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1.
Artículo en Inglés | MEDLINE | ID: mdl-39082483

RESUMEN

Hepatic injuries in COVID-19 are not yet fully understood and indirect pathways (without viral replication in the liver) have been associated with the activation of vascular mechanisms of liver injury in humans infected with SARS-CoV-2. Golden Syrian hamsters are an effective model for experimental reproduction of moderate and self-limiting lung disease during SARS-CoV-2 infection. As observed in humans, this experimental model reproduces lesions of bronchointerstitial pneumonia and pulmonary vascular lesions, including endotheliitis (attachment of lymphoid cells to the luminal surface of endothelium). Extrapulmonary vascular lesions are well documented in COVID-19, but such extrapulmonary vascular lesions have not yet been described in the Golden Syrian hamster model of SARS-CoV-2 infection. The study aimed to evaluate microscopic liver lesions in Golden Syrian hamsters experimentally infected with SARS-CoV-2. In total, 38 conventional Golden Syrian hamsters, divided into infected group (n=24) and mock-infected group (n=14), were euthanized at 2-, 3-, 4-, 5-, 7-, 14-, and 15-days post infection with SARS-CoV-2. Liver fragments were evaluated by histopathology and immunohistochemical detection of SARS-CoV-2 Spike S2 antigens. The frequencies of portal vein endotheliitis, lobular activity, hepatocellular degeneration, and lobular vascular changes were higher among SARS-CoV-2-infected animals. Spike S2 antigen was not detected in liver. The main results indicate that SARS-CoV-2 infection exacerbated vascular and inflammatory lesions in the liver of hamsters with pre-existing hepatitis of unknown origin. A potential application of this animal model in studies of the pathogenesis and evolution of liver lesions associated with SARS-CoV-2 infection still needs further evaluation.


Asunto(s)
COVID-19 , Modelos Animales de Enfermedad , Hígado , Mesocricetus , SARS-CoV-2 , Animales , COVID-19/patología , Cricetinae , Hígado/patología , Hígado/virología , Masculino
2.
Front Immunol ; 15: 1347318, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38500881

RESUMEN

Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged.


Asunto(s)
Paracoccidioidomicosis , Ratones , Animales , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1 , Ratones Endogámicos C57BL , Gravedad del Paciente , Inmunoglobulina G
3.
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1569547

RESUMEN

ABSTRACT Hepatic injuries in COVID-19 are not yet fully understood and indirect pathways (without viral replication in the liver) have been associated with the activation of vascular mechanisms of liver injury in humans infected with SARS-CoV-2. Golden Syrian hamsters are an effective model for experimental reproduction of moderate and self-limiting lung disease during SARS-CoV-2 infection. As observed in humans, this experimental model reproduces lesions of bronchointerstitial pneumonia and pulmonary vascular lesions, including endotheliitis (attachment of lymphoid cells to the luminal surface of endothelium). Extrapulmonary vascular lesions are well documented in COVID-19, but such extrapulmonary vascular lesions have not yet been described in the Golden Syrian hamster model of SARS-CoV-2 infection. The study aimed to evaluate microscopic liver lesions in Golden Syrian hamsters experimentally infected with SARS-CoV-2. In total, 38 conventional Golden Syrian hamsters, divided into infected group (n=24) and mock-infected group (n=14), were euthanized at 2-, 3-, 4-, 5-, 7-, 14-, and 15-days post infection with SARS-CoV-2. Liver fragments were evaluated by histopathology and immunohistochemical detection of SARS-CoV-2 Spike S2 antigens. The frequencies of portal vein endotheliitis, lobular activity, hepatocellular degeneration, and lobular vascular changes were higher among SARS-CoV-2-infected animals. Spike S2 antigen was not detected in liver. The main results indicate that SARS-CoV-2 infection exacerbated vascular and inflammatory lesions in the liver of hamsters with pre-existing hepatitis of unknown origin. A potential application of this animal model in studies of the pathogenesis and evolution of liver lesions associated with SARS-CoV-2 infection still needs further evaluation.

4.
Cells ; 12(7)2023 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-37048165

RESUMEN

The COVID-19 pandemic was triggered by the coronavirus SARS-CoV-2, whose peak occurred in the years 2020 and 2021. The main target of this virus is the lung, and the infection is associated with an accentuated inflammatory process involving mainly the innate arm of the immune system. Here, we described the induction of a pulmonary inflammatory process triggered by the intranasal (IN) instillation of UV-inactivated SARS-CoV-2 in C57BL/6 female mice, and then the evaluation of the ability of vitamin D (VitD) to control this process. The assays used to estimate the severity of lung involvement included the total and differential number of cells in the bronchoalveolar lavage fluid (BALF), histopathological analysis, quantification of T cell subsets, and inflammatory mediators by RT-PCR, cytokine quantification in lung homogenates, and flow cytometric analysis of cells recovered from lung parenchyma. The IN instillation of inactivated SARS-CoV-2 triggered a pulmonary inflammatory process, consisting of various cell types and mediators, resembling the typical inflammation found in transgenic mice infected with SARS-CoV-2. This inflammatory process was significantly decreased by the IN delivery of VitD, but not by its IP administration, suggesting that this hormone could have a therapeutic potential in COVID-19 if locally applied. To our knowledge, the local delivery of VitD to downmodulate lung inflammation in COVID-19 is an original proposition.


Asunto(s)
COVID-19 , Neumonía , Ratones , Animales , Femenino , Humanos , SARS-CoV-2 , Vitamina D/farmacología , Pandemias , Ratones Endogámicos C57BL , Vitaminas , Ratones Transgénicos
5.
Cells ; 12(5)2023 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-36899820

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an exceptionally transmissible and pathogenic coronavirus that appeared at the end of 2019 and triggered a pandemic of acute respiratory disease, known as coronavirus disease 2019 (COVID-19). COVID-19 can evolve into a severe disease associated with immediate and delayed sequelae in different organs, including the central nervous system (CNS). A topic that deserves attention in this context is the complex relationship between SARS-CoV-2 infection and multiple sclerosis (MS). Here, we initially described the clinical and immunopathogenic characteristics of these two illnesses, accentuating the fact that COVID-19 can, in defined patients, reach the CNS, the target tissue of the MS autoimmune process. The well-known contribution of viral agents such as the Epstein-Barr virus and the postulated participation of SARS-CoV-2 as a risk factor for the triggering or worsening of MS are then described. We emphasize the contribution of vitamin D in this scenario, considering its relevance in the susceptibility, severity and control of both pathologies. Finally, we discuss the experimental animal models that could be explored to better understand the complex interplay of these two diseases, including the possible use of vitamin D as an adjunct immunomodulator to treat them.


Asunto(s)
COVID-19 , Infecciones por Virus de Epstein-Barr , Esclerosis Múltiple , Animales , SARS-CoV-2 , Herpesvirus Humano 4 , Vitamina D
6.
J Neurochem ; 163(2): 113-132, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35880385

RESUMEN

COVID-19 causes more than million deaths worldwide. Although much is understood about the immunopathogenesis of the lung disease, a lot remains to be known on the neurological impact of COVID-19. Here, we evaluated immunometabolic changes using astrocytes in vitro and dissected brain areas of SARS-CoV-2 infected Syrian hamsters. We show that SARS-CoV-2 alters proteins of carbon metabolism, glycolysis, and synaptic transmission, many of which are altered in neurological diseases. Real-time respirometry evidenced hyperactivation of glycolysis, further confirmed by metabolomics, with intense consumption of glucose, pyruvate, glutamine, and alpha ketoglutarate. Consistent with glutamine reduction, the blockade of glutaminolysis impaired viral replication and inflammatory response in vitro. SARS-CoV-2 was detected in vivo in hippocampus, cortex, and olfactory bulb of intranasally infected animals. Our data evidence an imbalance in important metabolic molecules and neurotransmitters in infected astrocytes. We suggest this may correlate with the neurological impairment observed during COVID-19, as memory loss, confusion, and cognitive impairment.


Asunto(s)
COVID-19 , Animales , Astrocitos , Carbono , Cricetinae , Modelos Animales de Enfermedad , Glucosa , Glutamina , Ácidos Cetoglutáricos , Mesocricetus , Piruvatos , SARS-CoV-2
7.
Immunity ; 54(9): 2024-2041.e8, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34473957

RESUMEN

Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease.


Asunto(s)
Adenosina/inmunología , Antígenos CD/inmunología , Apirasa/inmunología , Tolerancia Inmunológica/inmunología , Macrófagos/inmunología , Células Plasmáticas/inmunología , Sepsis/inmunología , Adenosina/metabolismo , Animales , Antígenos CD/metabolismo , Apirasa/metabolismo , Reprogramación Celular/inmunología , Macrófagos/metabolismo , Ratones , Células Plasmáticas/metabolismo , Receptor de Adenosina A2A/inmunología , Receptor de Adenosina A2A/metabolismo , Sepsis/metabolismo
8.
Int J Mol Sci ; 22(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33671896

RESUMEN

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). MS and its animal model called experimental autoimmune encephalomyelitis (EAE) immunopathogenesis involve a plethora of immune cells whose activation releases a variety of proinflammatory mediators and free radicals. Vitamin D3 (VitD) is endowed with immunomodulatory and antioxidant properties that we demonstrated to control EAE development. However, this protective effect triggered hypercalcemia. As such, we compared the therapeutic potential of VitD and paricalcitol (Pari), which is a non-hypercalcemic vitamin D analog, to control EAE. From the seventh day on after EAE induction, mice were injected with VitD or Pari every other day. VitD, but not Pari, displayed downmodulatory ability being able to reduce the recruitment of inflammatory cells, the mRNA expression of inflammatory parameters, and demyelination at the CNS. Lower production of proinflammatory cytokines by lymph node-derived cells and IL-17 by gut explants, and reduced intestinal inflammation were detected in the EAE/VitD group compared to the EAE untreated or Pari groups. Dendritic cells (DCs) differentiated in the presence of VitD developed a more tolerogenic phenotype than in the presence of Pari. These findings suggest that VitD, but not Pari, has the potential to be used as a preventive therapy to control MS severity.


Asunto(s)
Antioxidantes/administración & dosificación , Colecalciferol/administración & dosificación , Encefalomielitis Autoinmune Experimental/prevención & control , Ergocalciferoles/administración & dosificación , Factores Inmunológicos/administración & dosificación , Profilaxis Posexposición/métodos , Animales , Antioxidantes/farmacología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Colecalciferol/farmacología , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/inmunología , Ergocalciferoles/farmacología , Femenino , Factores Inmunológicos/farmacología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/prevención & control , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
9.
Sci Rep ; 10(1): 22190, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-33335128

RESUMEN

Multiple sclerosis is an autoimmune disease that affects the myelinated central nervous system (CNS) neurons and triggers physical and cognitive disabilities. Conventional therapy is based on disease-modifying drugs that control disease severity but can also be deleterious. Complementary medicines have been adopted and evidence indicates that yeast supplements can improve symptoms mainly by modulating the immune response. In this investigation, we evaluated the therapeutic potential of Saccharomyces cerevisiae and its selenized derivative (Selemax) in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice submitted to EAE induction were orally supplemented with these yeasts by gavage from day 0 to day 14 after EAE induction. Both supplements determined significant reduction in clinical signs concomitantly with diminished Th1 immune response in CNS, increased proportion of Foxp3+ lymphocytes in inguinal and mesenteric lymph nodes and increased microbiota diversity. However, Selemax was more effective clinically and immunologically; it reduced disease prevalence more sharply, increased the proportion of CD103+ dendritic cells expressing high levels of PD-L1 in mesenteric lymph nodes and reduced the intestinal inflammatory process more strongly than S. cerevisiae. These results suggest a clear gut-brain axis modulation by selenized S. cerevisiae and suggest their inclusion in clinical trials.


Asunto(s)
Suplementos Dietéticos , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/metabolismo , Inmunomodulación , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Saccharomyces cerevisiae/inmunología , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Susceptibilidad a Enfermedades , Encefalomielitis Autoinmune Experimental/patología , Tolerancia Inmunológica , Recuento de Linfocitos , Ratones , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
10.
Front Immunol ; 11: 692, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32391011

RESUMEN

Changing the immune responses to allergens is the cornerstone of allergen immunotherapy. Allergen-specific immunotherapy that consists of repeated administration of increasing doses of allergen extract is potentially curative. The major inconveniences of allergen-specific immunotherapy include failure to modify immune responses, long-term treatment leading to non-compliance and the potential for developing life-threating anaphylaxis. Here we investigated the effect of a novel liposomal formulation carrying low dose of allergen combined with CpG-ODN, a synthetic TLR9 agonist, on established allergic lung inflammation. We found that challenge with allergen (OVA) encapsulated in cationic liposome induced significantly less severe cutaneous anaphylactic reaction. Notably, short-term treatment (three doses) with a liposomal formulation containing co-encapsulated allergen plus CpG-ODN, but not allergen or CpG-ODN alone, reversed an established allergic lung inflammation and provided long-term protection. This liposomal formulation was also effective against allergens derived from Blomia tropicalis mite extract. The attenuation of allergic inflammation was not associated with increased numbers of Foxp3-positive or IL-10-producing regulatory T cells or with increased levels of IFN-gamma in the lungs. Instead, the anti-allergic effect of the liposomal formulation was dependent of the innate immune signal transduction generated in CD11c-positive putative dendritic cells expressing MyD88 molecule. Therefore, we highlight the pivotal role of dendritic cells in mediating the attenuation of established allergic lung inflammation following immunotherapy with a liposomal formulation containing allergen plus CpG-ODN.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Alérgenos/administración & dosificación , Asma/inmunología , Células Dendríticas/inmunología , Desensibilización Inmunológica/métodos , Sistemas de Liberación de Medicamentos/métodos , Factor 88 de Diferenciación Mieloide/metabolismo , Oligodesoxirribonucleótidos/administración & dosificación , Transducción de Señal/efectos de los fármacos , Alérgenos/efectos adversos , Anafilaxia/inmunología , Anafilaxia/prevención & control , Animales , Asma/inducido químicamente , Modelos Animales de Enfermedad , Femenino , Técnicas de Inactivación de Genes , Liposomas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Resultado del Tratamiento
11.
Pharmacol Res ; 151: 104580, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31786317

RESUMEN

Neutrophils are peripheral immune cells that represent the first recruited innate immune defense against infections and tissue injury. However, these cells can also induce overzealous responses and cause tissue damage. Although the role of neutrophils activating the immune system is well established, only recently their critical implications in neuro-immune interactions are becoming more relevant. Here, we review several aspects of neutrophils in the bidirectional regulation between the nervous and immune systems. First, the role of neutrophils as a diffuse source of acetylcholine and catecholamines is controversial as well as the effects of these neurotransmitters in neutrophil's functions. Second, neutrophils contribute for the activation and sensitization of sensory neurons, and thereby, in events of nociception and pain. In addition, nociceptor activation promotes an axon reflex triggering a local release of neural mediators and provoking neutrophil activation. Third, the recruitment of neutrophils in inflammatory responses in the nervous system suggests these immune cells as innovative targets in the treatment of central infectious, neurological and neurodegenerative disorders. Multidisciplinary studies involving immunologists and neuroscientists are required to define the role of the neurons-neutrophils communication in the pathophysiology of infectious, inflammatory, and neurological disorders.


Asunto(s)
Neuroinmunomodulación , Neutrófilos/inmunología , Animales , Humanos , Inmunidad Innata , Inflamación/inmunología , Neurotransmisores/inmunología , Nocicepción , Dolor/inmunología , Células Receptoras Sensoriales/inmunología
12.
J Leukoc Biol ; 106(3): 501-503, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31369695

RESUMEN

Discussion on changes in gut microbiota driving the breakdown of mucosal barrier in NOD mice; the resulting inflammation and impairment of oral tolerance induces the autoimmune diabetes.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Animales , Ratones , Ratones Endogámicos NOD , Membrana Mucosa
13.
Cell Rep ; 27(3): 750-761.e7, 2019 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-30995474

RESUMEN

Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection.


Asunto(s)
Butiratos/administración & dosificación , Clostridioides difficile/patogenicidad , Colitis/prevención & control , Factor 1 Inducible por Hipoxia/metabolismo , Administración Oral , Animales , Antibacterianos/farmacología , Butiratos/farmacología , Clostridioides difficile/metabolismo , Colitis/etiología , Colitis/microbiología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Ácidos Grasos Volátiles/metabolismo , Humanos , Insulina/administración & dosificación , Mucosa Intestinal/citología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Uniones Estrechas/metabolismo , Toxinas Biológicas/toxicidad , Triglicéridos/administración & dosificación
14.
Front Immunol ; 8: 1213, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29033934

RESUMEN

The identification of anti-inflammatory mediators can reveal important targetable molecules capable of counterbalancing Trypanosoma cruzi-induced myocarditis. Composed of Ebi3 and IL-27p28 subunits, IL-27 is produced by myeloid cells and is able to suppress inflammation by inducing IL-10-producing Tr1 cells, thus emerging as a potential candidate to ameliorate cardiac inflammation induced by T. cruzi. Although IL-27 has been extensively characterized as a suppressive cytokine that prevents liver immunopathogenesis after T. cruzi infection, the mechanisms underlying its effects on T. cruzi-induced myocarditis remain largely unknown. Here, wild-type (WT) and Ebi3-deficient animals were intraperitoneally infected with trypomastigotes of T. cruzi Y strain and used to evaluate the potential anti-inflammatory properties of Ebi3 during T. cruzi infection. The survival rates of mice were daily recorded, the frequency of inflammatory cells was analyzed by flow cytometry and inflammatory mediators were measured by ELISA, real-time PCR and PCR array. We reported that T. cruzi-induced myocarditis was prevented by Ebi3. Stressors mainly recognized by TLR2 and TLR4 receptors on myeloid cells were essential to trigger IL-27p28 production. In addition, Ebi3 regulated IFN-γ-mediated myocarditis by promoting an anti-inflammatory environment through IL-10, which was most likely produced by Tr1 cells rather than classical regulatory T cells (Tregs), in the heart tissue of T. cruzi-infected animals. Furthermore, in vivo IFN-γ blockade ameliorated the host survival without compromising the parasite control in the bloodstream. In humans, IL-27p28 was correlated with cardiac protection during Chagas disease. Patients with mild clinical forms of the disease produced high levels of IL-27p28, whereas lower levels were found in those with severe forms. In addition, polymorphic sites at Ebi3 gene were associated with severe cardiomyopathy in patients with Chagas disease. Collectively, we describe a novel regulatory mechanism where Ebi3 dampens cardiac inflammation by modulating the overproduction of IFN-γ, the bona fide culprit of Chagas disease cardiomyopathy.

15.
Hum Vaccin Immunother ; 13(5): 1040-1050, 2017 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-28059670

RESUMEN

Previously we showed that 65-kDa Mycobacterium leprae heat shock protein (Hsp65) is a target for the development of a tuberculosis vaccine. Here we evaluated peripheral blood mononuclear cells (PBMC) from healthy individuals or tuberculosis patients stimulated with two forms of Hsp65 antigen, recombinant DNA that encodes Hsp65 (DNA-HSP65) or recombinant Hsp65 protein (rHsp65) in attempting to mimic a prophylactic or therapeutic study in vitro, respectively. Proliferation and cytokine-producing CD4+ or CD8+ cell were assessed by flow cytometry. The CD4+ cell proliferation from healthy individuals was stimulated by DNA-HSP65 and rHsp65, while CD8+ cell proliferation from healthy individuals or tuberculosis patients was stimulated by rHSP65. DNA-HSP65 did not improve the frequency of IFN-gamma+ cells from healthy individuals or tuberculosis patients. Furthermore, we found an increase in the frequency of IL-10-producing cells in both groups. These findings show that Hsp65 antigen activates human lymphocytes and plays an immune regulatory role that should be addressed as an additional antigen for the development of antigen-combined therapies.


Asunto(s)
Proteínas Bacterianas/inmunología , Chaperonina 60/inmunología , Inmunidad Celular , Activación de Linfocitos , Tuberculosis/inmunología , Adulto , Proteínas Bacterianas/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Chaperonina 60/genética , Citotoxicidad Inmunológica , Femenino , Voluntarios Sanos , Humanos , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Leucocitos Mononucleares/inmunología , Macrófagos Alveolares/inmunología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , Proteínas Recombinantes/inmunología , Vacunas contra la Tuberculosis/inmunología , Regulación hacia Arriba , Vacunas de ADN/farmacología , Adulto Joven
16.
Cell ; 163(2): 354-66, 2015 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-26451485

RESUMEN

Infections have been proposed as initiating factors for inflammatory disorders; however, identifying associations between defined infectious agents and the initiation of chronic disease has remained elusive. Here, we report that a single acute infection can have dramatic and long-term consequences for tissue-specific immunity. Following clearance of Yersinia pseudotuberculosis, sustained inflammation and associated lymphatic leakage in the mesenteric adipose tissue deviates migratory dendritic cells to the adipose compartment, thereby preventing their accumulation in the mesenteric lymph node. As a consequence, canonical mucosal immune functions, including tolerance and protective immunity, are persistently compromised. Post-resolution of infection, signals derived from the microbiota maintain inflammatory mesentery remodeling and consequently, transient ablation of the microbiota restores mucosal immunity. Our results indicate that persistent disruption of communication between tissues and the immune system following clearance of an acute infection represents an inflection point beyond which tissue homeostasis and immunity is compromised for the long-term. VIDEO ABSTRACT.


Asunto(s)
Microbioma Gastrointestinal , Enfermedades del Sistema Inmune/microbiología , Enfermedades del Sistema Inmune/patología , Enfermedades Linfáticas/patología , Infecciones por Yersinia pseudotuberculosis/inmunología , Yersinia pseudotuberculosis/fisiología , Movimiento Celular , Enfermedad Crónica , Células Dendríticas/patología , Femenino , Humanos , Enfermedades Linfáticas/microbiología , Tejido Linfoide/inmunología , Tejido Linfoide/patología , Masculino , Mesenterio/inmunología , Mesenterio/patología , Organismos Libres de Patógenos Específicos , Infecciones por Yersinia pseudotuberculosis/patología
17.
Cancer Res ; 75(18): 3788-99, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26208902

RESUMEN

The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL17 levels. Studying the role of IL17 in invasive breast tumor pathogenesis, we found that metastatic primary tumor-infiltrating T lymphocytes produced elevated levels of IL17, whereas IL17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, producing CXCL1, MMP9, VEGF, and TNFα, and their depletion suppressed tumor growth. IL17A also induced IL6 and CCL20 production in metastatic tumor cells, favoring the recruitment and differentiation of Th17. In addition, IL17A changed the gene-expression profile and the behavior of nonmetastatic tumor cells, causing tumor growth in vivo, confirming the protumor role of IL17. Furthermore, high IL17 expression was associated with lower disease-free survival and worse prognosis in IDC patients. Thus, IL17 blockade represents an attractive approach for the control of invasive breast tumors.


Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/secundario , Quimiotaxis de Leucocito/fisiología , Interleucina-17/fisiología , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas de Neoplasias/fisiología , Neutrófilos/inmunología , Animales , Neoplasias de la Mama/química , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/mortalidad , Citocinas/biosíntesis , Citocinas/genética , Citocinas/metabolismo , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-17/análisis , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/inmunología , Neutrófilos/metabolismo , Pronóstico , Células Th17/inmunología
18.
PLoS One ; 9(8): e104736, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25119429

RESUMEN

CCR5, an important receptor related to cell recruitment and inflammation, is expressed during experimental Toxoplasma gondii infection. However, its role in the immunopathology of toxoplasmosis is not clearly defined yet. Thus, we inoculated WT and CCR5(-/-) mice with a sub lethal dose of the parasite by oral route. CCR5(-/-) mice were extremely susceptible to infection, presenting higher parasite load and lower tissue expression of IL-12p40, IFN-γ, TNF, IL-6, iNOS, Foxp3, T-bet, GATA-3 and PPARα. Although both groups presented inflammation in the liver with prominent neutrophil infiltration, CCR5(-/-) mice had extensive tissue damage with hepatocyte vacuolization, steatosis, elevated serum triglycerides and transaminases. PPARα agonist Gemfibrozil improved the vacuolization but did not rescue CCR5(-/-) infected mice from high serum triglycerides levels and enhanced mortality. We also found intense inflammation in the ileum of CCR5(-/-) infected mice, with epithelial ulceration, augmented CD4 and decreased frequency of NK cells in the gut lamina propria. Most interestingly, these findings were accompanied by an outstanding accumulation of neutrophils in the ileum, which seemed to be involved in the gut immunopathology, once the depletion of these cells was accompanied by reduced local damage. Altogether, these data demonstrated that CCR5 is essential to the control of T. gondii infection and to maintain the metabolic, hepatic and intestinal integrity. These findings add novel information on the disease pathogenesis and may be relevant for directing future approaches to the treatment of multi-deregulated diseases.


Asunto(s)
Receptores CCR5/genética , Receptores CCR5/inmunología , Toxoplasmosis/inmunología , Toxoplasmosis/metabolismo , Análisis de Varianza , Animales , Citocinas/metabolismo , Cartilla de ADN/genética , Femenino , Citometría de Flujo , Gemfibrozilo , Técnicas de Inactivación de Genes , Íleon/inmunología , Íleon/patología , Inmunohistoquímica , Estimación de Kaplan-Meier , Ratones , Ratones Noqueados , Neutrófilos/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Estadísticas no Paramétricas , Triglicéridos/sangre
19.
Immunol Rev ; 259(1): 75-87, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24712460

RESUMEN

The immune system of the gastrointestinal tract must be tightly regulated to limit pathologic responses toward innocuous antigens while simultaneously allowing for rapid development of effector responses against invading pathogens. Highly specialized antigen-presenting cell (APC) subsets present in the gut play a dominant role in balancing these seemingly disparate functions. In this review, we discuss new findings associated with the function of gut APCs and particularly the contextual role of these cells in both establishing tolerance to orally acquired antigens in the steady state and regulating acute inflammation during infection.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Tracto Gastrointestinal/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/microbiología , Homeostasis/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunomodulación , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Monocitos/inmunología , Monocitos/metabolismo , Fagocitos/inmunología , Fagocitos/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
20.
J Immunol ; 190(6): 2614-21, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23390295

RESUMEN

We have previously shown that regulatory T (Treg) cells that accumulate in the airways of allergic mice upregulate CC-chemokine receptor 4 (CCR4) expression. These Treg cells suppressed in vitro Th2 cell proliferation but not type 2 cytokine production. In the current study, using a well-established murine model of allergic lung disease or oral tolerance, we evaluated the in vivo activity of Treg cells in allergic airway inflammation with special focus on CCR4 function. We found that allergic, but not tolerant, mice treated with anti-CD25 Ab showed increased airway eosinophilia and IL-5- or IL-4-producing Th2 cells when compared with untreated mice. Notably, mice with CCR4 deficiency displayed an augmented airway allergic inflammation compared with wild-type or CCR2 knockout (KO) mice. The allergic phenotype of CCR4KO mice was similar to that observed in anti-CD25-treated mice. The exacerbated allergic inflammation of CCR4KO mice was directly associated with an impaired migration of Treg cells to airways and augmented frequency of pulmonary Th2 cells. Adoptive transfer of CD25(+)CD4(+) T cells expressing high levels of CCR4, but not CCR4KO CD25(+)CD4(+) T cells, attenuated the severe airway Th2 response of CCR4KO mice. Our results show that CCR4 is critically involved in the migration of Treg cells to allergic lungs that, in turn, attenuate airway Th2 activation and allergic eosinophilic inflammation.


Asunto(s)
Movimiento Celular/inmunología , Eosinofilia/inmunología , Neumonía/inmunología , Receptores CCR4/fisiología , Índice de Severidad de la Enfermedad , Linfocitos T Reguladores/inmunología , Animales , Eosinofilia/genética , Eosinofilia/patología , Femenino , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/genética , Neumonía/patología , Receptores CCR4/deficiencia , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/patología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología
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