Papel del receptor de dopamina D5 expresado en cĂ©lulas del sistema inmune en el desarrollo de esclerosis mĂșltiple.
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Fecha
2013
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Facultad/escuela
Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
RESUMEN: Los linfocitos T (LT) CD4+ son fundamentales en dirigir la respuesta inmune
antĂgeno (Ag)-especĂfica y la tolerancia. Las cĂ©lulas dendrĂticas (DCs) son las
responsables de activar LT vĂrgenes y promover su diferenciaciĂłn hacia el
fenotipo funcional mĂĄs apropiado. Debido a su importante rol en el control de la
inmunidad, la activaciĂłn y diferenciaciĂłn de DCs y LT CD4+ requieren de
mecanismos altamente regulados. Numerosos estudios han demostrado que la
dopamina (DA), no sĂłlo media interacciones en el sistema nervioso, sino que
también puede contribuir a la modulación de la inmunidad. En esta tesis, se
estudiĂł el papel que este neurotransmisor juega como un regulador de la
funciĂłn de DCs y LT CD4+ y su consecuente participaciĂłn en la regulaciĂłn de la
respuesta inmune in vivo. EspecĂficamente, este trabajo se enfoca en el anĂĄlisis
del rol del receptor de DA D5 (D5R) expresado en DCs y LT CD4+ en la
modulación de la función de estas células. Para estudiar in vivo la relevancia de
la expresiĂłn del D5R en ambas poblaciones se utilizĂł un modelo animal de
autoinmunidad, anĂĄlogo a la esclerosis mĂșltiple (EM) en humanos.
Respecto a las DCs, los resultados obtenidos indican que expresan la
maquinaria necesaria para sintetizar y almacenar DA. También expresan los
receptores de DA (DARs) D1R, D2R, D3R y D5R, pero sĂłlo este Ășltimo modula
su expresiĂłn dependiendo del estado de maduraciĂłn de las DCs. La ausencia
del D5R en DCs resulta en una menor producciĂłn de IL-12 e IL-23, y por ende,
una menor capacidad de inducir la expansiĂłn de LT CD4+ Th17. In vivo la
transferencia de DCs deficientes en el D5R (D5RKO) en ratones recipientes
normales (WT) reduce la severidad de la Encefalomielitis Autoinmune
Experimental (EAE), debido a una menor frecuencia de LT CD4+ Th17 que
infiltran el sistema nervioso central (SNC).
Los LT CD4+ vĂrgenes (Tn) y reguladores naturales (nTregs) tambiĂ©n poseen la
maquinaria necesaria para sintetizar y almacenar DA; sin embargo, a nivel de
proteĂna expresan preferencialmente el D1R y el D5R. En Tn la expresiĂłn del
D5R no serĂa importante para la activaciĂłn y diferenciaciĂłn a fenotipos
efectores/reguladores. En nTregs en cambio, la ausencia de este receptor
resulta en una disminución parcial en la actividad supresora de estas células in
vitro e in vivo en el desarrollo de EAE.
En conjunto estos resultados indican que el D5R expresado en DCs es capaz
de modular el desarrollo de una respuesta autoinmune in vivo, promoviendo la
producciĂłn de IL-23 necesaria para la diferenciaciĂłn terminal y expansiĂłn de la
poblaciĂłn Th17. En cambio, el D5R expresado en nTregs favorece parcialmente
la capacidad supresora de éstas células.
ABSTRACT: CD4+ T-cells are central players orchestrating antigen-specific immunity and tolerance. Importantly, dendritic cells (DCs) are responsible for priming T-cells and for promoting their differentiation from naĂŻve CD4+ T-cells into appropriate functional phenotype. Because of their fundamental roles in controlling immunity, activation and differentiation of DCs and CD4+ T-cells require tight regulatory mechanisms. Several studies have shown that dopamine (DA), not only mediate interactions into the nervous system, but it can also contribute to the modulation of immunity. In this thesis, we studied the emerging role of this neurotransmitter as a regulator of DCs and CD4+ T-cells function and its consequent involvement in the regulation of an immune response in vivo. We specially focus the analysis in the role of dopamine receptor D5 (D5R) expressed on DCs and CD4+ T-cells in the initiation, progression and severity of a murine model of multiple sclerosis. DCs express the machinery necessary for DA synthesis and storage as well as D1R, D2R, D3R and D5R dopamine receptors. Notably, only D5R expression decreased during DCs maturation. Deficiency of D5R on DCs results in reduced IL-12 and IL-23 production and consequently attenuated capacity to promote Th17 population expansion. In vivo, D5RKO DCs transferred into wild-type animals were able to reduce the severity of Experimental Autoimmune Encephalomyelitis (EAE), by decreasing the frequency of Th17 cells in the central nervous system (CNS). Both naĂŻve CD4+ T-cells (Tn) and natural regulatory T-cells (nTregs) express the machinery necessary for DA synthesis, but only D1R and D5R were detected in these populations. D5R expression did not play relevant roles in Tn neither in the activation nor in the differentiation to functional phenotypes. However, deficiency of D5R partially reduces the suppressive ability of nTregs in vitro as well as in vivo during EAE progression. Together, these results indicate that D5R expressed on DCs contributes to the development of an autoimmune response in vivo by promoting IL-23 production, which is necessary for the final differentiation and expansion of the Th17 population. On the other hand, expression of D5R on nTregs favours the suppressive capatity of these cells.
ABSTRACT: CD4+ T-cells are central players orchestrating antigen-specific immunity and tolerance. Importantly, dendritic cells (DCs) are responsible for priming T-cells and for promoting their differentiation from naĂŻve CD4+ T-cells into appropriate functional phenotype. Because of their fundamental roles in controlling immunity, activation and differentiation of DCs and CD4+ T-cells require tight regulatory mechanisms. Several studies have shown that dopamine (DA), not only mediate interactions into the nervous system, but it can also contribute to the modulation of immunity. In this thesis, we studied the emerging role of this neurotransmitter as a regulator of DCs and CD4+ T-cells function and its consequent involvement in the regulation of an immune response in vivo. We specially focus the analysis in the role of dopamine receptor D5 (D5R) expressed on DCs and CD4+ T-cells in the initiation, progression and severity of a murine model of multiple sclerosis. DCs express the machinery necessary for DA synthesis and storage as well as D1R, D2R, D3R and D5R dopamine receptors. Notably, only D5R expression decreased during DCs maturation. Deficiency of D5R on DCs results in reduced IL-12 and IL-23 production and consequently attenuated capacity to promote Th17 population expansion. In vivo, D5RKO DCs transferred into wild-type animals were able to reduce the severity of Experimental Autoimmune Encephalomyelitis (EAE), by decreasing the frequency of Th17 cells in the central nervous system (CNS). Both naĂŻve CD4+ T-cells (Tn) and natural regulatory T-cells (nTregs) express the machinery necessary for DA synthesis, but only D1R and D5R were detected in these populations. D5R expression did not play relevant roles in Tn neither in the activation nor in the differentiation to functional phenotypes. However, deficiency of D5R partially reduces the suppressive ability of nTregs in vitro as well as in vivo during EAE progression. Together, these results indicate that D5R expressed on DCs contributes to the development of an autoimmune response in vivo by promoting IL-23 production, which is necessary for the final differentiation and expansion of the Th17 population. On the other hand, expression of D5R on nTregs favours the suppressive capatity of these cells.
Notas
Tesis (Doctor en BiotecnologĂa)
Palabras clave
Receptores de Dopamina., Esclerosis MĂșltiple., Sistema InmunolĂłgico.