60 research outputs found
IL-17RA-signaling modulates CD8+ T Cell survival and exhaustion during trypanosoma cruzi infection
The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms that are not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes, and their survival and ability to mount cytotoxic responses are orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. The absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells, while in vitro recombinant IL-17 down-regulated the pro-Apoptotic protein BAD and promoted the survival of activated CD8+ T cells. Phenotypic, functional, and transcriptomic profiling showed that T. cruzi-specific CD8+ T cells derived from IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.Fil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Araujo Furlan, Cintia Liliana. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Fiocca Vernengo, Facundo. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Rodriguez, Constanza. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Ramello, MarĂa Cecilia. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Amezcua Vesely, Maria Carolina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Gorosito Serran, Melisa. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Nuñez, Nicolás G.. Institute Curie; Francia. Institut National de la SantĂ© et de la Recherche MĂ©dicale; FranciaFil: Richer, Wilfrid. Institut National de la SantĂ© et de la Recherche MĂ©dicale; Francia. Institute Curie; FranciaFil: Piaggio, Eliane. Institut National de la SantĂ© et de la Recherche MĂ©dicale; Francia. Institute Curie; FranciaFil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Gruppi, Adriana. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentin
The induction and function of the anti-inflammatory fate of TH17 cells
TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-β signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.Fil: Xu, Hao. University of Yale. School of Medicine; Estados UnidosFil: Agalioti, Theodora. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Zhao, Jun. University of Yale. School of Medicine; Estados UnidosFil: Steglich, Babett. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Wahib, Ramez. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Amezcua Vesely, Maria Carolina. University of Yale. School of Medicine; Estados Unidos. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Bielecki, Piotr. University of Yale. School of Medicine; Estados UnidosFil: Bailis, Will. University of Yale. School of Medicine; Estados UnidosFil: Jackson, Ruaidhri. University of Yale. School of Medicine; Estados UnidosFil: Perez, Daniel. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Izbicki, Jakob. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Licona-LimĂłn, Paula. University of Yale. School of Medicine; Estados UnidosFil: Kaartinen, Vesa. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Geginat, Jens. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Esplugues, Enric. University of Yale. School of Medicine; Estados UnidosFil: Tolosa, Eva. University of Yale. School of Medicine; Estados UnidosFil: Huber, Samuel. University of Yale. School of Medicine; Estados UnidosFil: Flavell, Richard A.. University of Yale. School of Medicine; Estados UnidosFil: Gagliani, Nicola. University Medical Center Hamburg-Eppendorf; Alemani
IL-17RA-Signaling Modulates CD8+ T Cell Survival and Exhaustion During Trypanosoma cruzi Infection
The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms that are not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes, and their survival and ability to mount cytotoxic responses are orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. The absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells, while in vitro recombinant IL-17 down-regulated the pro-apoptotic protein BAD and promoted the survival of activated CD8+ T cells. Phenotypic, functional, and transcriptomic profiling showed that T. cruzi-specific CD8+ T cells derived from IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi
Dynamics of soluble immune mediators in COVID-19 patients from an Argentinean cohort with moderate and severe symptoms
The cytokine storm, a form of systemic inflammatory response syndrome, is one of the most dreadful complications that can occur during COVID-19. The severity of infection is associated at different levels of these immune mediators and many molecules are considered marker of COVID mortality. Because of its central role in the pathogenesis of SARS-CoV-2 infection, the cytokine storm have become a therapeutic target in the treatment of COVID-19 patients.In this work, we aimed at studying the concentration of different pro- and anti-inflammatory cytokines in a cohort of COVID-19 patients from CĂłrdoba (Argentine). The immunological reaction triggered by infection with SARS-CoV-2 mobilizes numerous cytokines, mainly of proinflammatory character. Changes in their levels are associated with the presence of the disease and with a more severe prognosis. Although our data have similarities with those in international reports, the complete profiling of different parameters (cytokine/chemokines, risk factors, epidemiological and clinical characteristics) in the local cases add value by identifying particularities that may be relevant for the management and prognosis during SARS-CoV2 infection in Argentine.Fil: Almada, Laura. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Angiolin, Sofia C.. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Dho, Nicolás. Universidad Nacional de CĂłrdoba; ArgentinaFil: Dutto, Jeremias. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Gazzon, Yamila. Universidad Nacional de CĂłrdoba; ArgentinaFil: Manzone, Clarisa. Universidad Nacional de CĂłrdoba; ArgentinaFil: Marin, Constanza. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Ponce, Nicolás Eric. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Iribarren, Pablo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Cerban, Fabio Marcelo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: MorĂłn, Gabriel. Universidad Nacional de CĂłrdoba; ArgentinaFil: Amezcua Vesely, Carolina. Universidad Nacional de CĂłrdoba; ArgentinaFil: Ana, Yamile. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Cervi, Laura Alejandra. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Chiapello, Laura Silvina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Fozzatt, Laura. Universidad Nacional de CĂłrdoba; ArgentinaFil: Icely, Paula Alejandra. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Maccioni, Mariana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Mena, Cristian Javier. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Motrán, Cristina. Universidad Nacional de CĂłrdoba; ArgentinaFil: RodrĂguez Galán, Cecilia. Universidad Nacional de CĂłrdoba; ArgentinaFil: Stempin, Cinthia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Viano, MarĂa EstefanĂa. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Bertone, M.. Hospital Privado Universitario de CĂłrdoba; ArgentinaFil: Abiega, Claudio Daniel. Hospital Privado Universitario de CĂłrdoba; ArgentinaFil: Escudero, Daiana Sabrina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Hospital Privado Universitario de CĂłrdoba; ArgentinaFil: Kahn, Adrian Mario. Hospital Privado Universitario de CĂłrdoba; ArgentinaFil: Caeiro, Juan Pablo. Hospital Privado Universitario de CĂłrdoba; ArgentinaFil: Arroyo, Daniela Soledad. Hospital Privado Universitario de CĂłrdoba; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Maletto, Belkys AngĂ©lica. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Gruppi, Adriana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Sotomayor, Claudia Elena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaLXVI reuniĂłn anual de la sociedad argentina de investigaciĂłn clĂnica (saic), LXIX reuniĂłn anual de la sociedad argentina de inmunologĂa (sai), LIII reuniĂłn anual de la asociaciĂłn argentina de farmacologĂa experimental (aafe), XI reuniĂłn anual de la asociaciĂłn argentina de nanomedicinas (nanomed-ar)Buenos AiresArgentinaSociedad Argentina de InmunologĂ
IL-17RA Signaling Reduces Inflammation and Mortality during Trypanosoma cruzi Infection by Recruiting Suppressive IL-10-Producing Neutrophils
Members of the IL-17 cytokine family play an important role in protection against pathogens through the induction of different effector mechanisms. We determined that IL-17A, IL-17E and IL-17F are produced during the acute phase of T. cruzi infection. Using IL-17RA knockout (KO) mice, we demonstrate that IL-17RA, the common receptor subunit for many IL-17 family members, is required for host resistance during T. cruzi infection. Furthermore, infected IL-17RA KO mice that lack of response to several IL-17 cytokines showed amplified inflammatory responses with exuberant IFN-Îł and TNF production that promoted hepatic damage and mortality. Absence of IL-17RA during T. cruzi infection resulted in reduced CXCL1 and CXCL2 expression in spleen and liver and limited neutrophil recruitment. T. cruzi-stimulated neutrophils secreted IL-10 and showed an IL-10-dependent suppressive phenotype in vitro inhibiting T-cell proliferation and IFN-Îł production. Specific depletion of Ly-6G+ neutrophils in vivo during T. cruzi infection raised parasitemia and serum IFN-Îł concentration and resulted in increased liver pathology in WT mice and overwhelming wasting disease in IL-17RA KO mice. Adoptively transferred neutrophils were unable to migrate to tissues and to restore resistant phenotype in infected IL-17RA KO mice but migrated to spleen and liver of infected WT mice and downregulated IFN-Îł production and increased survival in an IL-10 dependent manner. Our results underscore the role of IL-17RA in the modulation of IFN-Îł-mediated inflammatory responses during infections and uncover a previously unrecognized regulatory mechanism that involves the IL-17RA-mediated recruitment of suppressive IL-10-producing neutrophils
BAFF Mediates Splenic B Cell Response and Antibody Production in Experimental Chagas Disease
Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Central and South America. It affects 20 million people and about 100 million people are at risk of infection in endemic areas. Some cases have been identified in non-endemic countries as a consequence of blood transfusion and organ transplantation. Chagas disease presents three stages of infection. The acute phase appears one to two weeks after infection and includes fever, swelling around the bite site, enlarged lymph glands and spleen, and fatigue. This stage is characterized by circulating parasites and many immunological disturbances including a massive B cell response. In general, the acute episode self-resolves in about 2 months and is followed by a clinically silent indeterminate phase characterized by absence of circulating parasites. In about one-third of the cases, the indeterminate phase evolves into a chronic phase with clinically defined cardiac or digestive disturbances. Current knowledge suggests that the persistence of parasites coupled with an unbalanced immune response sustain inflammatory response in the chronic stage. We believe that an effective treatment for chronic Chagas disease should combine antiparasitic drugs with immunomodulators aimed at reducing inflammation and autoreactive response. Our findings enlighten a new role of BAFF-BAFF-R signaling in parasite infection that partially controls polyclonal B cell response but not parasitespecific class-switched primary effectors B cells
COVID-19 patients display changes in lymphocyte subsets with a higher frequency of dysfunctional CD8lo T cells associated with disease severity
This work examines cellular immunity against SARS-CoV-2 in patients from Córdoba, Argentina, during two major waves characterized by different circulating viral variants and different social behavior. Using flow cytometry, we evaluated the main lymphocyte populations of peripheral blood from hospitalized patients with moderate and severe COVID-19 disease. Our results show disturbances in the cellular immune compartment, as previously reported in different cohorts worldwide. We observed an increased frequency of B cells and a significant decrease in the frequency of CD3+ T cells in COVID-19 patients compared to healthy donors (HD). We also found a reduction in Tregs, which was more pronounced in severe patients. During the first wave, the frequency of GZMB, CD107a, CD39, and PD-1-expressing conventional CD4+ T (T conv) cells was significantly higher in moderate and severe patients than in HD. During the second wave, only the GZMB+ T conv cells of moderate and severe patients increased significantly. In addition, these patients showed a decreased frequency in IL-2-producing T conv cells. Interestingly, we identified two subsets of circulating CD8+ T cells with low and high CD8 surface expression in both HD and COVID-19 patients. While the percentages of CD8hi and CD8lo T cells within the CD8+ population in HD are similar, a significant increase was observed in CD8lo T cell frequency in COVID-19 patients. CD8lo T cell populations from HD as well as from SARS-CoV-2 infected patients exhibited lower frequencies of the effector cytokine-producing cells, TNF, IL-2, and IFN-γ, than CD8hi T cells. Interestingly, the frequency of CD8lo T cells increased with disease severity, suggesting that this parameter could be a potential marker for disease progression. Indeed, the CD8hi/CD8lo index helped to significantly improve the patient’s clinical stratification and disease outcome prediction. Our data support the addition of, at least, a CD8hi/CD8lo index into the panel of biomarkers commonly used in clinical labs, since its determination may be a useful tool with impact on the therapeutic management of the patients
InmunobiologĂa de los linfocitos B : rol de FcgammaRIIb y BAFF en el control de la sobrevida de los linfocitos B1
Tesis (Dr. en Ciencias QuĂmicas)--Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas, 2012.Fil: Amezcua Vesely, MarĂa Carolina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina.Fil: Amezcua Vesely, MarĂa Carolina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro de InvestigaciĂłn en BioquĂmica ClĂnica e InmunologĂa (CIBICI); Argentina.Los LiB1 representan una poblaciĂłn particular de linfocitos B que pueden ser distinguidos de los LiB convencionales (LiB2) por su fenotipo, localizaciĂłn anatĂłmica y propiedades funcionales. Estas cĂ©lulas representan solo una pequeña fracciĂłn de los LiB esplĂ©nicos, pero constituyen una poblaciĂłn mayoritaria en cavidad pleural y peritoneal. La localizaciĂłn diferencial de los LiB1 les permite ser uno de los primeros tipos celulares que interaccionan con patĂłgenos que atraviesan el epitelio intestinal. Los LiB1 producen la mayorĂa de la IgM sĂ©rica y mucha de la IgA presente en el epitelio intestinal. Estas cĂ©lulas tienen un repertorio de BCR (de la sigla en inglĂ©s B Cell Receptor, receptor para antĂgeno de los linfocitos B) enriquecido en poli-especificidades de baja afinidad para una amplia variedad de antĂgenos. Por todo lo mencionado anteriormente, se sabe que los LiB1 juegan un rol crucial en la temprana y eficiente remociĂłn de patĂłgenos, lo que concomitantemente facilita una optima transiciĂłn entre la inmunidad innata y adaptativa. Los LiB1 secretan espontáneamente Inmunoglobulinas (Igs) y, en comparaciĂłn con los LiB2, tienen una cinĂ©tica más rápida para secretar anticuerpos cuando son activados con lipopolisacárido bacteriano (LPS). Aumentos en el compartimiento de LiB1 se han asociado a fenĂłmenos autoinmunes. AsĂ, altos nĂşmeros LiB1 están presentes en cepas de animales que desarrollan enfermedades autoinmunes, como los ratones NZB/W. Se observĂł que en animales deficientes en la proteĂna SPA-1, hay un aumento en la poblaciĂłn de LiB1 y dicho incremento está acompañado de elevados tĂtulos de anticuerpos contra ADN junto a una nefritis, similar a la que se presenta en el Lupus Eritematoso SistĂ©mico (LES). Se observĂł que animales deficientes en CD22 y en Siglec-G presentan un gran incremento en el nĂşmero de LiB1 y desarrollan autoinmunidad. Por ello, la identificaciĂłn de factores reguladores capaces de controlar diferencialmente la expansiĂłn y sobrevida de LiB1,podrĂan ser importantes herramientas a manipular durante el progreso de una deletĂ©rea respuesta autoinmune. En los Ăşltimos años, FcgammaRIIb, receptor para porciĂłn Fc de la IgG de tipo inhibitorio, emergiĂł como un posible mediador de la sobrevida de los LiB. Este receptor es expresado, como muchos de los receptores para la porciĂłn Fc de IgG, sobre cĂ©lulas mieloides. Sin embargo, FcgammaRIIb es el Ăşnico receptor para la porciĂłn Fc de la IgG expresado por los LiB. Durante el proceso de diferenciaciĂłn de los LiB en cĂ©lulas plasmáticas, se observĂł la disminuciĂłn de la expresiĂłn de muchos marcadores de linaje de LiB como CD19, B220, Igs, etc. FcgammaRIIb es uno de los pocos receptores que no disminuyen su expresiĂłn durante este proceso. Por otra parte, es conocido que el solo entrecruzamiento de FcgammaRIIb induce apoptosis de los LiB y de cĂ©lulas plasmáticas (CP). FcgammaRIIb une complejos inmunes y gatilla asĂ la apoptosis de LiB. Este proceso ocurre de manera independiente de BCR. Podemos concluir entonces que la habilidad de FcgammaRIIb para inducir la apoptosis de los LiB, tiene la potencialidad de actuar en distintos puntos durante etapas de proliferaciĂłn y diferenciaciĂłn de estas cĂ©lulas. Consecuentemente, la deficiencia de FcgammaRIIb puede contribuir al desarrollo de enfermedades autoinmunes como LES, artritis reumatoidea y encefalitis autoinmune experimental. Por otra parte, es conocido que miembros de la familia de factor de necrosis tumoral (TNF), como CD40 y Fas juegan un rol fundamental en el mantenimiento de la sobrevida de LiB. Recientemente, se ha identificado a BAFF, (factor activador de linfocitos B perteneciente a la familia TNF, de la sigla en inglĂ©s, B cell Activating Factor) tambiĂ©n conocido como BLyS, como una citoquina que influye sobre la sobrevida de los LiB. La manipulaciĂłn de la expresiĂłn de BAFF en animales de experimentaciĂłn llevĂł a concluir que alteraciones en la expresiĂłn de dicha citoquina tiene consecuencias en la homeostasis de los LiB. Se observĂł que elevados niveles sĂ©ricos de BAFF, no solo en animales de experimentaciĂłn sino tambiĂ©n en humanos, se asocian con fenĂłmenos de autoinmunidad mediada por anticuerpos y con una alterada selecciĂłn negativa de Linfocitos B. En este trabajo de tesis identificamos que: · Los LiB1 expresan altos niveles de FcgammaRIIb y son más susceptibles, que los LiB2, a la muerte mediada por este receptor. · FcgammaRIIb regula la sobrevida de los LiB1 in vivo.
· La expresiĂłn de FcgammaRIIb en LiB1 es regulada por ligandos de Receptores Tipo Toll (TLR), IL4 y BAFF. · BAFF protege a los LiB1 peritoneales de la apoptosis inducida vĂa FcgammaRIIb. · Los LiB1 peritoneales provenientes de animales BAFF-Tg presentan niveles disminuidos de FcgammaRIIb en condiciones de ¨reposo¨ y de activaciĂłn, y se encuentran protegidos de la muerte mediada vĂa FcgammaRIIb. Los datos obtenidos posicionan a FcgammaRIIb como un receptor clave en el control de la sobrevida de LiB1. Su expresiĂłn puede ser regulada por una citoquina importante en patologĂas autoinmunes mediadas por Acs como es BAFF. Con vista al emergente rol que poseen molĂ©culas capaces de bloquear in vivo la actividad de BAFF, la correcciĂłn de los niveles de expresiĂłn de FcgammaRIIb con estos agentes farmacolĂłgico, provee un efecto adicional, para poder interferir con la patogĂ©nesis de procesos autoinmunes y restaurar de esta manera la tolerancia hacia lo propio.Fil: Amezcua Vesely, MarĂa Carolina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina.Fil: Amezcua Vesely, MarĂa Carolina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro de InvestigaciĂłn en BioquĂmica ClĂnica e InmunologĂa (CIBICI); Argentina
Interleukin-17 mediated immunity during infections with Trypanosoma cruzi and other protozoans
Host resistance during infection with Trypanosoma cruzi, and other protozoans, is dependent on a balanced immune response. Robust immunity against these pathogens requires of the concerted action of many innate and adaptive cell populations including macrophages, neutrophils, dendritic cells, CD4+, and CD8+ T cells and B cells among others. Indeed, during most protozoan infections only a balanced production of inflammatory (TH1) and anti-inflammatory (TH2/regulatory) cytokines will allow the control of parasite spreading without compromising host tissue integrity. The description of TH17 cells, a novel effector helper T cell lineage that produced IL-17 as signature cytokine, prompted the revision of our knowledge about the mechanisms that mediate protection and immunopathology during protozoan infections. In this manuscript we discuss the general features of IL-17 mediated immune responses as well as the cellular sources, effector mechanisms and overall role of IL-17 in the immune response to T. cruzi and other protozoan infections.Fil: Amezcua Vesely, Maria Carolina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Rodriguez, Constanza. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Gruppi, Adriana. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Acosta Rodriguez, Eva Virginia. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentin
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