RESUMEN

Mycobacterium tuberculosis (MTB) is known for its adaptive capability in developing resistance to antibiotics, through the selection of spontaneous mutations that arise during treatment. Generating spontaneous antibiotic-resistant mutants in vitro is challenging but necessary for studying this phenomenon. A protocol was designed and tested to select stable, MTB spontaneous, d-cycloserine (DCS) resistant mutants. Twenty-four colonies resistant to DCS were selected, demonstrating an increase between 1 and 4 times the Minimum Inhibitory Concentration (MIC) set for Mycobacterium tuberculosis H37Rv ATCC 27294 reference strain.

RESUMEN

In this work, we model a 5G downlink channel using millimeter-wave (mmWave) and massive Multiple-Input Multiple-Output (mMIMO) technologies, considering the following localization parameters: Time of Arrival (TOA), Two-Dimensional Angle of Departure (2D-AoD), and Two-Dimensional Angle of Arrival (2D-AoA), both encompassing azimuth and elevation. Our research focuses on the precise estimation of these parameters within a three-dimensional (3D) environment, which is crucial in Industry 4.0 applications such as smart warehousing. In such scenarios, determining the device localization is paramount, as products must be handled with high precision. To achieve these precise estimations, we employ an adaptive approach built upon the Distributed Compressed Sensing-Subspace Orthogonal Matching Pursuit (DCS-SOMP) algorithm. We obtain better estimations using an adaptive approach that dynamically adapts the sensing matrix during each iteration, effectively constraining the search space. The results demonstrate that our approach outperforms the traditional method in terms of accuracy, speed to convergence, and memory use.

RESUMEN

Extracellular vesicles (EVs) include a heterogeneous group of particles. Microvesicles, apoptotic bodies and exosomes are the most characterized vesicles. They can be distinguished by their size, morphology, origin and molecular composition. To date, increasing studies demonstrate that EVs mediate intercellular communication. EVs reach considerable interest in the scientific community due to their role in diverse processes including antigen-presentation, stimulation of anti-tumoral immune responses, tolerogenic or inflammatory effects. In pathogens, EV shedding is well described in fungi, bacteria, protozoan and helminths parasites. For Trypanosoma cruzi EV liberation and protein composition was previously described. Dendritic cells (DCs), among other cells, are key players promoting the immune response against pathogens and also maintaining self-tolerance. In previous reports we have demonstrate that T. cruzi downregulates DCs immunogenicity in vitro and in vivo. Here we analyze EVs from the in vitro interaction between blood circulating trypomastigotes (Tp) and bone-marrow-derived DCs. We found that Tp incremented the number and the size of EVs in cultures with DCs. EVs displayed some exosome markers and intracellular RNA. Protein analysis demonstrated that the parasite changes the DC protein-EV profile. We observed that EVs from the interaction of Tp-DCs were easily captured by unstimulated-DCs in comparison with EVs from DCs cultured without the parasite, and also modified the activation status of LPS-stimulated DCs. Noteworthy, we found protection in animals treated with EVs-DCs+Tp and challenged with T. cruzi lethal infection. Our goal is to go deep into the molecular characterization of EVs from the DCs-Tp interaction, in order to identify mediators for therapeutic purposes.

Asunto(s)

Enfermedad de Chagas , Exosomas , Vesículas Extracelulares , Trypanosoma cruzi , Animales , Comunicación Celular , Enfermedad de Chagas/terapia

RESUMEN

Lipoteichoic acid (LTA) from Gram-positive bacteria exerts different immune effects depending on the bacterial source from which it is isolated. Lacticaseibacillus rhamnosus GG LTA (LGG-LTA) oral administration reduces UVB-induced immunosuppression and skin tumor development in mice. In the present work, we evaluate the immunomodulatory effect exerted by LGG-LTA in dendritic cells (DC) and T cells, both in vitro and in the gut-associated lymphoid tissue (GALT). During cell culture, LTA-stimulated BMDC increased CD86 and MHC-II expression and secreted low levels of pro and anti-inflammatory cytokines. Moreover, LTA-treated BMDC increased T cell priming capacity, promoting the secretion of IL-17A. On the other hand, in orally LTA-treated mice, a decrease in mature DC (lamina propria and Peyer's patches) was observed. Concomitantly, an increase in IL-12p35 and IFN-γ transcription was presented (lamina propria and Peyer's Patches). Finally, an increase in the number of CD103+ DC was observed in Peyer's patches. Together, our data demonstrate that LGG-LTA activates DC and T cells. Moreover, we show that a Th1-biased immune response is triggered in vivo after oral LTA administration. These effects justify the oral LTA activity previously observed.

Asunto(s)

Células Dendríticas , Linfocitos T , Animales , Lipopolisacáridos/farmacología , Ratones , Ácidos Teicoicos/metabolismo , Ácidos Teicoicos/farmacología

RESUMEN

SUMMARY: The normal morphology of the colon differs among mammal species.The ascending colon presents several types of cells, responsible for carrying different functions for this organ. Among them, the mucus-secreting cells ensure the integrity of the mucosa, local defense, protection against different external factors, inflammatory diseases, cancer, etc. The ascending colon from 5 adult male chinchillas were processed for paraffin embedding and stained with three methods: Goldner's trichrome, PAS reaction, and Alcian blue staining procedure. The results showed that the structure of the ascending colon is similar to the one described in other species, i.e. mucosa, submucosa, muscularis externa, and serosa. Regarding the mucus-secreting cells present in the deeper part of the mucosal crypts (deep crypt secretory or DCS cells) turned out to be different not only morphologically from the surface goblet cells but also regarding the type of mucus synthesized. DCS cells have a multivacuolated, faintly stained cytoplasm with moderately PAS-positive reaction and intensely positive reaction to Alcian blue stain. The mean surface of DCS cells was 521.6 μm2 as compared to 437.9 μm2 for goblet cells (p<0.05). In conclusion, our study describes for the first time in chinchilla (Chinchilla lanigera) the presence of formerly known non-goblet or vacuolated cells, and recently entitled DCS cells in the glandular epithelium of the colon. The understanding of morphological peculiarities in chinchilla may serve as a good basis to understand the pathophysiology of various conditions that may arise.

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RESUMEN: La morfología normal del colon es diferente entre las especies de mamíferos. El colon ascendente presenta varios tipos de células, encargadas de llevar varias funciones a este órgano. Entre ellos, las células secretoras aseguran la integridad de la mucosa, defensa local, protección frente a diferentes factores externos, enfermedades inflamatorias, cáncer, etc. Se procesaron para su inclusión en parafina el colon ascendente de 5 chinchillas machos adultos y se tiñeron con tres métodos: tricrómico de Goldner, reacción PAS y Azul de Alcian. Los resultados mostraron que la estructura de del colon ascendente es similar a la descrita en otras especies, es decir, mucosa, submucosa, muscular externa y serosa. Las células secretoras de la mucosa presente en la parte más profunda de las criptas mucosas (células secretoras de la cripta profunda o células DCS) resultaron ser diferentes morfológicamente de las células caliciformes superficiales, con citoplasma levemente teñido con reacción PAS positiva moderada y reacción intensamente positiva a Azul de Alcian. La superficie media de las células DCS fue de 521,6 μm2 en comparación con 437,9 μm2 de las células caliciformes (p <0,05). En conclusión, nuestro estudio describe por primera vez en chinchilla (Chinchilla lanigera) la presencia de células no caliciformes o vacuoladas anteriormente conocidas, y recientemente denominadas células DCS en el epitelio glandular del colon. La comprensión de las peculiaridades morfológicas de la chinchilla puede servir como una buena base para comprender la fisiopatología de las diversas afecciones.

Asunto(s)

Animales , Chinchilla/anatomía & histología , Colon Ascendente/citología

RESUMEN

BACKGROUND & AIMS: The precise determination of non-alcoholic fatty liver disease (NAFLD) onset is challenging. Thus, the initial hepatic responses to fat accumulation, which may be fundamental to our understanding of NAFLD evolution and clinical outcomes, are largely unknown. Herein, we chronologically mapped the immunologic and metabolic changes in the liver during the early stages of fatty liver disease in mice and compared this with human NAFLD samples. METHODS: Liver biopsies from patients with NAFLD (NAFLD activity score [NAS] 2-3) were collected for gene expression profiling. Mice received a high-fat diet for short periods to mimic initial steatosis and the hepatic immune response was investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays. RESULTS: We observed major immunologic changes in patients with NAS 2-3 and in mice in the initial stages of NAFLD. In mice, these changes significantly increased mortality rates upon drug-induced liver injury, as well as predisposing mice to bacterial infections. Moreover, deletion of Toll-like receptor 4 in liver cells dampened tolerogenesis, particularly in Kupffer cells, in the initial stages of dietary insult. CONCLUSION: The hepatic immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon dietary insult. Priming of liver immune cells by gut-derived Toll-like receptor 4 ligands plays an important role in liver tolerance in initial phases, but continuous exposure to insults may lead to damage and reduced ability to control infections. LAY SUMMARY: Fatty liver is a very common form of hepatic disease, leading to millions of cases of cirrhosis every year. Patients are often asymptomatic until becoming very sick. Therefore, it is important that we expand our knowledge of the early stages of disease pathogenesis, to enable early diagnosis. Herein, we show that even in the early stages of fatty liver disease, there are significant alterations in genes involved in the inflammatory response, suggesting that the hepatic immune system is disturbed even following minor and undetectable changes in liver fat content. This could have implications for the diagnosis and clinical management of fatty liver disease.

RESUMEN

Prevention of secondary damage is an important goal in the treatment of severe neurological conditions, such as major head trauma or stroke. However, there is currently a lack of non-invasive methods for monitoring cerebral physiology. Diffuse optical methods have been proposed as an inexpensive, non-invasive bedside monitor capable of providing neurophysiology information in neurocritical patients. However, the reliability of the technique to provide accurate longitudinal measurement during the clinical evolution of a patient remains largely unaddressed. Here, we report on the translation of a hybrid diffuse optical system combining frequency domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS) for real-time monitoring of cerebral physiology in a neuro intensive care unit (neuro-ICU). More specifically, we present a case study of a patient admitted with a high-grade aneurysmal subarachnoid hemorrhage, who was monitored throughout hospitalization. We show that the neurophysiological parameters measured by diffuse optics at the bedside are consistent with the clinical evolution of the patient at all the different stages following its brain lesion. These data provide support for clinical translation of DOS/DCS as a useful biomarker of neurophysiology in the neuro-ICU, particularly in locations where other clinical resources are limited.

RESUMEN

Introduction: 122,129 dives by 10,358 recreational divers were recorded by dive computers from 11 manufacturers in an exploratory study of how dive profile, breathing gas (air or nitrox [N2/O2] mixes), repetitive diving, gender, age, and dive site conditions influenced observed decompression sickness (DCSobs). Thirty-eight reports were judged as DCS. Overall DCSobs was 3.1 cases/104 dives. Methods: Three dive groups were studied: Basic (live-aboard and shore/dayboat), Cozumel Dive Guides, and Scapa Flow wreck divers. A probabilistic decompression model, BVM(3), controlled dive profile variability. Chi-squared test, t-test, logistic regression, and log-rank tests evaluated statistical associations. Results: (a) DCSobs was 0.7/104 (Basic), 7.6/104 (Guides), and 17.3/104 (Scapa) and differed after control for dive variability (p ≺ 0.001). (b) DCSobs was greater for 22%-29% nitrox (12.6/104) than for 30%-50% nitrox (2.04/104) (p ≤ 0.0064) which did not differ from air (2.97/10104). (c) For daily repetitive dives (≺12-hour surface intervals (SI)), DCS occurred only following one or two dives (4.3/10104 DCSobs; p ≺ 0.001) where SIs were shorter than after three or more dives. (d) For multiday repetitive dives (SIs ≺ 48 hours), DCS was associated with high multiday repetitive dive counts only for Guides (p = 0.0018). (e) DCSobs decreased with age at 3%/year (p ≤ 0.0144). (f) Males dived deeper (p ≺ 0.001) but for less time than females (p ≺ 0.001). Conclusion: Collecting dive profiles with dive computers and controlling for profile variability by probabilistic modeling was feasible, but analytical results require independent confirmation due to limited observed DCS. Future studies appear promising if more DCS cases are gathered, stakeholders cooperate, and identified data collection problems are corrected.

Asunto(s)

Enfermedad de Descompresión/epidemiología , Buceo/estadística & datos numéricos , Adulto , Factores de Edad , Aire , Distribución de Chi-Cuadrado , Intervalos de Confianza , Enfermedad de Descompresión/complicaciones , Femenino , Humanos , Incidencia , Modelos Logísticos , Masculino , México , Microcomputadores , Nitrógeno , Oxígeno , Estudios Prospectivos , Riesgo , Escocia , Factores Sexuales , Estadísticas no Paramétricas , Factores de Tiempo

RESUMEN

The development of new subunit vaccines has promoted the rational design of adjuvants able to induce a strong T-cell activation by targeting specific immune receptors. The S-layer is a (glyco)-proteinaceous envelope constituted by subunits that self-assemble to form a two-dimensional lattice that covers the surface of different species of Bacteria and Archaea. Due to their ability to self-assemble in solution, they are attractive tools to be used as antigen/hapten carriers or adjuvants. Recently, we have demonstrated that S-layer glycoprotein from Lactobacillus kefiri CIDCA 8348 (SLP-8348) enhanced the LPS-induced response on macrophages in a Ca2+-dependent manner, but the receptors involved in these immunomodulatory properties remain unknown. Therefore, we aim to determine the C-type lectin receptors (CLRs) recognizing this bacterial surface glycoprotein as well as to investigate the role of glycans in both the immunogenicity and adjuvant capacity of SLP-8348. Here, using a mild periodate oxidation protocol, we showed that loss of SLP-8348 glycan integrity impairs the cell-mediated immune response against the protein. Moreover, our data indicate that the adjuvant capacity of SLP-8348 is also dependent of the biological activity of the SLP-8348 glycans. In order to evaluate the CLRs involved in the interaction with SLP-8348 an ELISA-based method using CLR-hFc fusion proteins showed that SLP-8348 interacts with different CLRs such as Mincle, SingR3, and hDC-SIGN. Using BMDCs derived from CLR-deficient mice, we show that SLP-8348 uptake is dependent of Mincle. Furthermore, we demonstrate that the SLP-8348-induced activation of BMDCs as well as its adjuvant capacity relies on the presence of Mincle and its signaling adaptor CARD9 on BMDCs, since SLP-8348-activated BMDCs from Mincle-/- or CARD9-/- mice were not capable to enhance OVA-specific response in CD4+ T cells purified from OT-II mice. These findings significantly contribute to the understanding of the role of glycans in the immunomodulation elicited by bacterial SLPs and generate a great opportunity in the search for new adjuvants derived from non-pathogenic microorganisms.

Asunto(s)

Factores Inmunológicos/inmunología , Lactobacillus/inmunología , Lectinas Tipo C/inmunología , Glicoproteínas de Membrana/inmunología , Proteínas de la Membrana/inmunología , Animales , Humanos , Factores Inmunológicos/genética , Lactobacillus/genética , Lectinas Tipo C/genética , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Células RAW 264.7

RESUMEN

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) have co-evolved with humans for thousands of years and are present at a high prevalence in the population worldwide. HSV infections are responsible for several illnesses including skin and mucosal lesions, blindness and even life-threatening encephalitis in both, immunocompetent and immunocompromised individuals of all ages. Therefore, diseases caused by HSVs represent significant public health burdens. Similar to other herpesviruses, HSV-1 and HSV-2 produce lifelong infections in the host by establishing latency in neurons and sporadically reactivating from these cells, eliciting recurrences that are accompanied by viral shedding in both, symptomatic and asymptomatic individuals. The ability of HSVs to persist and recur in otherwise healthy individuals is likely given by the numerous virulence factors that these viruses have evolved to evade host antiviral responses. Here, we review and discuss molecular mechanisms used by HSVs to evade early innate antiviral responses, which are the first lines of defense against these viruses. A comprehensive understanding of how HSVs evade host early antiviral responses could contribute to the development of novel therapies and vaccines to counteract these viruses.

Asunto(s)

Herpesvirus Humano 1/patogenicidad , Herpesvirus Humano 2/patogenicidad , Interacciones Huésped-Patógeno , Evasión Inmune , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 2/inmunología , Humanos

RESUMEN

The human respiratory syncytial virus (hRSV) is the leading cause of pneumonia in infants and produces a significant burden in the elderly. It can also infect and produce disease in otherwise healthy adults and recurrently infect those previously exposed to the virus. Importantly, recurrent infections are not necessarily a consequence of antigenic variability, as described for other respiratory viruses, but most likely due to the capacity of this virus to interfere with the host's immune response and the establishment of a protective and long-lasting immunity. Although some genes encoded by hRSV are known to have a direct participation in immune evasion, it seems that repeated infection is mainly given by its capacity to modulate immune components in such a way to promote non-optimal antiviral responses in the host. Importantly, hRSV is known to interfere with dendritic cell (DC) function, which are key cells involved in establishing and regulating protective virus-specific immunity. Notably, hRSV infects DCs, alters their maturation, migration to lymph nodes and their capacity to activate virus-specific T cells, which likely impacts the host antiviral response against this virus. Here, we review and discuss the most important and recent findings related to DC modulation by hRSV, which might be at the basis of recurrent infections in previously infected individuals and hRSV-induced disease. A focus on the interaction between DCs and hRSV will likely contribute to the development of effective prophylactic and antiviral strategies against this virus.

Asunto(s)

Células Dendríticas/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitial Respiratorio Humano/inmunología , Inmunidad Adaptativa/inmunología , Animales , Células Dendríticas/virología , Humanos , Ganglios Linfáticos/inmunología , Linfocitos T/inmunología

RESUMEN

Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naïve CD4⁺ and CD8⁺ T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles.

RESUMEN

Abstract Introduction: Death concern is a conscious contemplation of the reality of death combined with a negative evaluation of that reality. The Death Concern Scale (DCS) is related to thinking, and death fear or anxiety about death. The aim of the present study was to develop a Farsi version of the DCS and to explore its psychometric properties in a sample of Iranian nurses. Methods: A cross-sectional study was conducted to investigate the reliability, validity, and factorial structure of the Farsi version of the DCS in a convenience sample of 106 Iranian nurses in two hospitals in Tehran, Iran. The nurses completed the DCS, the Collett-Lester Fear of Death Scale (CLFDS), the Death Anxiety Scale (DAS), the Reasons for Death Fear Scale (RDFS), the Death Depression Scale (DDS), and the Death Obsession Scale (DOS). Results: For the DCS, Cronbach's α was 0.77, the Spearman-Brown coefficient 0.63, the Guttman split-half coefficient 0.62, and two-week test-retest reliability 0.77. The DCS correlated at 0.51 with the CLFDS, 0.52 with the DAS, 0.34 with the RDFS, 0.40 with the DDS, and 0.48 with the DOS, indicating good construct and criterion-related validity. The results of an exploratory factor analysis for the DCS identified seven factors, accounting for 64.30% of the variance and indicating considerable heterogeneity in the content of the items. Conclusions: The Farsi version of the DCS has good validity and reliability, and it can be used in clinical, educational, and research settings to assess death concerns in the Iranian society.

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Resumo Introdução: A preocupação com a morte é uma contemplação consciente da realidade da morte combinada com uma avaliação negativa dessa realidade. A Death Concern Scale (DCS) aborda o pensamento, o medo da morte ou a ansiedade em relação à morte. O objetivo deste estudo foi desenvolver uma versão da DCS na língua persa e explorar suas propriedades psicométricas em uma amostra de enfermeiros iranianos. Métodos: Um estudo transversal foi conduzido para investigar a confiabilidade, validade e estrutura fatorial da versão persa da DCS em uma amostra de conveniência de 106 enfermeiros iranianos em dois hospitais de Teerã, no Irã. Os enfermeiros completaram os seguintes instrumentos: DCS, Collett-Lester Fear of Death Scale (CLFDS), Death Anxiety Scale (DAS), Reasons for Death Fear Scale (RDFS), Death Depression Scale (DDS) e Death Obsession Scale (DOS). Resultados: Para a DCS, o α de Cronbach foi 0,77, o coeficiente de Spearman-Brown 0,63, o coeficiente split-half de Guttman 0,62 e a confiabilidade teste-reteste de duas semanas 0,77. A DCS apresentou correlação de 0,51 com CLFDS, 0,52 com DAS, 0,34 com RDFS, 0,40 com DDS e 0,48 com a DOS, indicando a qualidade do construto e a validade dos critérios relacionados. Os resultados de uma análise fatorial exploratória para a DCS identificaram sete fatores, respondendo por 64,30% da variância e indicando uma heterogeneidade considerável no conteúdo dos itens. Conclusões: A versão persa da DCS tem boa validade e confiabilidade e pode ser usada em contextos clínicos, educacionais e de pesquisa para avaliar preocupação com a morte na sociedade iraniana.

Asunto(s)

Humanos , Masculino , Femenino , Adulto , Adulto Joven , Pruebas Psicológicas , Actitud Frente a la Muerte , Ansiedad/diagnóstico , Ansiedad/etiología , Pensamiento , Traducción , Actitud del Personal de Salud , Conocimientos, Actitudes y Práctica en Salud , Reproducibilidad de los Resultados , Análisis Factorial , Miedo , Persona de Mediana Edad , Enfermeras y Enfermeros/psicología

RESUMEN

Artisanal fishermen around the world employ scuba and surface-supplied diving for their livelihoods and often undergo provocative dive profiles due to economic pressures. Consequently, rates of decompression sickness (DCS) are much greater than in recreational scuba divers. Here we present the case of a surface-supplied diving fisherman from the Yucatán Peninsula of Mexico, who suffered a significant episode of spinal DCS and underwent hyperbaric oxygen therapy treatments, with a favorable outcome. Additionally, we review the proposed mechanisms underlying spinal DCS.

Asunto(s)

Enfermedad de Descompresión/etiología , Enfermedad de Descompresión/terapia , Buceo/efectos adversos , Oxigenoterapia Hiperbárica , Traumatismos de la Médula Espinal/etiología , Traumatismos de la Médula Espinal/terapia , Adulto , Animales , Enfermedad de Descompresión/fisiopatología , Peces , Humanos , Masculino , México , Enfermedades Profesionales/etiología , Enfermedades Profesionales/fisiopatología , Enfermedades Profesionales/terapia , Alimentos Marinos , Traumatismos de la Médula Espinal/fisiopatología , Vértebras Torácicas

RESUMEN

We reported thyroid hormone (TH) receptor expression in murine dendritic cells (DCs) and 3,5,3'-triiodothyronine (T3)-dependent stimulation of DC maturation and ability to develop a Th1-type adaptive response. Moreover, an increased DC capacity to promote antigen-specific cytotoxic T-cell activity, exploited in a DC-based antitumor vaccination protocol, was revealed. However, putative effects of the main circulating TH, l-thyroxine (T4) and the mechanisms of TH transport and metabolism at DC level, crucial events for TH action at target cell level, were not known. Herein, we show that T4 did not reproduce those registered T3-dependent effects, finding that may reflect a homoeostatic control to prevent unspecific systemic activation of DCs. Besides, DCs express MCT10 and LAT2 TH transporters, and these cells mainly transport T3 with a favored involvement of MCT10 as its inhibition almost prevented T3 saturable uptake mechanism and reduced T3-induced IL-12 production. In turn, DCs express iodothyronine deiodonases type 2 and 3 (D2, D3) and exhibit both enzymatic activities with a prevalence towards TH inactivation. Moreover, T3 increased MCT10 and LAT2 expression and T3 efflux from DCs but not T3 uptake, whereas it induced a robust induction of D3 with a parallel slight reduction in D2. These findings disclose pivotal events involved in the mechanism of action of THs on DCs, providing valuable tools for manipulating the immunogenic potential of these cells. Furthermore, they broaden the knowledge of the TH mechanism of action at the immune system network.

Asunto(s)

Células Dendríticas/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Triyodotironina/metabolismo , Animales , Transporte Biológico/fisiología , Femenino , Homeostasis/fisiología , Yoduro Peroxidasa/metabolismo , Ratones

RESUMEN

Rotavirus is the most common cause of acute infectious diarrhea in human neonates and infants. However, the studies aimed at dissecting the anti-virus immune response have been mainly performed in adults. Dendritic cells (DCs) play a crucial role in innate and acquired immune responses. Therefore, it is very important to determine the response of neonatal and infant DCs to rotavirus and to compare it to the response of adult DCs. Thus, we determined the response of monocyte-derived DCs from umbilical cord blood (UCB) and adult peripheral blood (PB) to rotavirus in vitro. It was found that the rotavirus and its genome, composed of segmented doubled stranded RNA (dsRNA), induced the activation of neonatal DCs, as these cells up-regulated the levels of CD40, CD86, MHC II, TLR-3 and TLR-4, the production of cytokines IL-6, IL-12/23p40, IL-10, TGF-ß (but not of IL-12p70), and the message for TNF-α and IFN-ß. This activation enabled the neonatal DCs to induce a strong proliferation of allogeneic CD4+ T cells and the production of IFN-γ. Moreover, neonatal DCs could be infected by rotavirus and sustain its replication. Neonatal DCs had a similar response as adult DCs towards rotavirus and its genome. However, adult DCs had a biased pro-inflammatory response compared to neonatal DCs, which showed a biased regulatory profile, as they produced higher levels of IL-10 and TGF-ß, and were less efficient in inducing a Th1 type response. So it can be concluded that rotavirus and its genome can induce the activation of neonatal DCs in spite of their tolerogenic bias.

Asunto(s)

Células Dendríticas/inmunología , Rotavirus/inmunología , Células Cultivadas , Citocinas/metabolismo , Femenino , Sangre Fetal , Citometría de Flujo , Voluntarios Sanos , Humanos , Monocitos/inmunología , Receptores Inmunológicos/análisis

RESUMEN

As it has been established that demethylation of lysine 27 of histone H3 by the lysine-specific demethylase JMJD3 increases immune responses and thus elicits inflammation, we hypothesize that inhibition of JMJD3 may attenuate autoimmune disorders. We found that in vivo administration of GSK-J4, a selective inhibitor of JMJD3 and UTX, ameliorates the severity of experimental autoimmune encephalomyelitis (EAE). In vitro experiments revealed that the anti-inflammatory effect of GSK-J4 was exerted through an effect on dendritic cells (DCs), promoting a tolerogenic profile characterized by reduced expression of costimulatory molecules CD80/CD86, an increased expression of tolerogenic molecules CD103 and TGF-ß1, and reduced secretion of proinflammatory cytokines IL-6, IFN-γ, and TNF. Adoptive transfer of GSK-J4-treated DCs into EAE mice reduced the clinical manifestation of the disease and decreased the extent of inflammatory CD4+ T cells infiltrating the central nervous system. Notably, Treg generation, stability, and suppressive activity were all exacerbated by GSK-J4-treated DCs without affecting Th1 and Th17 cell production. Our data show that GSK-J4-mediated modulation of inflammation is achieved by a direct effect on DCs and that systemic treatment with GSK-J4 or adoptive transfer of GSK-J4-treated DCs ex vivo may be promising approaches for the treatment of inflammatory and autoimmune disorders.

Asunto(s)

Benzazepinas/farmacología , Células Dendríticas/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/prevención & control , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Pirimidinas/farmacología , Traslado Adoptivo , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígeno B7-1/inmunología , Antígeno B7-1/metabolismo , Antígeno B7-2/inmunología , Antígeno B7-2/metabolismo , Western Blotting , Linfocitos T CD4-Positivos/inmunología , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Expresión Génica/efectos de los fármacos , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Cadenas alfa de Integrinas/inmunología , Cadenas alfa de Integrinas/metabolismo , Histona Demetilasas con Dominio de Jumonji/inmunología , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta1/inmunología , Factor de Crecimiento Transformador beta1/metabolismo

RESUMEN

Mast cells (MCs) are tissue resident cells, rich in inflammatory mediators, involved in allergic reactions, and with an increasingly recognized role in immunomodulation. Dendritic cells (DCs), on the other hand, are central to the determination of immune response patterns, being highly efficient antigen-presenting cells that respond promptly to changes in their microenvironment. Here, we show that direct cell contact between immature monocyte-derived DCs (iDCs) and MC bends DCs toward tolerance induction. DCs that had direct contact with MC (MC-iDC) decreased HLA-DR but increased PD-L1 expression and stimulated regulatory T lymphocytes, which expresses FoxP3(+), secrete TGF-ß and IL-10, and suppress the proliferation of mitogen-stimulated naïve T lymphocytes. Furthermore, MC-iDC expressed higher levels of indoleamine-2,3-deoxigenase (IDO), a phenomenon that was blocked by treatment of MC with anti-PD-1 or by the treatment of DCs with anti-PD-L1 or anti-PD-L2, but not by blocking of H1 and H2 histamine receptors on DCs. Contact with MC also increased phosphorylated STAT-3 levels in iDCs. When a STAT-3 inhibitor, JSI-124, was added to the DCs before contact with MC, the MC-iDC recovered their ability to induce allogeneic T cell proliferation and did not increase their IDO expression.

RESUMEN

Measles virus (MeV) represents one of the main causes of death among young children, particularly in developing countries. Upon infection, MeV controls both interferon induction (IFN) and the interferon signaling pathway which results in a severe host immunosuppression that can persists for up to 6 mo after infection. Despite the global biology of MeV infection is well studied, the role of the plasmacytoid dendritic cells (pDCs) during the host innate immune response after measles vaccination remains largely uncharacterized. Here we investigated the role of pDCs, the major producers of interferon in response to viral infections, in the development of adaptive immune response against MeV vaccine. We report that there is a strong correlation between pDCs population and the humoral immune response to Edmonston Zagreb (EZ) measles vaccination in 9-month-old mexican infants. Five infants were further evaluated after vaccination, showing a clear increase in pDCs at baseline, one week and 3 months after immunization. Three months postvaccination they showed increase in memory T-cells and pDCs populations, high induction of adaptive immunity and also observed a correlation between pDCs number and the humoral immune response. These findings suggest that the development and magnitude of the adaptive immune response following measles immunization is directly dependent on the number of pDCs of the innate immune response.

Asunto(s)

Anticuerpos Antivirales/análisis , Células Dendríticas/inmunología , Vacuna Antisarampión/inmunología , Sarampión/inmunología , Inmunidad Adaptativa/inmunología , Adulto , Factores de Edad , Anticuerpos Neutralizantes/análisis , Recuento de Células , Femenino , Humanos , Inmunidad Humoral/inmunología , Inmunidad Innata/inmunología , Lactante , Masculino , Vacuna Antisarampión/efectos adversos , México , Linfocitos T/inmunología , Vacunación , Ensayo de Placa Viral