RESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease that causes joint destruction. Although its etiology remains unknown, citrullinated proteins have been considered as an auto-antigen able to trigger an inflammatory response in RA. Herein, we modified the classical antigen-induced arthritis (AIA) model by using citrullinated human plasma fibrinogen (hFIB) as an immunogen to investigate the mechanism of inflammation-driven joint damage by citrullinated hFIB in C57BL/6 mice. We found that hFIB-immunized mice showed high serum levels of anti-citrullinated peptides antibodies (ACPAs). Moreover, hFIB immunized mice showed increased mechanical hyperalgesia, massive leukocyte infiltration, high levels of inflammatory mediators, and progressive joint damage after the intra-articular challenge with citrullinated hFIB. Interestingly, hFIB-induced arthritis was dependent on IL-23/IL-17 immune axis-mediated inflammatory responses since leukocyte infiltration and mechanical hyperalgesia were abrogated in Il17ra-/- and Il23a-/- mice. Thus, we have characterized a novel model of experimental arthritis suitable to investigate the contribution of ACPAs and Th17 cell-mediated immune response in the pathogenesis of RA.
Asunto(s)
Artritis/inducido químicamente , Fibrinógeno/toxicidad , Inflamación/inducido químicamente , Interleucina-23/metabolismo , Animales , Citrulinación , Fibrinógeno/química , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoglobulina G , Inflamación/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-23/genética , Masculino , Ratones , Ratones Noqueados , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismoRESUMEN
The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligand highly expressed on TH17 cells, and AHR-deficient CD4+ T cells have impaired production of IL-17A and IL-22. Although AHR activation can exacerbate in vivo TH17 cell-mediated autoimmunity, accumulating data indicate that AHR is a nonpathogenic TH17 marker. Thus it remains unclear how AHR activation is regulated and impacts on the generation of TH17 subsets. Here we demonstrated that AHR pathway is activated during in vitro pathogenic TH17 polarization, but it is quickly downregulated. Under these conditions, additional AHR activation promoted IL-22 but not IL-17A. Interestingly, AHR high sustained expression and IL-17A promotion were only achieved when TGFß1 was present in the culture. In addition to the effect on AHR regulation, TGFß1 presented a dual role by simultaneously suppressing the TH17 pathogenic phenotype acquisition. This latter effect was independent of AHR stimulation, since its activation did not confer a TH17 anti-inflammatory profile and Ahr-/- cells did not upregulate any TH17 pathogenic marker. Through the use of EAE model, we demonstrated that AHR is still functional in encephalitogenic CD4+ T cells and the adoptive transfer of Ahr-/- TH17 cells to recipient mice resulted in milder EAE development when compared to their WT counterparts. Altogether, our data demonstrated that although AHR is highly expressed on in vitro-generated nonpathogenic TH17 cells, its ligation does not shift TH17 cells to an anti-inflammatory phenotype. Further studies investigating the role of AHR beyond TH17 differentiation may provide a useful understanding of the physiopathology of autoimmune diseases.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Receptores de Hidrocarburo de Aril/inmunología , Transducción de Señal/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta1/farmacología , Traslado Adoptivo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Regulación de la Expresión Génica , Humanos , Inmunofenotipificación , Interleucina-17/genética , Interleucina-17/inmunología , Interleucinas/genética , Interleucinas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Fenotipo , Cultivo Primario de Células , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/genética , Células Th17/efectos de los fármacos , Células Th17/patología , Células Th17/trasplante , Interleucina-22RESUMEN
Epidemiological and experimental studies support the idea that helminth infections can induce a protective effect against the development of autoimmune and allergic diseases. In this study we characterized the immune response induced by Strongyloides venezuelensis infection in C57BL/6 mice and then evaluated the effect of a previous contact with this helminth in the outcome of type 1 diabetes. Animals were initially infected with 2000 L3 larvae from S. venezuelensis and euthanized 22 days later. An acute phase, identified by a high amount of eggs per gram of feces, was established between days 7 and 9 post-infection. Recovery from infection was associated with a Th2 polarized response characterized by a significant level of serum IgG1 specific antibodies and also a significant production of IL-5 and IL-10 by spleen cells stimulated with S. venezuelensis soluble antigen. Immunization with soluble S. venezuelensis antigen associated with complete Freund's adjuvant followed by infection with S. venezuelensis protected mice from diabetes development induced by streptozotocin. Protection was characterized by a higher body weight gain, lower glycemic levels, much less severe insulitis and preserved insulin production. Together, these results indicate that S. venezuelensis contributed to protect C57BL/6 mice against experimental diabetes induced by streptozotocin.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Strongyloides/inmunología , Estrongiloidiasis/inmunología , Células Th2/inmunología , Animales , Anticuerpos Antihelmínticos/sangre , Glucemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Tipo 1/inmunología , Heces/parasitología , Insulina/análisis , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Recuento de Huevos de Parásitos , Ratas , Ratas Wistar , Bazo/inmunología , Estreptozocina , Estrongiloidiasis/complicacionesRESUMEN
Cellular immunity is critical for protection against tuberculosis, but its integrity is compromised during undernutrition. The present study was designed to evaluate if the attenuated mycobacterium BCG is a safe vaccine for undernourished individuals. An experimental model of undernutrition was established by subjecting BALB/c mice to dietary restriction. These animals received 70% of the amount of food consumed by the healthy control group and exhibited physiological alterations compatible with malnutrition, including body weight loss, reduced levels of triglycerides and glucose, and reduced lymphocyte numbers. Undernourished mice were immunized with BCG, and the mycobacterial loads in lymph nodes, spleen, liver, lungs, and thymus were determined. A much higher proportion of undernourished mice exhibited bacterial dissemination to the lymph nodes, spleen and liver. In addition, only undernourished animals had bacteria in the lungs and thymus. Concomitant with higher mycobacterial loads and more widespread BCG dissemination in undernourished mice, production of TNF-α, IFN-γ, and IL-10 was also diminished in these mice. Taken together, these results indicate that BCG infection is more severe in undernourished mice. Whether a similar phenomenon exists in undernourished children or not remains to be thoroughly investigated.