicidad Inmunológica , Regulación Neoplásica de la Expresión Génica , Receptores Androgénicos/genética , Receptores Estrogénicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Reparación del ADN , Femenino , Humanos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Terapia Neoadyuvante , Pronóstico , ARN Mensajero , Receptores Androgénicos/metabolismo , Receptores Estrogénicos/genética , Resultado del Tratamiento
9.
PLoS Pathog ; 15(6): e1007872, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31194844

RESUMEN

Innate recognition of invading intracellular pathogens is essential for regulating robust and rapid CD4+ T cell effector function, which is critical for host-mediated immunity. The intracellular apicomplexan parasite, Toxoplasma gondii, is capable of infecting almost any nucleated cell of warm-blooded animals, including humans, and establishing tissue cysts that persist throughout the lifetime of the host. Recognition of T. gondii by TLRs is essential for robust IL-12 and IFN-γ production, two major cytokines involved in host resistance to the parasite. In the murine model of infection, robust IL-12 and IFN-γ production have been largely attributed to T. gondii profilin recognition by the TLR11 and TLR12 heterodimer complex, resulting in Myd88-dependent IL-12 production. However, TLR11 or TLR12 deficiency failed to recapitulate the acute susceptibility to T. gondii infection seen in Myd88-/- mice. T. gondii triggers inflammasome activation in a caspase-1-dependent manner resulting in cytokine release; however, it remains undetermined if parasite-mediated inflammasome activation impacts IFN-γ production and host resistance to the parasite. Using mice which lack different inflammasome components, we observed that the inflammasome played a limited role in host resistance when TLR11 remained functional. Strikingly, in the absence of TLR11, caspase-1 and -11 played a significant role for robust CD4+ TH1-derived IFN-γ responses and host survival. Moreover, we demonstrated that in the absence of TLR11, production of the caspase-1-dependent cytokine IL-18 was sufficient and necessary for CD4+ T cell-derived IFN-γ responses. Mechanistically, we established that T. gondii-mediated activation of the inflammasome and IL-18 were critical to maintain robust CD4+ TH1 IFN-γ responses during parasite infection in the absence of TLR11.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Inmunidad Innata , Inflamasomas/inmunología , Interferón gamma/inmunología , Receptores Toll-Like/inmunología , Toxoplasma/inmunología , Toxoplasmosis Animal/inmunología , Animales , Linfocitos T CD4-Positivos/parasitología , Linfocitos T CD4-Positivos/patología , Caspasa 1/genética , Caspasa 1/inmunología , Caspasas/genética , Caspasas/inmunología , Inflamasomas/genética , Interferón gamma/genética , Interleucina-18/genética , Interleucina-18/inmunología , Ratones , Ratones Noqueados , Receptores Toll-Like/genética , Toxoplasmosis Animal/genética , Toxoplasmosis Animal/patología
10.
Glia ; 67(9): 1694-1704, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31106910

RESUMEN

Secondary progressive multiple sclerosis (SPMS) is an autoimmune disease of the central nervous system (CNS) characterized by progressive motor dysfunction, sensory deficits, and visual problems. The pathological mechanism of SPMS remains poorly understood. In this study, we investigated the role of microglia, immune cells in the CNS, in a secondary progressive form of experimental autoimmune encephalomyelitis (EAE), the mouse model of SPMS. We induced EAE in nonobese diabetic mice and treated the EAE mice with PLX3397, an antagonist of colony stimulating factor-1 receptor, during secondary progression in order to deplete microglia. The results showed that PLX3397 treatment significantly exacerbated secondary progression of EAE and increased mortality rates. Additionally, histological analysis showed that PLX3397 treatment significantly promoted inflammation, demyelination, and axonal degeneration. Moreover, the number of CD4+ T cells in the spinal cord of EAE mice was expanded due to PLX3397-mediated proliferation. These results suggest that microglia suppressed secondary progression of EAE by inhibiting the proliferation of CD4+ T cells in the CNS.


Asunto(s)
Encefalomielitis Autoinmune Experimental/fisiopatología , Microglía/fisiología , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Animales , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/fisiología , Proliferación Celular/fisiología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Inflamación/patología , Inflamación/fisiopatología , Ratones Endogámicos NOD , Microglía/patología , Esclerosis Múltiple Crónica Progresiva/patología , Médula Espinal/patología , Médula Espinal/fisiopatología
11.
Rinsho Shinkeigaku ; 59(6): 360-364, 2019 Jun 22.
Artículo en Japonés | MEDLINE | ID: mdl-31142711

RESUMEN

An 84-year-old woman developed blepharoptosis, diplopia, weakness of extremities, and dysphagia with elevation of serum CK levels after treatment with nivolumab against renal cell carcinoma. 3 Hz repetitive stimulation showed waning in the trapezius muscle, leading to the diagnosis of myasthenia gravis. Laboratory examination showed that anti-acetylcholine receptor antibody was negative. We performed IVIg and steroid therapy. However, her symptoms did not improve, and she died of respiratory failure, although serum CK levels ameliorated to the normal range. The results of autopsy showed atrophy of muscle fibers and massive infiltration of inflammatory cells in the endomysium of the iliopsoas muscle and diaphragm, indicating occurrence of myositis. Immunohistochemical analysis showed that CD8-positive T cells mainly infiltrates in the endomysium with a small number of CD4-potive T cells. Here, we report an autopsy case of nivolumab-induced myasthenia gravis and myositis.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Miastenia Gravis/inducido químicamente , Miastenia Gravis/patología , Miositis/inducido químicamente , Miositis/patología , Nivolumab/efectos adversos , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Autopsia , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Carcinoma de Células Renales/tratamiento farmacológico , Creatina Quinasa/sangre , Resultado Fatal , Femenino , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Miastenia Gravis/diagnóstico , Miastenia Gravis/tratamiento farmacológico , Miositis/diagnóstico , Miositis/tratamiento farmacológico , Nivolumab/uso terapéutico , Insuficiencia Respiratoria/inducido químicamente
12.
J Cutan Pathol ; 46(10): 717-722, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31062372

RESUMEN

BACKGROUND: In cases of herpes virus infection without typical histologic (and clinical) signs it is difficult to achieve the correct diagnosis by histology alone. Some of those cases are prone to be misdiagnosed as cutaneous lymphoma. METHODS: This retrospective study included five patients with herpes simplex virus (HSV)-associated pseudolymphoma. We investigated clinical, histomorphologic and immunophenotypic features of all patients. RESULTS: All biopsy specimens presented a superficial and deep perivascular lymphohistiocytic infiltrate with epidermotropism, atypia and admixed plasma cells to varying degrees. Four of five samples showed lining-up of lymphocytes in the junctional zone with predominance of CD8+ lymphocytes, in contrast to the dermal part (inverse CD8:CD4 ratio). Papillary edema was found in four of five cases. Clinically, patchy erythema located on the buttocks and adjacent areas was typical, sometimes with erosions and crusts. Medical history of recurrent blisters, pain or itching was additionally helpful. CONCLUSION: We point out subtle but consistent histomorphologic criteria, which were helpful to diagnose HSV-associated pseudolymphoma in context with the clinical presentation.


Asunto(s)
Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Herpes Simple , Seudolinfoma , Simplexvirus/inmunología , Enfermedades de la Piel , Adolescente , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Niño , Preescolar , Femenino , Herpes Simple/inmunología , Herpes Simple/patología , Humanos , Masculino , Persona de Mediana Edad , Seudolinfoma/inmunología , Seudolinfoma/patología , Estudios Retrospectivos , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/patología
13.
Immunopharmacol Immunotoxicol ; 41(2): 231-241, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31056969

RESUMEN

Context: Leaf extracts of plants of the genus Betula have traditionally been used as diuretic, anti-rheumatic and diaphoretic preparations. One of the main active ingredients of Betula bark is betulin, lupane-type triterpene alcohol, with multiple biological activities. Objectives: The aim of this study was to investigate in vitro and in vivo immunomodulatory effects of a newly synthesized ester of betulin: 28-O-phosphatidylbetulin [28-O-(1,2-diacyl-sn-glycero-3-phospho)-betulin, DAPB] in comparison with betulin in mice. Materials and methods: Cytotoxic activity of DAPB or betulin was tested against non-cancer (D10.G4.1 and J774E.1) and cancer (GL-1; CL-1 and Jurkat) cell lines. The in vivo part assessed total lymphocyte count, weight ratio and subsets of lymphocytes in the lymphatic organs, and humoral immune response to sheep erythrocytes (SRBC). Results: In vitro assay showed that DAPB, contrary to betulin, had no antiproliferative activity. Exposure to four doses of DAPB increased the absolute count of immature CD4+CD8+ thymic cells as well as the percentage and absolute count of mature CD4+ and CD8+ thymocytes. DAPB enhanced the percentage or absolute count of CD3+ cells in spleen and lymph nodes with corresponding decrease in the percentage and/or absolute count of CD19+ cells. Both DAPB and betulin enhanced the percentage and absolute count of CD8+ lymphocytes in lymph nodes. In SRBC-immunized mice, betulin contrary to DAPB enhanced the number of splenocytes producing anti-SRBC antibodies (PFC). Both DAPB and betulin increased the level of total (IgM + IgG) and IgG titers. Conclusion: Despite the lack of cytotoxic activity, DAPB shows valuable immunomodulatory properties.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Yema de Huevo/química , Inmunidad Celular/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Lecitinas/farmacología , Triterpenos/farmacología , Animales , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Femenino , Humanos , Células Jurkat , Lecitinas/química , Masculino , Ratones Endogámicos BALB C , Neoplasias/inmunología , Neoplasias/patología , Ovinos
14.
Ann Hematol ; 98(8): 1953-1959, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31025161

RESUMEN

The change in the incidence of lymphomas in function of the presence or absence of sustained virological response after anti-hepatitis C therapy in a cohort of human immunodeficiency (HIV)-hepatitis C (HCV) viruses coinfected patients was analyzed. A prospective cohort of 755 HIV-HCV coinfected patients who received their first anti-HCV therapy, based on interferon + ribavirin schemas, was evaluated. Incidence and histologic types of lymphomas were analyzed in two periods: (1) before administration of anti-HCV therapy and (2) after anti-HCV therapy. The association between lymphoma incidence and demographic, HIV- (minimum CD4+ cell count and CD4+ cell count at diagnosis of lymphoma, antiretroviral therapy, maximal HIV load and HIV load at diagnosis of lymphoma) and HCV-related variables (HCV load, genotype, sustained viral response to anti-HCV therapy) were analyzed. A total of 13 lymphomas [incidence rate (95% confidence interval), 0.72 (0.33-1.11) × 1000 person-years, time from HIV diagnosis to lymphoma diagnosis (median, interquartile range), 15 (11-19) years] were diagnosed. Nine of them were non-Hodgkin and four Hodgkin lymphomas. The median CD4+ T cell count at diagnosis of lymphoma was 457/mm3, with only two cases with values lower than 200/mm3. The incidence rate of non-Hodgkin lymphomas was similar pre- and post-anti HCV therapy [0.33 (0.00-0.65) vs 0.68 (0.08-1.26) × 1000 person-years, respectively, p > 0.05]. Patients with sustained virologic HCV response showed similar incidence rate of lymphomas than that of those without anti-HCV response. In conclusion, anti-HCV therapy does not modify the incidence rate of lymphomas in HIV-HCV coinfected patients.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Enfermedad de Hodgkin/tratamiento farmacológico , Interferón alfa-2/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Ribavirina/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Coinfección , Combinación de Medicamentos , VIH/efectos de los fármacos , VIH/crecimiento & desarrollo , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Infecciones por VIH/virología , Hepacivirus/efectos de los fármacos , Hepacivirus/crecimiento & desarrollo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/virología , Humanos , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Carga Viral/efectos de los fármacos
15.
Cardiovasc Pathol ; 40: 68-71, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30928813

RESUMEN

Enterocolic lymphocytic phlebitis (ELP) is a rare enteropathy characterized by lymphocytic phlebitis of the mesenteric veins without arteritis. Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare disease similar to ELP, characterized by myointimal hyperplasia that constricts the lumen of veins, causing mucosal injury. A 62-year-old man with chief complaint of abdominal pain was treated by partial resection of the ileum after 3 months of conservative therapy. The pathologic diagnosis was ELP with prominent myointimal hyperplasia. Histologically, the lesion consisted of lymphocytic infiltration into the vein accompanied by prominent myointimal hyperplasia and perivenous concentric fibrosis, which are characteristics shared by ELP and IMHMV. The observations in this case suggest that some of ELP and IMHMV may belong to the same disease spectrum. Furthermore, perivascular concentric fibrosis was a remarkable observation that may contribute to differential diagnosis between ELP and "true" IMHMV.


Asunto(s)
Linfocitos T CD4-Positivos/patología , Enfermedades Intestinales/patología , Venas Mesentéricas/patología , Flebitis/patología , Túnica Íntima/patología , Biopsia , Angiografía por Tomografía Computarizada , Diagnóstico Diferencial , Fibrosis , Humanos , Hiperplasia , Inmunohistoquímica , Enfermedades Intestinales/diagnóstico por imagen , Enfermedades Intestinales/cirugía , Masculino , Venas Mesentéricas/diagnóstico por imagen , Venas Mesentéricas/cirugía , Persona de Mediana Edad , Flebitis/diagnóstico por imagen , Flebitis/cirugía , Flebografía/métodos , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Túnica Íntima/diagnóstico por imagen , Túnica Íntima/cirugía
16.
Br J Cancer ; 120(9): 903-912, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30956278

RESUMEN

BACKGROUND: The immunosuppressive role of the cytokine IL-35 in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, we analysed the localisation and regulation of IL-35 in the lung of patients with non-small cell lung cancer (NSCLC) to further elucidate the immune-escape of cancer cells in perioperative course of disease. METHODS: Interleukin 35 (IL-35) was measured by ELISA in postoperative serum from 7 patients with NSCLC as well as 8 samples from healthy controls. Immunohistochemistry, FACS analysis, real-time PCR, as well as western blot from samples of the control (CTR), peri-tumoural (PT) and the tumoural (TU) region of the lung derived from patients with NSCLC and 10 controls were performed. RESULTS: Here we found elevated levels of IL-35 in the TU region as well as postoperative serum from patients with lung adenocarcinoma. Consistently, we found an increased expression of IL-35+Foxp-3+ cells, which associated with ARG1 mRNA expression and decreased TNFA in the TU region of the lung of patients with NSCLC as compared to their CTR region. Furthermore, in the CTR region of the lung of patients with NSCLC, CD68+ macrophages were induced and correlated with IL-35+ cells. Finally, IL-35 positively correlated with TTF-1+PD-L1+ cells in the TU region of NSCLC patients. CONCLUSIONS: Induced IL-35+Foxp3+ cell numbers in the TU region of the lung of patients with NSCLC associated with ARG1 mRNA expression and with TTF-1+PD-L1+ cells. In the tumour-free CTR area, IL-35 correlated with CD68+ macrophages. Thus inhibitors to IL-35 would probably succeed in combination with antibodies against immune checkpoints like PD-L1 and PD-1 currently used against NSCLC because they would inhibit immunosuppressive macrophages and T regulatory cells while promoting T cell-mediated anti-tumoural immune responses in the microenvironment as well as the TU region of NSCLC patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inmunología , Interleucinas/inmunología , Neoplasias Pulmonares/inmunología , Células A549 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Estudios de Casos y Controles , Citometría de Flujo , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/inmunología , Humanos , Inmunohistoquímica , Subunidad p35 de la Interleucina-12/biosíntesis , Subunidad p35 de la Interleucina-12/genética , Subunidad p35 de la Interleucina-12/inmunología , Interleucinas/biosíntesis , Interleucinas/genética , Pulmón/inmunología , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Antígenos de Histocompatibilidad Menor/biosíntesis , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Escape del Tumor
17.
Microbes Infect ; 21(8-9): 386-392, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31009807

RESUMEN

The purpose of this study is to explore the role of different T cell subgroups in the pathogenesis of sepsis in children. Flow cytometry was used to detect the changes in the activation status and the number of T cell subgroups in the peripheral blood of children with sepsis; healthy children were selected as the control group. Compared with healthy children, the number of CD4+ T cells in the peripheral blood of children with sepsis did not change significantly (Z = 1.945, P = 0.052); though the ratio decreased and the median level dropped from 34.6% to 30.7% (Z = 2.257, P = 0.024). However, the number of CD8+ T cells in the blood of children with sepsis increased, and the median level also increased from 0.2 × 109/L to 0.4 × 109/L (Z = -2.404, P = 0.016). In addition, CD3+CD8+HLA-DR + cell level significantly increased, and the median level increased from 4.2% to 24.3% (Z = -5.370, P = 0.000). There was a large heterogeneity in the hospitalization time of sepsis in clinical patients. Compared to patients with a mean hospital stay of 6 days, patients with a median hospital stay of 13 days had a lower CD3+CD4+CD25 + cells percentage, while the percentage of CD3+CD8+HLA-DR+ was higher, resulting in a more apparent increase of CD3+ CD8+HLA-DR+/CD3+CD4+CD25+. Therefore, the failure of CD4+ T cell activation and proliferation, and the excessive activation and proliferation of CD8+ T cells play an important role in the pathogenesis of sepsis. The increase of CD3+CD8+HLA-DR+/CD3+CD4+CD25 + ratio was associated with the extended course of sepsis.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Sepsis/inmunología , Subgrupos de Linfocitos T/inmunología , Antígenos CD/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Niño , Preescolar , Citocinas/sangre , Femenino , Humanos , Lactante , Tiempo de Internación , Activación de Linfocitos , Recuento de Linfocitos , Masculino , Estudios Prospectivos , Sepsis/sangre , Subgrupos de Linfocitos T/patología
18.
PLoS One ; 14(4): e0215408, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30986254

RESUMEN

Cathepsin L (CTSL) has been proved to help contain leishmaniasis and mycoplasma infection in mice by supporting cellular immune responses, but the regulatory functions of CTSL on mucosal immune responses haven't been tested and remain undefined. Here, we investigated the effects of CTSL on SIgA responses and invariant chain (Ii) degradations in the co-cultured swine dendritic cells (DCs) and B cells system in vitro. When the cells system were transfected with vector CTSL-GFP or incubated with recombinant CTSL (rCTSL) before they were infected with Mycoplasma hyopneumoniae (M.hp), SIgA significantly increased and Ii chain was degraded into smaller intermediates, while SIgA decreased when CTSL was knockdown or inhibited with E64. To confirm the SIgA responses promoted by CTSL contribute to the resistance to mycoplasma pneumonia, pigs injected with rCTSL before they were challenged with M.hp, showed milder clinical symptoms and histopathological damage of lungs, less mycoplasma burden together with higher secretion of SIgA, percentages of CD4+ T cells and level of MHC II molecules comparing with the group without rCTSL. Collectively, these results suggested that rCTSL could provide effective protection for piglets against mycoplasma pneumonia by enhancing M.hp-specific mucosal immune responses through its role in antigen presentation by processing the invariant chain.


Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Catepsina L/farmacología , Inmunidad Mucosa/efectos de los fármacos , Inmunoglobulina A/inmunología , Mycoplasma hyopneumoniae/inmunología , Neumonía Porcina por Mycoplasma/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Catepsina L/inmunología , Femenino , Antígenos de Histocompatibilidad Clase II/inmunología , Masculino , Neumonía Porcina por Mycoplasma/tratamiento farmacológico , Neumonía Porcina por Mycoplasma/patología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacocinética , Porcinos
19.
J Immunol ; 202(10): 2856-2872, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-30936293

RESUMEN

CD4 T cell activation is critical to the initiation of adaptive immunity. CD4 T cells are also the main targets of HIV infection, and their activation status contributes to the maintenance and outcome of infection. Although the role of activation in the differentiation and proliferation of CD4 T cells is well studied, its impact on the processing and MHC class I (MHC-I) presentation of epitopes and immune recognition by CD8 T cells are not investigated. In this study, we show that the expression and hydrolytic activities of cellular peptidases are increased upon TCR-dependent and MHC-peptide activation of primary CD4 T cells from healthy or HIV-infected persons. Changes in peptidase activities altered the degradation patterns of HIV Ags analyzed by mass spectrometry, modifying the amount of MHC-I epitopes produced, the antigenicity of the degradation products, and the coverage of Ags by degradation peptides presentable by MHC-I. The computational analysis of 2237 degradation peptides generated during the degradation of various HIV-antigenic fragments in CD4 T cells identified cleavage sites that were predictably enhanced, reduced, or unchanged upon cellular activation. Epitope processing and presentation by CD4 T cells may be modulated by the activation state of cells in a sequence-dependent manner. Accordingly, cellular activation modified endogenous Ag processing and presentation and killing of HIV-infected CD4 T cells by CD8 T cells in a way that mirrored differences in in vitro epitope processing. The clearance of HIV-infected cells may rely on different immune responses according to activation state during HIV infection.


Asunto(s)
Presentación de Antígeno , Antígenos Virales/inmunología , Linfocitos T CD4-Positivos/inmunología , Proliferación Celular , Epítopos de Linfocito T/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Adulto , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Femenino , Infecciones por VIH/patología , Humanos , Masculino , Persona de Mediana Edad
20.
Cell Physiol Biochem ; 52(2): 354-367, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30816679

RESUMEN

BACKGROUND/AIMS: Although a cross-talk between immune and endocrine systems has been well established, the precise pathways by which these signals co-regulate pro- and antiinflammatory responses on antigen-presenting cells remain poorly understood. In this work we investigated the mechanisms by which triiodothyronine (T3) controls T cell activity via dendritic cell (DC) modulation. METHODS: DCs from wild-type (WT) and IL-6-deficient mice were pulsed with T3. Cytokine production and programmed death protein ligands (PD-L) 1 and 2 expression were assayed by flow cytometry and ELISA. Interferon-regulatory factor-4 (IRF4) expression was evaluated by RT-qPCR and flow cytometry. The ability of DCs to stimulate allogenic splenocytes was assessed in a mixed lymphocyte reaction and the different profile markers were analyzed by flow cytometry and ELISA. For in vivo experiments, DCs treated with ovalbumin and T3 were injected into OTII mice. Proliferation, cytokine production, frequency of FoxP3+ regulatory T (Treg) cells and PD-1+ cells were determined by MTT assay, ELISA and flow cytometry, respectively. RESULTS: T3 endows DCs with pro-inflammatory potential capable of generating IL-17-dominant responses and down-modulating expression of PD-L1 and 2. T3-stimulated WT-DCs increased the proportion of IL-17-producing splenocytes, an effect which was eliminated when splenocytes were incubated with T3-treated DCs derived from IL-6-deficient mice. Enhanced IL-17 expression was recorded in both, CD4- and CD4+ populations and involved the IRF-4 pathway. Particularly, γδ-T cells but not natural killer (NK), NKT, B lymphocytes nor CD8+ T cells were the major source of IL-17-production from CD4- cells. Moreover, T3-conditioned DCs promoted a decrease of the FoxP3+ Treg population. Furthermore, T3 down-modulated PD-1 expression on CD4- cells thereby limiting inhibitory signals driven by this co-inhibitory pathway. Thus, T3 acts at the DC level to drive proinflammatory responses in vitro. Accordingly, we found that T3 induces IL-17 and IFNγ-dominant antigen-specific responses in vivo. CONCLUSION: These results emphasize the relevance of T3 as an additional immune-endocrine checkpoint and a novel therapeutic target to modulate IL-17-mediated pro-inflammatory responses.


Asunto(s)
Células Dendríticas/inmunología , Interleucina-17/inmunología , Transducción de Señal/efectos de los fármacos , Triyodotironina/farmacología , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células Dendríticas/patología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Interleucina-17/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Ratones , Ratones Noqueados , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Proteína 2 Ligando de Muerte Celular Programada 1/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Transducción de Señal/inmunología
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