RESUMEN

To achieve global herd immunity, widespread vaccination is the most effective strategy. Vaccines stimulate the immune system, generating cytokines and chemokines, isotype antibodies, and neutralizing antibodies; all these molecules collectively provide a more comprehensive characterization of the immune response post-vaccination. We conducted a longitudinal study in northwestern Mexico, involving 120 individuals before vaccination and after the first dose of the SARS-CoV-2 vaccine, and 46 individuals after their second dose. Our findings reveal that antibody levels stabilize over time; cytokine levels generally increase following the first dose but decrease after the second dose and higher than normal levels in IgG1 and IgG3 concentrations are present. Most of the innate cytokines determined in this study were higher after the first dose of the vaccine. Regardless of previous infection history, this finding suggests that the first dose of the vaccine is crucial and may stimulate immunity by enhancing the innate immune response. Conversely, increased levels of IL-4, indicative of a Th2 response, were found in individuals without prior exposure to the virus and in those vaccinated with CoronaVac. These results suggest that the immune response to COVID-19 vaccines is multi-faceted, with preexisting immunity potentiating a more robust innate response. Vaccine type plays a critical role, with genetic vaccines favoring a Th1 response and inactivated vaccines like CoronaVac skewing toward a Th2 profile.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , Vacunas contra la COVID-19 , COVID-19 , ChAdOx1 nCoV-19 , Citocinas , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/prevención & control , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Masculino , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Citocinas/inmunología , Femenino , Adulto , Persona de Mediana Edad , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Vacuna BNT162/inmunología , Vacuna BNT162/administración & dosificación , México , Estudios Longitudinales , ChAdOx1 nCoV-19/inmunología , ChAdOx1 nCoV-19/administración & dosificación , SARS-CoV-2/inmunología , Células Th2/inmunología , Células TH1/inmunología , Inmunoglobulina G/sangre , Vacunación , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Adulto Joven , Anciano

RESUMEN

INTRODUCTION: In ST-elevation myocardial infarction (STEMI), inflammation is pivotal, with early senescent CD4+CD28null cells implicated in its pathogenesis. However, the functional phenotype of these cells within the coronary circulation remains unclear. METHODS: We examined CD4+ cell subpopulations in blood samples from the coronary sinus and vena cava of 24 STEMI patients and the cephalic vein of seven healthy controls. RESULTS: Our findings revealed reduced CD4+ cell counts in STEMI patients compared to controls (1,998, 1,275-3,268 vs. 4,278, 3,595-4,449), alongside an increased proportion of CD4+ cells lacking CD28 expression (20.1 vs. 6.1%). These CD4+CD28null cells in STEMI predominantly exhibited a Th1 phenotype (47.8% vs. 6.6%). Intriguingly, no significant differences were detected in CD4+CD28null cells between coronary sinus and vena cava, and cytokine levels in these compartments remained similar. CONCLUSION: CD4+CD28null cells are increased in STEMI, mainly polarized toward a Th1 phenotype, and distributed equally between the different vascular beds.

Asunto(s)

Antígenos CD28 , Linfocitos T CD4-Positivos , Circulación Coronaria , Citocinas , Fenotipo , Infarto del Miocardio con Elevación del ST , Células TH1 , Humanos , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/inmunología , Infarto del Miocardio con Elevación del ST/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios de Casos y Controles , Antígenos CD28/metabolismo , Células TH1/inmunología , Citocinas/sangre , Citocinas/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Senescencia Celular , Seno Coronario , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Recuento de Linfocito CD4 , Inmunofenotipificación

RESUMEN

Goto-Kakizaki (GK) rats develop a well-defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T-regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata-3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti-inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM.

Asunto(s)

Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Ratas Wistar , Animales , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Ratas , Masculino , Inflamación/metabolismo , Inflamación/patología , Inflamación/inmunología , Factor de Transcripción GATA3/metabolismo , Factor de Transcripción GATA3/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 1/genética , Células TH1/inmunología , Células TH1/metabolismo

RESUMEN

Sheep farming contributes to the socioeconomic development of small and medium-scale livestock farmers. However, several factors can hinder successful animal production, as is the case for infectious diseases, such as the one caused by Corynebacterium pseudotuberculosis, known as caseous lymphadenitis (CLA). CLA has >90% prevalence in Brazilian herds and antibiotic treatment is not effective, consequently causing significant economic losses to farmers. Given the above, effective vaccines need to be developed to prevent this disease. This study aimed to evaluate the adjuvant activity of the lipid extract from the macroalgae Iridaea cordata as a candidate for developing an effective vaccine formulation. For such, four groups of six sheep each were inoculated with sterile 0.9% saline solution (G1), rCP01850 (G2), rCP01850 + I. cordata (G3), and rCP01850 + saponin (G4). Each sheep received two vaccine doses 30 days apart. Total IgG production levels significantly increased in experimental groups G3 and G4 on days 30, 60, and 90. On day 90, G3 showed higher total IgG production (p < 0.05) when compared to G4. When analyzing cytokine production, G3 was the only experimental group with significantly increased IFN-γ, IL-12, TNF-α, and IL-10 mRNA expression levels. Our results show the vaccine formulation containing rCP01850 adjuvanted with the I. cordata lipid extract elicited a Th1 immune response in sheep, indicating I. cordata lipid extract may be a promising adjuvant for developing an effective vaccine against infection caused by C. pseudotuberculosis.

Asunto(s)

Adyuvantes Inmunológicos , Vacunas Bacterianas , Corynebacterium pseudotuberculosis , Enfermedades de las Ovejas , Células TH1 , Animales , Ovinos , Enfermedades de las Ovejas/prevención & control , Enfermedades de las Ovejas/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Células TH1/inmunología , Corynebacterium pseudotuberculosis/inmunología , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificación , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Citocinas/metabolismo , Citocinas/inmunología , Inmunoglobulina G/sangre , Infecciones por Corynebacterium/prevención & control , Infecciones por Corynebacterium/inmunología , Lípidos/inmunología , Brasil , Proteínas Bacterianas/inmunología

RESUMEN

The treatment for visceral leishmaniasis (VL) causes toxicity in patients, entails high cost and/or leads to the emergence of resistant strains. No human vaccine exists, and diagnosis presents problems related to the sensitivity or specificity of the tests. Here, we tested two phage clones, B1 and D11, which were shown to be protective against Leishmania infantum infection in a murine model as immunotherapeutics to treat mice infected with this parasite species. The phages were used alone or with amphotericin B (AmpB), while other mice received saline, AmpB, a wild-type phage (WTP) or WTP/AmpB. Results showed that the B1/AmpB and D11/AmpB combinations induced polarised Th1-type cellular and humoral responses, which were primed by high levels of parasite-specific IFN-γ, IL-12, TNF-α, nitrite and IgG2a antibodies, which reflected in significant reductions in the parasite load in distinct organs of the animals when analyses were performed 1 and 30 days after the treatments. Reduced organic toxicity was also found in these animals, as compared with the controls. In conclusion, preliminary data suggest the potential of the B1/AmpB and D11/AmpB combinations as immunotherapeutics against L. infantum infection.

Asunto(s)

Anfotericina B , Anticuerpos Antiprotozoarios , Inmunoterapia , Leishmania infantum , Leishmaniasis Visceral , Ratones Endogámicos BALB C , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/tratamiento farmacológico , Animales , Anfotericina B/uso terapéutico , Anfotericina B/administración & dosificación , Anticuerpos Antiprotozoarios/sangre , Leishmania infantum/inmunología , Leishmania infantum/efectos de los fármacos , Ratones , Inmunoterapia/métodos , Femenino , Antiprotozoarios/uso terapéutico , Antiprotozoarios/administración & dosificación , Inmunoglobulina G/sangre , Carga de Parásitos , Modelos Animales de Enfermedad , Técnicas de Visualización de Superficie Celular , Citocinas/metabolismo , Células TH1/inmunología

RESUMEN

Inflammation contributes to the onset and exacerbation of numerous age-related diseases, often manifesting as a chronic condition during aging. Given that cellular senescence fosters local and systemic inflammation, senotherapeutic interventions could potentially aid in managing or even reducing inflammation. Here, we investigated the immunomodulatory effects of the senotherapeutic Peptide 14 (Pep 14) in human peripheral blood mononuclear cells (PBMCs), monocytes, and macrophages. We found that, despite failing to significantly influence T cell activation and proliferation, the peptide promoted a Th2/Treg gene expression and cytokine signature in PBMCs, characterized by increased expression of the transcription factors GATA3 and FOXP3, as well as the cytokines IL-4 and IL-10. These observations were partially confirmed through ELISA, in which we observed increased IL-10 release by resting and PHA-stimulated PBMCs. In monocytes from the U-937 cell line, Pep 14 induced apoptosis in lipopolysaccharide (LPS)-stimulated cells and upregulated IL-10 expression. Furthermore, Pep 14 prevented LPS-induced activation and promoted an M2-like polarization in U-937-derived macrophages, evidenced by decreased expression of M1 markers and increased expression of M2 markers. We also showed that the conditioned media from Pep 14-treated macrophages enhanced fibroblast migration, indicative of a functional M2 phenotype. Taken together, our findings suggest that Pep 14 modulates immune cell function towards an anti-inflammatory and regenerative phenotype, highlighting its potential as a therapeutic intervention to alleviate immunosenescence-associated dysregulation.

Asunto(s)

Macrófagos , Monocitos , Células TH1 , Humanos , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo , Péptidos/farmacología , Lipopolisacáridos/farmacología , Citocinas/metabolismo , Interleucina-10/metabolismo , Activación de Linfocitos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos

RESUMEN

COVID-19, caused by SARS-CoV-2, and meningococcal disease, caused by Neisseria meningitidis, are relevant infectious diseases, preventable through vaccination. Outer membrane vesicles (OMVs), released from Gram-negative bacteria, such as N. meningitidis, present adjuvant characteristics and may confer protection against meningococcal disease. Here, we evaluated in mice the humoral and cellular immune response to different doses of receptor binding domain (RBD) of SARS-CoV-2 adjuvanted by N. meningitidis C:2a:P1.5 OMVs and aluminum hydroxide, as a combined preparation for these pathogens. The immunization induced IgG antibodies of high avidity for RBD and OMVs, besides IgG that recognized the Omicron BA.2 variant of SARS-CoV-2 with intermediary avidity. Cellular immunity showed IFN-γ and IL-4 secretion in response to RBD and OMV stimuli, demonstrating immunologic memory and a mixed Th1/Th2 response. Offspring presented transferred IgG of similar levels and avidity as their mothers. Humoral immunity did not point to the superiority of any RBD dose, but the group immunized with a lower antigenic dose (0.5 µg) had the better cellular response. Overall, OMVs enhanced RBD immunogenicity and conferred an immune response directed to N. meningitidis too.

Asunto(s)

Anticuerpos Antivirales , COVID-19 , Inmunoglobulina G , Neisseria meningitidis , SARS-CoV-2 , Animales , Ratones , Inmunoglobulina G/sangre , Neisseria meningitidis/inmunología , Femenino , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/prevención & control , COVID-19/inmunología , SARS-CoV-2/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Inmunidad Celular , Inmunidad Humoral , Ratones Endogámicos BALB C , Infecciones Meningocócicas/prevención & control , Infecciones Meningocócicas/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adyuvantes de Vacunas/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , Hidróxido de Aluminio/inmunología , Inmunización/métodos , Afinidad de Anticuerpos , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Vacunas Meningococicas/inmunología , Vacunas Meningococicas/administración & dosificación , Memoria Inmunológica , Células TH1/inmunología

RESUMEN

Takayasu arteritis (TAK) is a granulomatous vasculitis that affects large arteries. T cells are important in TAK pathophysiology as these cells orchestrate granulomatous infiltration in arteries. This study aims to evaluate effector CD4+ T cells in the peripheral blood and the aortic wall of TAK patients and to analyze associations with disease activity and therapy. We performed a longitudinal study including 30 TAK patients and 30 controls. CD3+ T cells, CD3+CD4- T cells, CD4+ T cells, and Th1, Th2, and Th17 cells were evaluated in peripheral blood by flow cytometry, and the expression of CD4, CD8, Tbet, GATA-3, and RORγT was analyzed in the aorta of six patients by immunohistochemistry. TAK patients presented lower CD3+ T cells and CD4+ T cells (P = 0.031 and P = 0.039, respectively) than controls. Patients with active disease and those in remission had higher proportions of Th17 cells than controls (P = 0.016 and P = 0.004, respectively). Therapy for TAK did not result in significant differences concerning CD4+ effector T-cell subpopulations. Disease duration correlated with the number and percentage of Th2 cells (rho = -0.610 and rho = -0.463, respectively) and with Th17 cells (rho = -0.365 and rho = -0.568). In the aorta, the expression of CD8 was higher than CD4, whereas GATA-3, Tbet, and RORγT were expressed in this order of frequency. In conclusion, TAK patients present an increased Th17 response in the peripheral blood regardless of disease activity, whereas in the aortic tissue CD8 cells and the Th2 response were predominant.

Asunto(s)

Aorta , Linfocitos T CD4-Positivos , Subgrupos de Linfocitos T , Arteritis de Takayasu , Humanos , Arteritis de Takayasu/inmunología , Arteritis de Takayasu/sangre , Femenino , Adulto , Masculino , Aorta/inmunología , Aorta/patología , Linfocitos T CD4-Positivos/inmunología , Subgrupos de Linfocitos T/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Persona de Mediana Edad , Factor de Transcripción GATA3/metabolismo , Proteínas de Dominio T Box/metabolismo , Células Th17/inmunología , Adulto Joven , Estudios Longitudinales , Células Th2/inmunología , Células TH1/inmunología

RESUMEN

Paracoccidioidomycosis (PCM) is a systemic mycosis with serious clinical consequences in which the use of antifungal drugs requires long-term treatment. Therefore, we studied the effect of low-level LASER therapy (LLLT) to evaluate its prospects as a complementary treatment for PCM and improve the clinical response to the disease. OBJECTIVES: Our study focused on the resolution of lesions caused by fungal infection using a subcutaneous air pouch model of infection. METHODS: We evaluated cell profile and cytokines, fungi viability, and the presence of fibroblasts and fibrocytes at the site of infection. Inoculation of P. brasiliensis (Pb) was performed using a subcutaneous air pouch model and the LLLT irradiation was performed on alternate days on the rear paws of mice for 10 days, after which the cells from the air pouch were collected and analyzed. RESULTS: In animals irradiated with LLLT, the influx of cells to the air pouch was reduced, but they were more activated and produced pro-inflammatory (IL-12, IL-17 and TNF-α) and neutrophil (PMN) activating cytokines (IL-8, GM-CSF and γ-IFN). A better resolution of the infection, evidenced by the reduction in the number of viable fungi with preserved morphology in the air pouch, and an increase in the number of fibrocytes, indicating a healing profile were also observed. CONCLUSION: LLLT decreased the influx of PMN, but those presents were highly activated, with increased fungicidal activity. LLLT irradiation also resulted in earlier cicatrization at the site of infection, leading to a better outcome of the infection. These data are favorable to the use of LLLT as a complementary therapy in PCM.

Asunto(s)

Citocinas , Terapia por Luz de Baja Intensidad , Paracoccidioidomicosis , Células TH1 , Células Th2 , Animales , Ratones , Citocinas/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Paracoccidioidomicosis/radioterapia , Paracoccidioidomicosis/inmunología , Paracoccidioidomicosis/patología , Células Th2/inmunología , Células Th2/metabolismo , Paracoccidioides/inmunología , Ratones Endogámicos BALB C , Masculino

RESUMEN

For several years, we have been committed to exploring the potential of Bordetella pertussis-derived outer membrane vesicles (OMVBp) as a promising third-generation vaccine against the reemerging pertussis disease. The results of our preclinical trials not only confirm its protective capacity against B. pertussis infection but also set the stage for forthcoming human clinical trials. This study delves into the examination of OMVBp as an adjuvant. To accomplish this objective, we implemented a two-dose murine schedule to evaluate the specific immune response induced by formulations containing OMVBp combined with 3 heterologous immunogens: Tetanus toxoid (T), Diphtheria toxoid (D), and the SARS-CoV-2 Spike protein (S). The specific levels of IgG, IgG1, and IgG2a triggered by the different tested formulations were evaluated using ELISA in dose-response assays for OMVBp and the immunogens at varying levels. These assays demonstrated that OMVBp exhibits adjuvant properties even at the low concentration employed (1.5 µg of protein per dose). As this effect was notably enhanced at medium (3 µg) and high concentrations (6 µg), we chose the medium concentration to determine the minimum immunogen dose at which the OMV adjuvant properties are significantly evident. These assays demonstrated that OMVBp exhibits adjuvant properties even at the lowest concentration tested for each immunogen. In the presence of OMVBp, specific IgG levels detected for the lowest amount of antigen tested increased by 2.5 to 10 fold compared to those found in animals immunized with formulations containing adjuvant-free antigens (p<0.0001). When assessing the adjuvant properties of OMVBp compared to the widely recognized adjuvant alum, we detected similar levels of specific IgG against D, T and S for both adjuvants. Experiments with OMVs derived from E. coli (OMVE.coli) reaffirmed that the adjuvant properties of OMVs extend across different bacterial species. Nonetheless, it's crucial to highlight that OMVBp notably skewed the immune response towards a Th1 profile (p<0.05). These collective findings emphasize the dual role of OMVBp as both an adjuvant and modulator of the immune response, positioning it favorably for incorporation into combined vaccine formulations.

Asunto(s)

Adyuvantes Inmunológicos , Bordetella pertussis , Inmunoglobulina G , Células TH1 , Tos Ferina , Bordetella pertussis/inmunología , Animales , Adyuvantes Inmunológicos/administración & dosificación , Ratones , Células TH1/inmunología , Tos Ferina/inmunología , Tos Ferina/prevención & control , Femenino , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Vacuna contra la Tos Ferina/inmunología , Vacuna contra la Tos Ferina/administración & dosificación , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antibacterianos/sangre , Glicoproteína de la Espiga del Coronavirus/inmunología , Ratones Endogámicos BALB C , SARS-CoV-2/inmunología , Proteínas de la Membrana Bacteriana Externa/inmunología , Humanos , COVID-19/inmunología , COVID-19/prevención & control , Toxoide Tetánico/inmunología

RESUMEN

During periodontitis, the extracellular capsule of Porphyromonas gingivalis favors alveolar bone loss by inducing Th1 and Th17 patterns of lymphocyte response in the infected periodontium. Dendritic cells recognize bacterial antigens and present them to T lymphocytes, defining their activation and polarization. Thus, dendritic cells could be involved in the Th1 and Th17 response induced against the P. gingivalis capsule. Herein, monocyte-derived dendritic cells were obtained from healthy individuals and then stimulated with different encapsulated strains of P. gingivalis or two non-encapsulated isogenic mutants. Dendritic cell differentiation and maturation were analyzed by flow cytometry. The mRNA expression levels for distinct Th1-, Th17-, or T-regulatory-related cytokines and transcription factors, as well as TLR2 and TLR4, were assessed by qPCR. In addition, the production of IL-1ß, IL-6, IL-23, and TNF-α was analyzed by ELISA. The encapsulated strains and non-encapsulated mutants of P. gingivalis induced dendritic cell maturation to a similar extent; however, the pattern of dendritic cell response was different. In particular, the encapsulated strains of P. gingivalis induced higher expression of IRF4 and NOTCH2 and production of IL-1ß, IL-6, IL-23, and TNF-α compared with the non-encapsulated mutants, and thus, they showed an increased capacity to trigger Th1 and Th17-type responses in human dendritic cells.

Asunto(s)

Citocinas , Células Dendríticas , Porphyromonas gingivalis , Células Th17 , Receptor Toll-Like 2 , Receptor Toll-Like 4 , Porphyromonas gingivalis/inmunología , Humanos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Células Th17/inmunología , Células Th17/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Citocinas/metabolismo , Diferenciación Celular , Células TH1/inmunología , Factores Reguladores del Interferón/metabolismo , Factores Reguladores del Interferón/genética , Receptor Notch2/genética , Receptor Notch2/metabolismo , Células Cultivadas , Cápsulas Bacterianas/inmunología , Cápsulas Bacterianas/metabolismo , Infecciones por Bacteroidaceae/inmunología , Infecciones por Bacteroidaceae/microbiología , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

The thymus plays a crucial role in T cell differentiation, a complex process influenced by various factors such as antigens, the microenvironment and thymic architecture. The way the thymus resolves infections is critical, as chronic persistence of microbes or inflammatory mediators can obstruct the differentiation. Here, we illustrate that following inflammatory T helper 1 infectious processes like those caused by Candida albicans or Trypanosoma cruzi, single positive thymocytes adopt a mature phenotype. Further investigations focused on T. cruzi infection, reveal a substantial existence of CD44+ cells in both the cortical and medullary areas of the thymus at the onset of infection. This disturbance coincides with heightened interferon gamma (IFNγ) production by thymocytes and an increased cytotoxic capacity against T. cruzi-infected macrophages. Additionally, we observe a reduced exportation capacity in T. cruzi-infected mice. Some alterations can be reversed in IFNγ knockout mice (KO). Notably, the majority of these effects can be replicated by systemic expression of interleukin (IL)-12+IL-18, underlining the predominantly inflammatory rather than pathogen-specific nature of these phenomena. Understanding the mechanisms through which systemic inflammation disrupts normal T cell development, as well as subsequent T cell exportation to secondary lymphoid organs (SLO) is pivotal for comprehending susceptibility to diseases in different pathological scenarios.

Asunto(s)

Enfermedad de Chagas , Citocinas , Ratones Noqueados , Células TH1 , Timo , Trypanosoma cruzi , Animales , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Enfermedad de Chagas/patología , Enfermedad de Chagas/metabolismo , Trypanosoma cruzi/inmunología , Ratones , Timo/inmunología , Timo/patología , Células TH1/inmunología , Citocinas/metabolismo , Interferón gamma/metabolismo , Interferón gamma/inmunología , Ratones Endogámicos C57BL , Inflamación/inmunología , Diferenciación Celular

RESUMEN

The relationship between psoriasis severity and psychological stress has been described in several studies. However, the mechanism by which chronic stress exacerbates psoriasis is not completely understood. This study aimed at investigating whether chronic psychological stress can aggravate psoriasis-like skin inflammation. Mice were subjected to a restraint stress model and topically treated with imiquimod (IMQ). Differentiated human keratinocytes were treated with high epinephrine levels and IMQ in vitro. Stress aggravated macroscopic features and the increase in epidermal thickness induced by IMQ in mouse skin. The increase in NF-κB and IL-17A expression induced by IMQ was potentiated by chronic stress in mouse skin. The skin of stressed mice treated with IMQ showed higher levels of ß2-adrenergic receptors (ß2-AR). In human keratinocytes, high epinephrine levels exacerbated the increase in the levels of ß2-AR and IL-17A induced by IMQ. ß-AR antagonist reversed the effects of chronic stress in IMQ-induced inflammation both in vivo and in vitro. In conclusion, stress-stimulated overactivation of the ß2-AR and NF-κB pathways potentiates a Th1/Th17 profile leading to an exacerbation of psoriasis.

Asunto(s)

Imiquimod , Interleucina-17 , Queratinocitos , FN-kappa B , Psoriasis , Receptores Adrenérgicos beta 2 , Transducción de Señal , Estrés Psicológico , Animales , Humanos , Masculino , Ratones , Modelos Animales de Enfermedad , Epinefrina , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-17/metabolismo , Queratinocitos/metabolismo , Queratinocitos/inmunología , FN-kappa B/metabolismo , Psoriasis/inmunología , Psoriasis/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Piel/patología , Piel/inmunología , Piel/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/inmunología , Células TH1/inmunología , Células Th17/inmunología

RESUMEN

High levels of T helper 17 cell (Th17)-related cytokines have been shown in acute Zika virus (ZIKV) infection. We hypothesized that the high levels of Th17-related cytokines, associated with a regulatory environment during pregnancy, create a favorable milieu for the differentiation of CD4+Th17 cells. We present data from a cross-sectional study on mothers who confirmed ZIKV infection by qRT-PCR and their children. We also recruited non-pregnant women infected with ZIKV in the same period. ZIKV infection occurred between 2015 and 2017. We collected samples for this study between 2018 and 2019, years after the initial infection. We highlight that, after in vitro stimulation with ZIKV CD4 megapool (ZIKV MP), we found a lower frequency of IL-17-producing CD4+ T cells (Th17), especially in the mothers, confirmed by the decrease in IL-17 production in the supernatant. However, a higher frequency of CD4+ IL-17+ IFN-γ+ T cells (Th1Th17) responding to the ZIKV MP was observed in the cells of the mothers and children but not in those of the non-pregnant women. Our data indicate that the priming of CD4 T cells of the Th1Th17 phenotype occurred preferentially in the mothers who gave birth to children with CZS and in the children.

Asunto(s)

Madres , Complicaciones Infecciosas del Embarazo/inmunología , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Infección por el Virus Zika/inmunología , Adulto , Linfocitos T CD4-Positivos/inmunología , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Interferón gamma/inmunología , Interleucina-17/inmunología , Células T de Memoria/inmunología , Persona de Mediana Edad , Embarazo , Receptores CCR6/inmunología , Células TH1/inmunología , Adulto Joven , Virus Zika/inmunología

RESUMEN

Innate immune cells present a dual role during leishmaniasis: they constitute the first line of host defense but are also the main host cells for the parasite. Response against the infection that results in the control of parasite growth and lesion healing depends on activation of macrophages into a classical activated phenotype. We report an essential role for the microbiota in driving macrophage and monocyte-derived macrophage activation towards a resistance phenotype against Leishmania major infection in mice. Both germ-free and dysbiotic mice showed a higher number of myeloid innate cells in lesions and increased number of infected cells, mainly dermal resident and inflammatory macrophages. Despite developing a Th1 immune response characterized by the same levels of IFN-γ production as the conventional mice, germ-free mice presented reduced numbers of iNOS+ macrophages at the peak of infection. Absence or disturbance of host microbiota impaired the capacity of bone marrow-derived macrophage to be activated for Leishmania killing in vitro, even when stimulated by Th1 cytokines. These cells presented reduced expression of inos mRNA, and diminished production of microbicidal molecules, such as ROS, while presenting a permissive activation status, characterized by increased expression of arginase I and il-10 mRNA and higher arginase activity. Colonization of germ-free mice with complete microbiota from conventional mice rescued their ability to control the infection. This study demonstrates the essential role of host microbiota on innate immune response against L. major infection, driving host macrophages to a resistance phenotype.

Asunto(s)

Inmunidad Innata , Leishmania major/patogenicidad , Leishmaniasis Cutánea/microbiología , Activación de Macrófagos , Macrófagos/microbiología , Microbiota , Animales , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Disbiosis , Femenino , Vida Libre de Gérmenes , Interacciones Huésped-Patógeno , Leishmania major/inmunología , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos BALB C , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/microbiología

RESUMEN

The prognosis of severe COVID-19 patients has motivated research communities to uncover mechanisms of SARS-CoV-2 pathogenesis also on a regional level. In this work, we aimed to understand the immunological dynamics of severe COVID-19 patients with different degrees of illness, and upon long-term recovery. We analyzed immune cellular subsets and SARS-CoV-2-specific antibody isotypes of 66 COVID-19 patients admitted to the Hospital Clínico Universidad de Chile, which were categorized according to the WHO ten-point clinical progression score. These included 29 moderate patients (score 4-5) and 37 severe patients under either high flow oxygen nasal cannula (18 patients, score 6), or invasive mechanical ventilation (19 patients, score 7-9), plus 28 convalescent patients and 28 healthy controls. Furthermore, six severe patients that recovered from the disease were longitudinally followed over 300 days. Our data indicate that severe COVID-19 patients display increased frequencies of plasmablasts, activated T cells and SARS-CoV-2-specific antibodies compared to moderate and convalescent patients. Remarkably, within the severe COVID-19 group, patients rapidly progressing into invasive mechanical ventilation show higher frequencies of plasmablasts, monocytes, eosinophils, Th1 cells and SARS-CoV-2-specific IgG than patients under high flow oxygen nasal cannula. These findings demonstrate that severe COVID-19 patients progressing into invasive mechanical ventilation show a distinctive type of immunity. In addition, patients that recover from severe COVID-19 begin to regain normal proportions of immune cells 100 days after hospital discharge and maintain high levels of SARS-CoV-2-specific IgG throughout the study, which is an indicative sign of immunological memory. Thus, this work can provide useful information to better understand the diverse outcomes of severe COVID-19 pathogenesis.

Asunto(s)

COVID-19/inmunología , Eosinófilos/inmunología , Células Plasmáticas/inmunología , SARS-CoV-2/fisiología , Células TH1/inmunología , Anciano , Anticuerpos Antivirales/sangre , Convalecencia , Progresión de la Enfermedad , Femenino , Humanos , Inmunidad Celular , Inmunoglobulina G/sangre , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad

RESUMEN

Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the immune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in the expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFß; p = 0.049), whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFß in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.

Asunto(s)

Neoplasias de la Mama/tratamiento farmacológico , Factor de Transcripción GATA3/genética , Interferón gamma/genética , Yodo/administración & dosificación , Factor de Crecimiento Transformador beta1/genética , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Apoptosis/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Inmunidad/genética , Yodo/efectos adversos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , México , Persona de Mediana Edad , RNA-Seq , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología

RESUMEN

Autoinflammatory and autoimmune diseases are characterized by an oversensitive immune system with loss of the physiological endogenous regulation, involving multifactorial self-reactive pathological mechanisms of mono- or polygenic nature. Failure in regulatory mechanisms triggers a complex network of dynamic relationships between innate and adaptive immunity, leading to coexistent autoinflammatory and autoimmune processes. Sustained exposure to a trigger or a genetic alteration at the level of the receptors of the natural immune system may lead to abnormal activation of the innate immune system, adaptive system activation, loss of self-tolerance, and systemic inflammation. The IL-1 family members critically activate and regulate innate and adaptive immune responses' diversity and plasticity in autoimmune and/or autoinflammatory conditions. The IL-23/IL-17 axis is key in the communication between innate immunity (IL-23-producing myeloid cells) and adaptive immunity (Th17- and IL-17-expressing CD8+ T cells). In psoriasis, these cytokines are decisive to the different clinical presentations, whether as plaque psoriasis (psoriasis vulgaris), generalized pustular psoriasis (pustular psoriasis), or mixed forms. These forms reflect a gradient between autoimmune pathophysiology with predominant adaptive immune response and autoinflammatory pathophysiology with predominant innate immune response.

Asunto(s)

Enfermedades Autoinmunes/etiología , Inflamación/etiología , Interleucina-1/fisiología , Psoriasis/inmunología , Inmunidad Adaptativa , Humanos , Inmunidad Innata , Inflamasomas/fisiología , Células TH1/inmunología , Células Th17/inmunología

RESUMEN

Multiple sclerosis (MS) is currently thought to arise by interactions between genetic susceptibility and environmental factors. Infections in general trigger autoimmune responses causing clinical manifestations of disease. However, as a result of regulatory T (Treg)- and regulatory B (Breg)-cell induction, helminth infections tend to dampen disease activity. IL-35, the newest member of the IL-12 family, is an inhibitory cytokine composed of an EBI3ß chain subunit, and an IL-12p35 subunit. The aim of this study was to investigate the role of IL-35 during parasite infections occurring in individuals with MS. Numbers of IL-35-producing Breg cells are higher in CSF from helminth-infected than from uninfected MS subjects, a finding associated with decreased MRI disease activity. Interestingly, stimulation of CD19+ B cells with IL-35 promotes conversion of these cells to Breg cells producing both IL-35 and IL-10. Coculture of B cells from helminth-infected MS patients inhibits proliferation of Th1 and Th17 myelin peptide-specific T cells, as well as production of IFN-γ and IL-17. Following activation, CD4+ CD25+ Treg cells significantly upregulate expression of EBI3 and IL-12p35 mRNA. Furthermore, CD4+ CD25- T cells activated in the presence of IL-35 induce a population of cells with regulatory function, known as iTR35. Finally, B cells from normal individuals cultured in vitro in the presence of the helminth antigen SEA increase expression of the transcription BATF, IRF4 and IRF8, acquiring a pattern similar to that of IL-35 Breg cells. These data highlight the important immunoregulatory effects of IL-35 on both Breg and Treg cells, observed in helminth-infected MS subjects.

Asunto(s)

Linfocitos B Reguladores/inmunología , Helmintiasis/inmunología , Interleucinas/metabolismo , Esclerosis Múltiple/complicaciones , Linfocitos T Reguladores/inmunología , Adulto , Animales , Linfocitos B Reguladores/metabolismo , Femenino , Helmintiasis/parasitología , Helmintos/inmunología , Helmintos/aislamiento & purificación , Interacciones Huésped-Parásitos , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/metabolismo , Células TH1/inmunología , Células Th17/inmunología

RESUMEN

An important strategy to reduce the risk of visceral leishmaniasis (VL) in humans is to control the infection and disease progression in dogs, the domestic reservoir of Leishmania infantum parasites. Certain therapeutic strategies that modulate the host immune response show great potential for the treatment of experimental VL, restoring the impaired effector functions or decreasing host excessive responses. It is known that the overproduction of interleukin-10 (IL-10) promotes parasite replication and disease progression in human VL as well as in canine visceral leishmaniasis (CVL). Thus, in the present study we investigated the potential of the anti-canine IL-10 receptor-blocking monoclonal antibody (Bloq IL-10R) to control and reduce in vitro infectivity of L. infantum and improve the ability of PBMC isolated from VL dogs to alter the lymphoproliferative response and intracytoplasmic cytokines. Overall, GFP+Leishmania showed lower capacity of in vitro infectivity in the presence of Bloq IL-10R. Moreover, addition of Bloq IL-10R in cultured PBMC enhanced T-CD4 and CD8 proliferative response and altered the intracytoplasmic cytokine synthesis, reducing CD4+IL-4+ cells and increasing CD8+IFN-γ+ cells after specific antigen stimulation in PBMC of dogs. Furthermore, we observed an increase of TNF-α levels in supernatant of cultured PBMC under IL-10R neutralizing conditions. Together, our findings are encouraging and reaffirm an important factor that could influence the effectiveness of immune modulation in dogs with VL and suggest that blocking IL-10R activity has the potential to be a useful approach to CVL treatment.

Asunto(s)

Enfermedades de los Perros/inmunología , Enfermedades de los Perros/parasitología , Leishmania infantum/inmunología , Leishmaniasis Visceral/inmunología , Leucocitos Mononucleares/inmunología , Receptores de Interleucina-10/inmunología , Células TH1/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/parasitología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/parasitología , Células Cultivadas , Perros , Femenino , Interferón gamma/inmunología , Leucocitos Mononucleares/parasitología , Masculino , Células TH1/parasitología