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1.
J Infect Dis ; 203(11): 1556-64, 2011 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21592984

RESUMEN

After vaccination of humans with tick-borne encephalitis virus (TBEV) vaccine, the extent of cross-neutralization between viruses of the European, Far Eastern, and Siberian subtypes of TBEV and Omsk hemorrhagic fever virus (OHFV) was analyzed. Hybrid viruses that encode the TBEV surface proteins for representative viruses within all subtypes, and OHFV, were constructed using the West Nile virus (WNV) backbone as vector. These viruses allow for unbiased head-to-head comparison in neutralization assays because they exhibit the antigenic characteristics of the TBEV strains from which the surface proteins were derived and showed equivalent biologic properties in cell culture. Human serum samples derived from a TBEV vaccine trial were analyzed and revealed comparable neutralizing antibody titers against European, Far Eastern, and Siberian subtype viruses, indicating equally potent cross-protection against these TBEV strains and a somewhat reduced but still protective neutralization capacity against more distantly related viruses, such as OHFV.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Reacciones Cruzadas/inmunología , Virus de la Encefalitis Transmitidos por Garrapatas/inmunología , Vacunas Virales/inmunología , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Análisis de Varianza , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/sangre , Línea Celular Tumoral , Chlorocebus aethiops , Clonación Molecular , Virus de la Encefalitis Transmitidos por Garrapatas/genética , Virus de la Encefalitis Transmitidos por Garrapatas/crecimiento & desarrollo , Encefalitis Transmitida por Garrapatas/sangre , Encefalitis Transmitida por Garrapatas/inmunología , Encefalitis Transmitida por Garrapatas/prevención & control , Humanos , Cinética , Persona de Mediana Edad , Datos de Secuencia Molecular , Pruebas de Neutralización , Fenotipo , Alineación de Secuencia , Células Vero , Vacunas Virales/genética , Cultivo de Virus , Virus del Nilo Occidental/genética , Adulto Joven
2.
Eur J Immunol ; 39(11): 3228-38, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19688741

RESUMEN

Mast cells play crucial roles in a variety of normal and pathophysiological processes and their activation has to be tightly controlled. Here, we demonstrate that the protein tyrosine kinase Tec is a crucial regulator of murine mast cell function. Tec was activated upon Fc epsilon RI stimulation of BM-derived mast cells (BMMC). The release of histamine in the absence of Tec was normal in vitro and in vivo; however, leukotriene C(4) levels were reduced in Tec(-) (/) (-) BMMC. Furthermore, the production of IL-4 was severely impaired, and GM-CSF, TNF-alpha and IL-13 levels were also diminished. Finally, a comparison of WT, Tec(-) (/) (-), Btk(-) (/) (-) and Tec(-) (/) (-)Btk(-) (/) (-) BMMC revealed a negative role for Btk in the regulation of IL-4 production, while for the efficient production of TNF-alpha, IL-13 and GM-CSF, both Tec and Btk were required. Our results demonstrate a crucial role for Tec in mast cells, which is partially different to the function of the well-characterized family member Btk.


Asunto(s)
Mastocitos/enzimología , Mastocitos/inmunología , Proteínas Tirosina Quinasas/inmunología , Proteínas Tirosina Quinasas/metabolismo , Agammaglobulinemia Tirosina Quinasa , Animales , Separación Celular , Citocinas/biosíntesis , Femenino , Citometría de Flujo , Immunoblotting , Masculino , Ratones , Ratones Noqueados
3.
Immunol Lett ; 109(2): 165-74, 2007 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-17368809

RESUMEN

The molecular mechanisms that regulate DC differentiation and subset distribution are largely unknown. In this study we report the identification of the C(2)H(2) zinc finger transcription factors (TF) CTCF as a regulator of DC differentiation. CTCF was expressed in human and murine DC and its expression was downregulated during the differentiation of human monocyte-derived DC. Enforced expression of CTCF during the differentiation of murine BM-derived DC (BMDC) caused increased apoptosis and reduced proliferation leading to a dramatically reduced number of CTCF transduced DC. The CTCF expressing BMDC that developed had a more immature phenotype than control cells, and showed defects in maturation upon TLR stimulation. Furthermore, in vivo expression of CTCF led to an increase in the percentage of plasmacytoid DC (pDC) within the DC lineage. Our data provide new insight into molecular mechanisms regulating DC differentiation and subset development and identify CTCF as a factor involved in the regulation of these important processes.


Asunto(s)
Proteínas de Unión al ADN/inmunología , Células Dendríticas/citología , Proteínas Represoras/inmunología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Factor de Unión a CCCTC , Diferenciación Celular/inmunología , Procesos de Crecimiento Celular/inmunología , Supervivencia Celular/inmunología , Proteínas de Unión al ADN/biosíntesis , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Regulación hacia Abajo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas Represoras/biosíntesis , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Factores de Transcripción/genética , Dedos de Zinc
4.
Vaccine ; 32(20): 2375-81, 2014 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-24613521

RESUMEN

BACKGROUND: Intervals longer than recommended are frequently encountered between doses of tick borne encephalitis virus (TBE) vaccines in both residents of and travelers to endemic regions. In clinical practice the management of individuals with lapsed TBE vaccination schedules varies widely and has in common that the underlying immunological evidence is scarce. STUDY PURPOSE AND METHODS: The aim of this study was to generate data reliable enough to derive practical recommendations on how to continue vaccination with FSME-IMMUN in subjects with an irregular TBE vaccination history. Antibody response to a single catch-up dose of FSME-IMMUN was assessed in 1115 adults (age ≥16 years) and 125 children (age 6-15 years) with irregular TBE vaccination histories. RESULTS: Subjects of all age groups developed a substantial increase in geometric mean antibody concentration after a single catch-up TBE vaccination which was consistently lower in subjects with only one previous TBE vaccination compared to subjects with two or more vaccinations. Overall, >94% of young adults and children, and >93% of elderly subjects with an irregular TBE vaccination history achieved antibody levels ≥25U/ml irrespective of the number of previous TBE vaccinations. CONCLUSION: We conclude that TBE vaccination of subjects with irregular vaccination histories should be continued as if the previous vaccinations had been administered in a regular manner, with the stage of the vaccination schedule being determined by the number of previous vaccinations. Although lapsed vaccination schedules may leave subjects temporarily with inadequate protection against TBE infection, adequate protection can quickly be re-established in >93% of the subjects by a single catch-up dose of FSME-IMMUN, irrespective of age, number of previous vaccinations, and time interval since the last vaccination.


Asunto(s)
Encefalitis Transmitida por Garrapatas/prevención & control , Esquemas de Inmunización , Inmunización Secundaria , Vacunas Virales/administración & dosificación , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto Joven
5.
J Immunol ; 180(12): 8048-56, 2008 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-18523268

RESUMEN

Tec family kinases have important roles in lymphocytes; however, little is known about their function in monocytes/macrophages. In this study we report that Tec family kinases are essential for M-CSF (M-CSF)-induced signaling pathways that regulate macrophage survival. Compared with wild-type bone marrow-derived macrophage (BMM) cultures, Tec(-/-)Btk(-/-) BMM cultures displayed increased cell death that correlated with a severe drop in macrophage numbers. In addition, macrophages deficient in either Tec or Btk showed expression and activation of caspase-11. Elucidation of M-CSF receptor (M-CSFR) signaling pathways revealed that the total tyrosine phosphorylation pattern upon M-CSF stimulation was altered in Tec(-/-)Btk(-/-) macrophages despite normal expression and phosphorylation of the M-CSFR. Further, Tec and Btk are required for proper expression of the GM-CSF receptor alpha (GM-CSFRalpha) chain in macrophages but not dendritic cells, implicating Tec family kinases in the lineage-specific regulation of GM-CSFRalpha expression. Taken together, our study shows that Tec and Btk regulate M-CSFR signaling-induced macrophage survival and provides a novel link between Tec family kinases and the regulation of caspase-11 and GM-CSFRalpha expression.


Asunto(s)
Macrófagos Peritoneales/citología , Macrófagos Peritoneales/enzimología , Proteínas Tirosina Quinasas/fisiología , Receptor de Factor Estimulante de Colonias de Macrófagos/fisiología , Transducción de Señal/inmunología , Agammaglobulinemia Tirosina Quinasa , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/enzimología , Células de la Médula Ósea/inmunología , Caspasas/biosíntesis , Caspasas/genética , Caspasas Iniciadoras , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Factor Estimulante de Colonias de Macrófagos/fisiología , Macrófagos Peritoneales/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Familia de Multigenes/inmunología , Células Mieloides/citología , Células Mieloides/enzimología , Células Mieloides/inmunología , Subunidades de Proteína/biosíntesis , Subunidades de Proteína/genética , Subunidades de Proteína/fisiología , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Receptor de Factor Estimulante de Colonias de Macrófagos/biosíntesis , Receptor de Factor Estimulante de Colonias de Macrófagos/genética
6.
Nat Immunol ; 7(4): 392-400, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16491076

RESUMEN

Coreceptor expression is tightly regulated during thymocyte development. Deletion of specific Cd8 enhancers leads to variegated expression of CD8alphabeta heterodimers in double-positive thymocytes. Here we show CD8 variegation is correlated with an epigenetic 'off' state, linking Cd8 enhancer function with chromatin remodeling of the adjacent genes Cd8a and Cd8b1 (Cd8). The zinc finger protein MAZR bound the Cd8 enhancer and interacted with the nuclear receptor corepressor N-CoR complex in double-negative thymocytes. MAZR was downregulated in double-positive and CD8 single-positive thymocytes. 'Enforced' expression of MAZR led to impaired Cd8 activation and variegated CD8 expression. Our results demonstrate epigenetic control of the Cd8 loci and identify MAZR as an important regulator of Cd8 expression.


Asunto(s)
Antígenos CD8/biosíntesis , Proteínas de Neoplasias/metabolismo , Proteínas Represoras/metabolismo , Linfocitos T/inmunología , Animales , Antígenos CD8/genética , Antígenos CD8/inmunología , Cromatina/inmunología , Metilación de ADN , Regulación hacia Abajo , Ensayo de Cambio de Movilidad Electroforética , Elementos de Facilitación Genéticos/inmunología , Epigénesis Genética , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Linfocitos T/citología , Transcripción Genética
7.
J Immunol ; 174(3): 1513-24, 2005 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-15661911

RESUMEN

Several developmental stage-, subset-, and lineage-specific Cd8 cis-regulatory regions have been identified. These include the E8(III) enhancer, which directs expression in double-positive (DP) thymocytes, and E8(II), which is active in DP cells and CD8(+) T cells. Using a transgenic reporter expression assay, we identified a 285-bp core fragment of the E8(III) enhancer that retains activity in DP thymocytes. In vitro characterization of the core enhancer revealed five regulatory elements that are required for full enhancer activity, suggesting that multiple factors contribute to the developmental stage-specific activity. Furthermore, deletion of E8(III) in the mouse germline showed that this enhancer is required for nonvariegated expression of CD8 in DP thymocytes when E8(II) is also deleted. These results indicate that E8(III) is one of the cis-elements that contribute to the activation of the Cd8a and Cd8b gene complex during T cell development.


Asunto(s)
Antígenos CD4/biosíntesis , Antígenos CD8/biosíntesis , Antígenos CD8/genética , Elementos de Facilitación Genéticos/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timo/inmunología , Timo/metabolismo , Animales , Sitios de Unión/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Línea Celular , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Elementos E-Box/genética , Eliminación de Gen , Regulación de la Expresión Génica , Marcación de Gen , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-myb/metabolismo , Subgrupos de Linfocitos T/citología , Timo/citología
8.
Int Arch Allergy Immunol ; 134(1): 65-78, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15133303

RESUMEN

Members of the Tec kinase family (Bmx, Btk, Itk, Rlk and Tec) are primarily expressed in the hematopoietic system and form, after the Src kinase family, the second largest class of non-receptor protein tyrosine kinases. During lymphocyte development and activation Tec kinases have important functions in signaling pathways downstream of the antigen receptors. Tec family kinases are also expressed in cells of the myeloid lineage. However, with the exception of mast cells and platelets, their biological role in the myeloid system is only poorly understood. This review summarizes the current knowledge about the function of Tec family kinases in hematopoietic cells of the myeloid lineage.


Asunto(s)
Células Mieloides/enzimología , Proteínas Tirosina Quinasas/fisiología , Plaquetas/enzimología , Células Dendríticas/enzimología , Activación Enzimática/fisiología , Células Eritroides/enzimología , Humanos , Mastocitos/enzimología , Transducción de Señal/fisiología
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