RESUMEN
Endemic Burkitt lymphoma (eBL) is an aggressive B cell cancer characterized by an IgH/c-myc translocation and the harboring of Epstein-Barr virus (EBV). Evidence accumulates that CD4 + T cells might contribute to eBL pathogenesis. Here, we investigate the presence of CD4 + T cells in primary eBL tissue and their potential dichotomous impact on an EBV-infected pre-eBL cell model using ex vivo material and in vitro co-cultures. In addition, we establish a novel method to study the effect of IgH/c-myc translocation in primary B cells by employing a CRISPR/Cas9 knock-in approach to introduce and tag de novo translocation. We unprecedently document that CD4 + T cells are present in primary eBL tumor tissue. Furthermore, we demonstrate that CD4 + T cells on the one hand suppress eBL development by killing pre-eBL cells lacking IgH/c-myc translocation in vitro and on the other hand indirectly promote eBL development by inducing crucial EBV Latency III to Latency I switching in pre-eBL cells. Finally, we show that while the mere presence of an IgH/c-myc translocation does not suffice to escape CD4 + T-cell-mediated killing in vitro, the CD4 + T-cell-mediated suppression of EBV's Latency III program in vivo may allow cells harboring an IgH/c-myc translocation and additional mutations to evade immune control and proliferate by means of deregulated c-myc activity, resulting in neoplasia. Thus, our study highlights the dichotomous effects of CD4 + T cells and the mechanisms involved in eBL pathogenesis, suggests mechanisms of their impact on eBL progression, and provides a novel in vitro model for further investigation of IgH/c-myc translocation.
Asunto(s)
Linfoma de Burkitt , Infecciones por Virus de Epstein-Barr , Linfocitos B/metabolismo , Linfoma de Burkitt/genética , Supervivencia Celular , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4 , HumanosRESUMEN
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy. The two-step BCP-ALL pathogenesis requires in utero-induced chromosomal aberrations and additional mutagenic events for overt leukemia. In mouse models, activation-induced cytidine deaminase (AID/AICDA) was suggested to contribute to BCP-ALL pathogenesis by off-target mutagenic activity. The role of AID in patients, however, remains unclear. Moreover, AID is usually not expressed in precursor B-cells but in germinal center B-cells, where it is induced upon T-helper (Th) cell stimulation. We have previously demonstrated that autologous Th-cells supportively interacted with BCP-ALL-cells. Here, we hypothesize that this interaction additionally induces AID expression in BCP-ALL-cells, leading to off-target mutagenic activity. We show that co-culture with autologous bone marrow Th-cells induced high AICDA expression in primary BCP-ALL-cells. This induction was mediated by a mechanism similar to the induction in mature B-cells involving IL-13/Stat6, CD40L/NF-κB and TGFß/Smad2/3 signaling. Even though Th-cell-induced AID seemed to be active in vitro in a BCP-ALL reporter cell line, extensive mutational signature analysis revealed no major contribution of AID activity to the mutational landscape in BCP-ALL patients. AID activity was neither detected in mutation clusters nor in known AID targets. Moreover, no recurrently mutated gene showed a relevant enrichment of mutations in the AID motif. Together, the lack of AID-induced mutational consequences argues towards a Th-cell-promoted yet AID-independent BCP-ALL pathogenesis and favors therapeutic research focusing on Th-cell-derived support of BCP-ALL-cells rather than AID-induced effects.
Asunto(s)
Médula Ósea/inmunología , Citidina Desaminasa/inmunología , Linfoma de Células B/inmunología , Mutagénesis/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Adulto , Linfocitos B/inmunología , Línea Celular Tumoral , Células Cultivadas , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación/inmunología , Transducción de Señal/inmunología , Adulto JovenRESUMEN
Epstein Barr virus (EBV) is one of the most ubiquitous human pathogens in the world, persistently infecting more than 90% of the adult human population. It drives some of the strongest human CD8+ T cell responses, which can be observed during symptomatic primary infection known as infectious mononucleosis (IM). Despite high viral loads and prolonged CD8+ T cell stimulation during IM, EBV enters latency and is under lifelong immune control in most individuals that experience this disease. We investigated whether changes in T cell function, as frequently characterized by PD-1 up-regulation, occur during IM due to the prolonged exposure to high antigen levels. We readily detected the expansion of PD-1 positive CD8+ T cells together with high frequencies of Tim-3, 2B4, and KLRG1 expression during IM and in mice with reconstituted human immune system components (huNSG mice) that had been infected with a high dose of EBV. These PD-1 positive CD8+ T cells, however, retained proliferation, cytokine production, and cytotoxic abilities. Multiple subsets of CD8+ T cells expanded during EBV infection, including PD-1+Tim-3+KLRG1+ cells that express CXCR5 and TCF-1 germinal center homing and memory markers, and may also contain BATF3. Moreover, blocking the PD-1 axis compromised EBV specific immune control and resulted in virus-associated lymphomagenesis. Finally, PD-1+, Tim-3+, and KLRG1+ CD8+ T cell expansion coincided with declining viral loads during low dose EBV infection. These findings suggest that EBV infection primes PD-1 positive CD8+ T cell populations that rely on this receptor axis for the efficient immune control of this ubiquitous human tumor virus.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Citotóxicos/inmunología , Carga Viral/inmunología , Adulto , Animales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Estudios de Casos y Controles , Citocinas/metabolismo , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/virología , Perfilación de la Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCIDRESUMEN
BACKGROUND: The burden and timeline of posttransplant infections are not comprehensively documented in the current era of immunosuppression and prophylaxis. METHODS: In this prospective study nested within the Swiss Transplant Cohort Study (STCS), all clinically relevant infections were identified by transplant-infectious diseases physicians in persons receiving solid organ transplant (SOT) between May 2008 and December 2014 with ≥12 months of follow-up. RESULTS: Among 3541 SOT recipients, 2761 (1612 kidney, 577 liver, 286 lung, 213 heart, and 73 kidney-pancreas) had ≥12 months of follow-up; 1520 patients (55%) suffered 3520 infections during the first year posttransplantation. Burden and timelines of clinically relevant infections differed between transplantations. Bacteria were responsible for 2202 infections (63%) prevailing throughout the year, with a predominance of Enterobacteriaceae (54%) as urinary pathogens in heart, lung, and kidney transplant recipients, and as digestive tract pathogens in liver transplant recipients. Enterococcus spp (20%) occurred as urinary tract pathogens in kidney transplant recipients and as digestive tract pathogens in liver transplant recipients, and Pseudomonas aeruginosa (9%) in lung transplant recipients. Among 1039 viral infections, herpesviruses predominated (51%) in kidney, liver, and heart transplant recipients. Among 263 fungal infections, Candida spp (60%) prevailed as digestive tract pathogens in liver transplant recipients. Opportunistic pathogens, including Aspergillus fumigatus (1.4%) and cytomegalovirus (6%), were rare, scattering over 12 months across all SOT recipients. CONCLUSIONS: In the current era of immunosuppression and prophylaxis, SOT recipients experience a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria.
Asunto(s)
Enfermedades Transmisibles , Trasplante de Órganos , Estudios de Cohortes , Enfermedades Transmisibles/epidemiología , Humanos , Trasplante de Órganos/efectos adversos , Estudios Prospectivos , Suiza/epidemiología , Receptores de TrasplantesRESUMEN
AIM: The European Network of Excellence for Paediatric Clinical Research, known as the TEDDY Network, carried out a survey to determine the capacity and competence of paediatric centres to perform research studies. METHODS: A cross-sectional, web-based pilot survey was conducted from October 2016 to April 2017 with paediatric clinical research centres in 11 countries: Albania, Austria, Belgium, Denmark, Iceland, Ireland, Italy, Norway, Spain, Switzerland and the United Kingdom. All were registered with the TEDDY Network database. RESULTS: We approached 107 centres and 63 provided data on their experiences and expertise in paediatric clinical trials. Four groups of performance indicators were identified, referring to scientific experience, trial readiness, trial competence, regulatory issues, ethics and patients. Most centres were actively involved in paediatric clinical research: 53 centres (84.1%) had received funds for more than five paediatric studies in the last 5 years, and 42 (66.7%) had a specific clinical trial unit and dedicated study coordinators. We concluded that the European centres we studied had the capability and capacity to conduct paediatric trials, but there was still room for improvement, including enhanced collaboration. CONCLUSION: This pilot survey demonstrated that there is potential for performing paediatric trials across Europe, but improvements are possible.
Asunto(s)
Estudios Transversales , Austria , Bélgica , Niño , Europa (Continente) , Humanos , Islandia , Irlanda , Italia , Noruega , España , Suiza , Reino UnidoRESUMEN
Nasal natural killer/T-cell lymphoma (NNKTL) is closely associated with Epstein-Barr virus (EBV) and is characterized by poor prognosis, resulting from rapid progression of lesions in the affected organs. Recent data have shown that NNKTL is associated with the aberrant expression of cyclin-dependent kinase 1 (CDK1) and its downstream target survivin, but little is known about the functional roles of CDK1 and survivin in NNKTL. In the current study, we show that knockdown of the EBV-encoded oncoprotein latent membrane protein 1 (LMP1) induces downregulation of CDK1 and survivin in NNKTL cells. Immunohistochemistry detected CDK1 and survivin expression in LMP1-positive cells of NNKTL biopsy specimens. Inhibition of CDK1 and survivin in NNKTL cells with several inhibitors led to a dose-dependent decrease in cell proliferation. In addition, the Sp1 inhibitor mithramycin, which can downregulate both CDK1 and survivin, significantly suppressed the growth of established NNKTL in a murine xenograft model. Our results suggest that LMP1 upregulation of CDK1 and survivin may be essential for NNKTL progression. Furthermore, targeting CDK1 and survivin with Sp1 inhibitors such as mithramycin may be an effective approach to treat NNKTL, which is considered to be a treatment-refractory lymphoma.
Asunto(s)
Proteína Quinasa CDC2/metabolismo , Células Asesinas Naturales/metabolismo , Linfoma de Células T/metabolismo , Neoplasias Nasales/metabolismo , Survivin/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína Quinasa CDC2/antagonistas & inhibidores , Proteína Quinasa CDC2/genética , Línea Celular Tumoral , Femenino , Humanos , Células Asesinas Naturales/efectos de los fármacos , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/genética , Masculino , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Persona de Mediana Edad , Neoplasias Nasales/tratamiento farmacológico , Neoplasias Nasales/genética , Plicamicina/administración & dosificación , Interferencia de ARN , Survivin/antagonistas & inhibidores , Survivin/genética , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
A growing body of evidence suggests that the human natural killer (NK)-cell compartment is phenotypically and functionally heterogeneous and is composed of several differentiation stages. Moreover, NK-cell subsets have been shown to exhibit adaptive immune features during herpes virus infection in experimental mice and to expand preferentially during viral infections in humans. However, both phenotype and role of NK cells during acute symptomatic Epstein-Barr virus (EBV) infection, termed infectious mononucleosis (IM), remain unclear. Here, we longitudinally assessed the kinetics, the differentiation, and the proliferation of subsets of NK cells in pediatric IM patients. Our results indicate that acute IM is characterized by the preferential proliferation of early-differentiated CD56(dim) NKG2A(+) immunoglobulin-like receptor(-) NK cells. Moreover, this NK-cell subset exhibits features of terminal differentiation and persists at higher frequency during at least the first 6 months after acute IM. Finally, we demonstrate that this NK-cell subset preferentially degranulates and proliferates on exposure to EBV-infected B cells expressing lytic antigens. Thus, early-differentiated NK cells might play a key role in the immune control of primary infection with this persistent tumor-associated virus.
Asunto(s)
Linfocitos B/virología , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4/inmunología , Mononucleosis Infecciosa/inmunología , Mononucleosis Infecciosa/virología , Células Asesinas Naturales/inmunología , Adolescente , Adulto , Antígeno CD56/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Línea Celular , Proliferación Celular , Niño , Preescolar , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Lactante , Células Asesinas Naturales/citología , Activación de Linfocitos , Adulto JovenRESUMEN
The ability of Epstein-Barr virus (EBV) to establish latency despite specific immune responses and to successfully persist lifelong in the human host shows that EBV has developed powerful strategies and mechanisms to exploit, evade, abolish, or downsize otherwise effective immune responses to ensure its own survival. This chapter focuses on current knowledge on innate immune responses against EBV and its evasion strategies for own benefit and summarizes the questions that remain to be tackled. Innate immune reactions against EBV originate both from the main target cells of EBV and from nontarget cells, which are elements of the innate immune system. Thus, we structured our review accordingly but with a particular focus on the innate recognition of EBV in its two stages in its life cycle, latent state and lytic replication. Specifically, we discuss (I) innate sensing and resulting innate immune responses against EBV by its main target cells, focusing on (i) EBV transmission between epithelial cells and B cells and their life cycle stages; and (ii) elements of innate immunity in EBV's target cells. Further, we debate (II) the innate recognition and resulting innate immune responses against EBV by cells other than the main target cells, focusing on (iii) myeloid cells: dendritic cells, monocytes, macrophages, and neutrophil granulocytes; and (iv) natural killer cells. Finally, we address (III) how EBV counteracts or exploits innate immunity in its latent and lytic life cycle stages, concentrating on (v) TLRs; (vi) EBERs; and (vii) microRNAs.
Asunto(s)
Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Inmunidad Innata , Animales , Linfocitos B/inmunología , Linfocitos B/virología , Células Dendríticas/inmunología , Células Dendríticas/virología , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/genética , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/virología , Macrófagos/inmunología , Macrófagos/virologíaRESUMEN
UNLABELLED: In order to understand and possibly treat B-cell malignancies associated with latent gammaherpesvirus infection, it is vital to understand the factors that control the balance between the two transcriptional states of gammaherpesviruses: latency and lytic replication. We used murine gammaherpesvirus 68 (MHV 68) as a model system to investigate how engagement of endosomal Toll-like receptors (TLRs) impacts reactivation from latency in vitro and establishment of latent infection in vivo. We found that treatment with TLR7 ligand R848 or TLR9 ligand CpG oligodeoxynucleotide (ODN) suppresses reactivation of MHV 68 in vitro. These suppressive effects correlated with the ability to activate cellular transcription factor NF-κB. Downregulation of TLR9 by RNA interference in vitro led to a reduction of nuclear levels of NF-κB p65 and consequently to an increase of spontaneous reactivation in cells latently infected with MHV 68, indicating that the TLR9 pathway suppresses spontaneous reactivation events. In vivo, sustained stimulation of TLR7 by repeated R848 treatment led to an increased frequency of infected splenocytes compared to mock-treated control results. Frequencies of infected splenic B cells in tlr7-/- or tlr9-/- mice after establishment of latency did not differ from those seen with their wild-type counterparts. Nevertheless, MHV 68-infected B cells from tlr9-/- mice showed a higher frequency of reactivation than B cells from wild-type or tlr7-/- mice in ex vivo reactivation assays. Thus, we show a suppressive effect of TLR7 or TLR9 triggering on MHV 68 reactivation that correlates with NF-κB activation and that the mere presence of a functional TLR9 signaling pathway contributes to dampen lytic gammaherpesvirus reactivation in infected cells. IMPORTANCE: A hallmark of gammaherpesviruses is their establishment of latency in B cells that is reversible through lytic reactivation. Latency can result in B-cell malignancies. Activation of the innate immune system is thought to contribute to controlling the switch between the transcriptional states of latency and reactivation. Nevertheless, the mechanisms involved are not clear. Here, we show that engagement of Toll-like receptor 7 (TLR7) and TLR9 suppresses reactivation of murine gammaherpesvirus MHV 68 in vitro and that stimulation of TLR7 in vivo increases the frequency of infected cells. TLR7 and TLR9 are innate immunity sensors of nucleic acids localized in endosomes. Additionally, we demonstrate that impairment of TLR9 signaling in latently infected B cells leads to increased reactivation. Thus, activated endosomal TLR7 and TLR9 pathways play an important role in promoting establishment of latent gammaherpesvirus infection. Counteracting signaling of these pathways allows reactivation and could represent treatment targets in gammaherpesvirus-associated malignancies.
Asunto(s)
Glicoproteínas de Membrana/inmunología , FN-kappa B/inmunología , Rhadinovirus/inmunología , Rhadinovirus/fisiología , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 9/inmunología , Activación Viral , Animales , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Ratones Endogámicos C57BL , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Latencia del VirusRESUMEN
NK cells constitute the first line of defense against pathogens and transformed cells. They mature in secondary lymphoid organs, including tonsils, where common pathogens, such as EBV, enter the host and potentially imprint differentiating cells, which then patrol the body via the blood stream. Therefore, we set out to characterize a distinct human NK cell population in tonsils that produces high amounts of the immunomodulatory and antiviral cytokine IFN-γ. We found that the tonsilar IFN-γ(high) NK cell subset is CD56(bright)NKG2A(+)CD94(+)CD54(+)CD62L(-), is present in tonsils ex vivo and is more mature than other CD56(bright) NK cells in tonsils and less mature than other NK cells in blood, shows very low plasticity even after prolonged cytokine stimulation, accumulates in tonsils of EBV carriers, and is able to potently restrict EBV-induced transformation of B cells. Thus, we characterized a distinct and stable IFN-γ(high) NK cell subpopulation that can specifically restrict malignant transformation of EBV-infected B cells. This subset should be exploited for future development of cell-based therapeutic approaches in EBV-associated malignancies.
Asunto(s)
Linfocitos B/inmunología , Linfocitos B/virología , Infecciones por Virus de Epstein-Barr/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Antígeno CD56/metabolismo , Herpesvirus Humano 4/inmunología , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Interferón gamma/biosíntesis , Interferón gamma/metabolismo , Selectina L/metabolismo , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Subfamília D de Receptores Similares a Lectina de las Células NK/metabolismo , Tonsila Palatina/citología , Tonsila Palatina/inmunologíaRESUMEN
Epstein-Barr virus (EBV) infects >90% of the human population within the first 2 decades of life and establishes reversible latent infection in B cells. The stimuli that lead to switching from latent to lytic EBV infection in vivo are still elusive. Group A streptococci (GAS) are a common cause of bacterial pharyngotonsillitis in children and adolescents and colonize the tonsils and pharynx of up to 20% of healthy children. Thus, concomitant presence of EBV and GAS in the same individual is frequent. Here, we show that EBV carriers who are colonized with GAS shed EBV particles in higher numbers in their saliva, compared with EBV carriers not colonized with GAS. Messenger RNA levels of the master lytic regulatory EBV gene BZLF1 were more frequently detected in tonsils from EBV carriers colonized with GAS than from EBV carriers not colonized. Heat-killed GAS, potentially mimicking GAS colonization, elicited lytic EBV in latently infected lymphoblastoid cell lines (LCLs) partially via Toll-like receptor 2 triggering, as did purified GAS peptidoglycan. Thus, colonization by GAS might benefit EBV by increasing the EBV load in saliva and thereby enhancing the likelihood of EBV spread to other hosts.
Asunto(s)
Portador Sano/virología , Coinfección/microbiología , Coinfección/virología , Infecciones por Virus de Epstein-Barr/virología , Orofaringe/microbiología , Infecciones Estreptocócicas/microbiología , Latencia del Virus , Adolescente , Niño , Preescolar , Infecciones por Virus de Epstein-Barr/complicaciones , Femenino , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/fisiología , Humanos , Masculino , Interacciones Microbianas , Tonsila Palatina/microbiología , ARN Mensajero/análisis , ARN Mensajero/genética , Saliva/virología , Infecciones Estreptocócicas/complicaciones , Streptococcus pyogenes/aislamiento & purificación , Streptococcus pyogenes/fisiología , Transactivadores/análisis , Transactivadores/genética , Esparcimiento de VirusRESUMEN
The pathogenesis of Mycoplasma pneumoniae encephalitis is not established. We report, for the first time, the case of a patient with severe Bickerstaff brain stem encephalitis in whom we detected intrathecal production of M. pneumoniae-specific antibodies, contrasting the findings in another patient with less severe encephalitis in whom we detected intrathecal M. pneumoniae DNA but no specific antibodies. Our observations suggest that intrathecal M. pneumoniae-specific antibody responses may contribute to a more severe course of M. pneumoniae encephalitis.
Asunto(s)
Anticuerpos Antibacterianos/líquido cefalorraquídeo , Tronco Encefálico , Encefalitis/diagnóstico , Mycoplasma pneumoniae/inmunología , Neumonía por Mycoplasma/diagnóstico , Tronco Encefálico/patología , Niño , Humanos , MasculinoRESUMEN
PURPOSE: It is unclear whether dermal fibroblasts are indispensable key players for tissue engineering of dermo-epidermal skin analogs. In this experimental study, we wanted to test the hypothesis that tonsil-derived mesenchymal cells can assume the role of dermal fibroblasts when culturing pigmented skin analogs for transplantation. METHODS: Mesenchymal cells from excised tonsils and keratinocytes, melanocytes, and fibroblasts from skin biopsies were isolated, cultured, and expanded. Melanocytes and keratinocytes were seeded in a ratio of 1:5 onto collagen gels previously populated either with tonsil-derived mesenchymal cells or with autologous dermal fibroblasts. These laboratory engineered skin analogs were then transplanted onto full-thickness wounds of immuno-incompetent rats and analyzed after 3 weeks with regard to macroscopic and microscopic epidermal characteristics. RESULTS: The skin analogs containing tonsil-derived mesenchymal cells showed the same macroscopic appearance as the ones containing dermal fibroblasts. Histologically, features of epidermal stratification, pigmentation, and cornification were identical to those of the controls assembled with autologous dermal fibroblasts. Transmission electron microscopy confirmed these findings. CONCLUSION: These data suggest that human tonsil-derived mesenchymal cells can assume dermal fibroblast functions, indicating that possibly various types of mesenchymal cells can successfully be employed for "skingineering" purposes. This aspect may have clinical implications when sources for dermal fibroblasts are scarce.
Asunto(s)
Fibroblastos/citología , Queratinocitos/citología , Melanocitos/citología , Tonsila Palatina/citología , Trasplante de Piel/métodos , Piel/citología , Ingeniería de Tejidos/métodos , Animales , Células Cultivadas , Dermis/citología , Dermis/trasplante , Femenino , Fibroblastos/trasplante , Prepucio , Humanos , Queratinocitos/trasplante , Masculino , Melanocitos/trasplante , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Microscopía Electrónica de Transmisión/métodos , Modelos Animales , Ratas , Pigmentación de la Piel/fisiología , Heridas y Lesiones/cirugíaRESUMEN
The frequency of HIV mother-to-child transmission in Switzerland is nowadays < 1 %, if the pregnant woman receives successful anti-HIV treatment and the newborn apt post-exposure prophylaxis (PEP) and is not breast-fed. The interdisciplinary approach in arranging the maternal anti-HIV treatment, birth mode and PEP for the child is essential. Nevertheless, HIV infection in the child needs to be considered when it presents with compatible signs and symptoms, as HIV infection of the mother may escape diagnosis.
Asunto(s)
Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Lactancia Materna , Preescolar , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/prevención & control , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Leche Humana/virología , Embarazo , Factores de Riesgo , Suiza , Carga Viral , Replicación ViralRESUMEN
The use and success of antiretroviral treatment in HIV-positive people has led to a reduction of vertical transmission of HIV. Pregnancy in HIV-positive women became more common. The success of prophylactic measures has led to a dramatic change in care of HIV-positive women. Today, a HIV-positive mother giving birth to a HIV-negative child is standard of care in industrialized countries. We describe the impact of an HIV-infection in pregnancy and outline the most important diagnostic and therapeutic aspects.
Asunto(s)
Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/epidemiología , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Cesárea , Estudios Transversales , Quimioterapia Combinada , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Humanos , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Trabajo de Parto Prematuro/epidemiología , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Carga ViralRESUMEN
Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered.
Asunto(s)
Linfocitos B/metabolismo , Linfocitos B/virología , Proteína Quinasa CDC2/genética , Infecciones por Virus de Epstein-Barr/genética , Proteínas Inhibidoras de la Apoptosis/genética , Trastornos Linfoproliferativos/genética , Trasplante de Órganos/efectos adversos , Apoptosis/genética , Proteína Quinasa CDC2/metabolismo , Ciclo Celular/genética , Ciclina B1/genética , Ciclina B1/metabolismo , Infecciones por Virus de Epstein-Barr/etiología , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/virología , Expresión Génica , Herpesvirus Humano 4 , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/metabolismo , Survivin , Transformación Genética , Regulación hacia ArribaRESUMEN
HIV infection is characterized by sustained immune activation, which is reflected by activated T cells and, in particular, by increased levels of phosphorylated STAT proteins. Here, we hypothesized that T-cell activation in HIV infection is partially due to the inability of SOCS-1 and SOCS-3 to control the JAK/STAT pathway. We found higher levels of SOCS-1/3 mRNA levels in CD4(+) T cells of HIV-infected patients than in healthy controls. However, SOCS protein levels were lower, explaining the lack of attenuation of the JAK/STAT pathway. Infection of CD4(+) T cells alone did not activate STATs, while ex vivo infection of PBMC did, indicating that non-T cells critical for shaping the immune response, e.g. DC were responsible for the STAT-1 activation. Supernatants from ex vivo-infected PBMC transferred to CD4(+) T cells induced JAK/STAT activation, pointing to a central role of soluble factors. Notably, over-expression of SOCS-1/3 in CD4(+) T cells prevented JAK/STAT activation. Thus, HIV infection interferes with SOCS-1/3 expression driving immune activation. Sustained immune activation disrupts the lymphoid system and favors HIV replication since HIV preferentially infects activated cells. We speculate that regulating SOCS may be a potential way to counteract immune activation in HIV disease.
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Infecciones por VIH/inmunología , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Adulto , Células Cultivadas , Regulación de la Expresión Génica , Infecciones por VIH/metabolismo , Humanos , Quinasas Janus/metabolismo , Persona de Mediana Edad , ARN Mensajero/genética , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Linfocitos T/inmunologíaRESUMEN
Bacterial translocation from the gut and subsequent immune activation are hallmarks of HIV infection and are thought to determine disease progression. Intestinal barrier integrity is impaired early in acute retroviral infection, but levels of plasma lipopolysaccharide (LPS), a marker of bacterial translocation, increase only later. We examined humanized mice infected with HIV to determine if disruption of the intestinal barrier alone is responsible for elevated levels of LPS and if bacterial translocation increases immune activation. Treating uninfected mice with dextran sodium sulfate (DSS) induced bacterial translocation, but did not result in elevated plasma LPS levels. DSS-induced translocation provoked LPS elevation only when phagocytic cells were depleted with clodronate liposomes (clodrolip). Macrophages of DSS-treated, HIV-negative mice phagocytosed more LPS ex vivo than those of control mice. In HIV-infected mice, however, LPS phagocytosis was insufficient to clear the translocated LPS. These conditions allowed higher levels of plasma LPS and CD8+ cell activation, which were associated with lower CD4+/CD8+ cell ratios and higher viral loads. LPS levels reflect both intestinal barrier and LPS clearance. Macrophages are essential in controlling systemic bacterial translocation, and this function might be hindered in chronic HIV infection.
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Infecciones por VIH/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lipopolisacáridos/metabolismo , Macrófagos/metabolismo , Animales , Bacterias , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Infecciones por VIH/metabolismo , Humanos , Mucosa Intestinal/inmunología , Lipopolisacáridos/inmunología , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Ratones , Carga ViralRESUMEN
BACKGROUND: Fever and chemotherapy-induced neutropenia (FN) is the most frequent potentially lethal complication of therapy in children with cancer. This study aimed to describe serious medical complications (SMC) in children with FN regarding incidence, clinical spectrum, and associated characteristics. PROCEDURE: Pediatric patients presenting with FN induced by non-myeloablative chemotherapy were observed in a prospective multicenter study. SMC was defined as potentially life-threatening complication (PLTC), transfer to the pediatric intensive care unit (PICU), or death. RESULTS: A total of 443 FN episodes were reported from 8 centers. Of these, 411 episodes were reported from 4 centers recruiting consecutively and without bias regarding the risk of complications. They were used for calculation of proportions. An SMC was reported in 23 episodes [5.6%; 95% confidence interval (CI): 3.7-8.1], usually defined by more than one criterion. These were PLTC in 13 episodes, PICU in 22, and death in 3 (mortality, 0.7%; 95% CI: 0.2-2.1). Both a delayed onset of SMC (14 of 23 episodes, 61%) and a biphasic clinical course (11 of 23, 48%) were frequently observed. In a multivariate logistic regression analysis, 4 characteristics were significantly and independently associated with the risk of SMC: diagnosis of acute myeloid leukemia, interval since chemotherapy ≤7 days, severely reduced general condition, and hemoglobin ≥9.0 g/dl at presentation. CONCLUSIONS: In children with FN, SMC were rare, and mortality was very low. Those with SMC often had a delayed onset and biphasic clinical course with secondary deterioration.
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Protocolos de Quimioterapia Combinada Antineoplásica , Fiebre , Leucemia Mieloide Aguda , Neutropenia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Fiebre/inducido químicamente , Fiebre/mortalidad , Alemania , Humanos , Unidades de Cuidados Intensivos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Neutropenia/inducido químicamente , Neutropenia/mortalidad , Estudios Prospectivos , Tasa de Supervivencia , SuizaRESUMEN
UNLABELLED: Our previous study showed that (1)H-magnetic resonance spectroscopy ((1)H-MRS) can detect lipid peaks characteristic for Mycobacterium tuberculosis infection in cerebral lesions of young children; therefore, we aimed to extend and validate the application of (1)H-MRS for the diagnosis of active pulmonary tuberculosis lesions in three adolescent patients. Here, we document lipid peaks characteristic for M. tuberculosis infection by (1)H-MRS from lung tissue surrounding lung cavities of two patients whose sputum samples were positive for acid-fast bacilli by microscopy and positive for M. tuberculosis by genetic testing, indicating active tuberculosis. A similar lipid peak was found also in the pleural effusion of a third patient with concurrent lung cavity compatible with active tuberculosis. However, in a patient with a pyogenic pulmonary abscess, (1)H-MRS of the drained pus displayed different characteristic peaks but no lipid peak at all. CONCLUSION: Our findings further validate (1)H-MRS as a rapid, non-invasive, and specific diagnostic tool for active tuberculosis in children with microbiologically documented infection outside the central nervous system, specifically in the lungs.