RESUMEN
Many countries continue to experience pertussis epidemics despite widespread vaccination. Waning protection after booster vaccination has highlighted the need for a better understanding of the immunological factors that promote durable protection. Here we apply systems vaccinology to investigate antibody responses in adolescents in the Netherlands (N = 14; NL) and the United Kingdom (N = 12; UK) receiving a tetanus-diphtheria-acellular pertussis-inactivated poliovirus (Tdap-IPV) vaccine. We report that early antiviral and interferon gene expression signatures in blood correlate to persistence of pertussis-specific antibody responses. Single-cell analyses of the innate response identified monocytes and myeloid dendritic cells (MoDC) as principal responders that upregulate antiviral gene expression and type-I interferon cytokine production. With public data, we show that Tdap vaccination stimulates significantly lower antiviral/type-I interferon responses than Tdap-IPV, suggesting that IPV may promote antiviral gene expression. Subsequent in vitro stimulation experiments demonstrate TLR-dependent, IPV-specific activation of the pro-inflammatory p38 MAP kinase pathway in MoDCs. Together, our data provide insights into the molecular host response to pertussis booster vaccination and demonstrate that IPV enhances innate immune activity associated with persistent, pertussis-specific antibody responses.
Asunto(s)
Vacunas contra Difteria, Tétanos y Tos Ferina Acelular , Difteria , Poliovirus , Tétanos , Tos Ferina , Adolescente , Humanos , Bordetella pertussis , Inmunidad Humoral , Tos Ferina/prevención & control , Difteria/prevención & control , Vacunas Combinadas , Anticuerpos Antibacterianos , Vacuna Antipolio de Virus Inactivados , Vacunación , Inmunización Secundaria , Corynebacterium , Interferones , AntiviralesRESUMEN
Primary immunodeficiencies (PID) are rare, complex diseases that can be characterised by a spectrum of phenotypes, from increased susceptibility to infections to autoimmunity, allergy, auto-inflammatory diseases and predisposition to malignancy. With the introduction of genetic testing in these patients and wider use of next-Generation sequencing techniques, a higher number of pathogenic genetic variants and conditions have been identified, allowing the development of new, targeted treatments in PID. The concept of precision medicine, that aims to tailor the medical interventions to each patient, allows to perform more precise diagnosis and more importantly the use of treatments directed to a specific defect, with the objective to cure or achieve long-term remission, minimising the number and type of side effects. This approach takes particular importance in PID, considering the nature of causative defects, disease severity, short- and long-term complications of disease but also of the available treatments, with impact in life-expectancy and quality of life. In this review we revisit how this approach can or is already being implemented in PID and provide a summary of the most relevant treatments applied to specific diseases.
Asunto(s)
Predisposición Genética a la Enfermedad , Síndromes de Inmunodeficiencia , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/terapia , Medicina de Precisión , Calidad de Vida , Pruebas Genéticas/métodosRESUMEN
C3 is a crucial protein of the complement system. Congenital C3 deficiency is extremely rare and manifests through recurrent, severe infections and should always be considered as a differential diagnosis of recurrent pyogenic infections. We report a case of a patient with a novel C3 gene mutation, responsible for complete C3 deficiency with impaired complement system activation and recurrent infections.
RESUMEN
Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post-vaccination reactogenicity and immunogenicity. Infants were randomised to receive control immunisations (PCV13 and DTaP-IPV-Hib) with or without 4CMenB at 2 and 4 months of age. Blood gene expression and plasma proteins were measured prior to, then 4 h, 24 h, 3 days or 7 days post-vaccination. 4CMenB vaccination was associated with increased expression of ENTPD7 and increased concentrations of 4 plasma proteins: CRP, G-CSF, IL-1RA and IL-6. Post-vaccination fever was associated with increased expression of SELL, involved in neutrophil recruitment. A murine model dissecting the vaccine components found the concomitant regimen to be associated with increased gene perturbation compared with 4CMenB vaccine alone with enhancement of pathways such as interleukin-3, -5 and GM-CSF signalling. Finally, we present transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine.
Asunto(s)
Fiebre/genética , Inmunidad/genética , Vacunas Meningococicas/inmunología , Animales , Análisis Químico de la Sangre , Vacuna contra Difteria, Tétanos y Tos Ferina/efectos adversos , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Femenino , Fiebre/sangre , Fiebre/epidemiología , Fiebre/etiología , Perfilación de la Expresión Génica , Vacunas contra Haemophilus/efectos adversos , Vacunas contra Haemophilus/inmunología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Incidencia , Lactante , Masculino , Infecciones Meningocócicas/prevención & control , Vacunas Meningococicas/efectos adversos , Ratones , Ratones Endogámicos C57BL , Análisis por Micromatrices , Vacunas Neumococicas/efectos adversos , Vacunas Neumococicas/inmunología , Vacuna Antipolio de Virus Inactivados/efectos adversos , Vacuna Antipolio de Virus Inactivados/inmunología , Proteoma/análisis , Transcriptoma , Vacunación/efectos adversos , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/inmunologíaRESUMEN
The prognosis of the association between Breast Cancer (BC) and Meningioma (M) is unknown. To evaluate the survival impact of tumor exposure sequence in patients with both tumors. Patients were divided in groups according to the tumors sequence: BC before M (group 1), synchronous BC + M (group 2) and BC after M (group 3). The SEER database was used. Demographics, meningioma and breast cancer variables were analyzed. The primary outcome was oncological survival. A total of 1715 patients were included (median follow-up:84 months). Group 2 had the shortest survival (median:32 months) and group 1 the longest (median:110 months). On the unadjusted analysis, group 2 had the shortest survival (HR:3.13, 95% CI 1.62-6.04) and adjusted analysis confirmed this finding (HR 3.11, 95% CI 1.58-6.19), with no statistical difference between the metachronous tumors groups. Increasing age (HR:1.13, 95% CI 1.11-1.15, p < 0.005) and grade III meningioma (HR:4.51, 95% CI 1.90-10.69, p < 0.005) were related with lower survival. Meningioma treatment had no influence on the survival (p > 0.05). The association between surgery and radiotherapy in BC treatment improved the outcome (HR 0.37, 95% CI 0.23-0.93, p < 0.05). Grade III meningioma and receptor hormonal status influenced synchronous tumors (p < 0.05) but had no influence on metachronous tumors survival (p > 0.05) on stratified analysis. Synchronous tumors were associated with lower survival. Increasing age had a negative influence on patient survival. Although surgery and radiotherapy for breast cancer had a positive influence in the outcome, meningioma treatment was not related with survival. Grade III meningioma and hormonal receptor status only influenced synchronous tumors patient survival.
Asunto(s)
Neoplasias de la Mama Masculina/mortalidad , Neoplasias de la Mama/mortalidad , Neoplasias Meníngeas/mortalidad , Meningioma/mortalidad , Anciano , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama Masculina/química , Neoplasias de la Mama Masculina/complicaciones , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Neoplasias Meníngeas/complicaciones , Meningioma/complicaciones , Persona de Mediana Edad , Neoplasias Primarias Múltiples/mortalidad , Neoplasias Primarias Secundarias/mortalidad , Estudios RetrospectivosRESUMEN
Immunocompromised children have a higher risk of developing infections and associated higher rates of mortality and morbidity. Although this group could benefit the most from vaccine administration, specific considerations regarding immunisations are required. This review is a summary of the vaccines that are relevant to the immunocompromised host, covering both live and non-live vaccines. The burden of disease, safety, immunogenicity/effectiveness and specific recommendations for each vaccine are described as well as specific guidelines from different organisations.
Asunto(s)
Huésped Inmunocomprometido , Vacunas/efectos adversos , Vacunas/inmunología , Niño , Humanos , Inmunización/métodos , Inmunización/normas , Inmunogenicidad Vacunal , Lactante , Guías de Práctica Clínica como Asunto , Vacunas/administración & dosificación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/efectos adversos , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/normas , Vacunas Vivas no Atenuadas/administración & dosificación , Vacunas Vivas no Atenuadas/efectos adversos , Vacunas Vivas no Atenuadas/inmunología , Vacunas Vivas no Atenuadas/normasRESUMEN
A 14-year-old adolescent presented with a prolonged fever, abnormal liver function, anaemia, thrombocytopaenia, but a good general status. Diagnosis of hemophagocytic lymphohistiocytosis (HLH) was suspected, in spite of the initial indolent course. Secondary causes were excluded, but no specific mutation indicative of primary HLH was found. The patient started with specific therapy, but progressed with reactivations and later with persistently active disease. Haematopoietic stem cell transplantation was not successful and the adolescent died 7 months after diagnosis.