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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.
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Giardiasis is a parasitic disease caused by Giardia lamblia (G. lamblia) that affects people worldwide. Still, few studies report on the immunoregulatory effects of the biomolecules of colostrum during interactions with G. lamblia. This study aimed to assess the concentrations of melatonin and cortisol hormones, the percentage of Treg cells, and the levels of cytokines IL-10 and TGF-ß in colostrum from mothers who tested positive for the parasite. This cross-sectional study analyzed colostrum samples from 25 puerperal. The samples were tested using an ELISA to determine if they were seropositive for G. lamblia and the type of antibody present (IgM and IgG). Based on the results, the samples were divided into three groups: a control group (N = 10) with no reaction to either IgM or IgG, a group seropositive for IgG (IgG+/IgM-; N = 8), and a group seropositive for IgM (IgM+/IgG-; N = 7). The concentrations of melatonin and cortisol were measured using the ELISA method. Additionally, cytokines IL-10 and TGF-ß and immunophenotyping were analyzed using flow cytometry. In the group that tested positive for IgM anti-G. lamblia, the concentration of melatonin was lower. However, in the colostrum from mothers who tested positive for IgG anti-G. lamblia, the level of this hormone had increased. The cortisol levels were similar between the groups, regardless of seropositivity. There was a higher percentage of Treg cells in the colostrum from mothers who tested positive for IgM anti-G. lamblia. TGF-ß levels also increased in the colostrum of mothers who tested positive for IgM anti-G. lamblia. In the seronegative group for G. lamblia, there was a positive correlation between melatonin concentration and the percentage of Treg cells. These data suggest that the increase in regulatory cells and cytokines and the reduction in melatonin in colostrum from mothers with recent giardia infection may contribute to the evolution and manifestation of the disease.
Assuntos
Colostro , Giardia lamblia , Giardíase , Melatonina , Linfócitos T Reguladores , Fator de Crescimento Transformador beta , Melatonina/metabolismo , Melatonina/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Humanos , Feminino , Giardíase/imunologia , Giardíase/parasitologia , Giardia lamblia/imunologia , Adulto , Colostro/imunologia , Colostro/química , Estudos Transversais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/imunologia , Interleucina-10/metabolismo , Interleucina-10/imunologia , Imunoglobulina M/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Hidrocortisona , Gravidez , Adulto JovemRESUMO
Endometriosis's pathophysiology remains incompletely understood, with evidence pointing towards a dysregulated immune response. Regulatory T (Treg) cells, pivotal in maintaining self-tolerance, may facilitate the survival of ectopic endometrial cells within the abdominal cavity, thereby contributing to endometriosis development. This study aimed to assess the prevalence of CD39+CD73+ suppressor Treg cell subsets in the peripheral blood of endometriosis patients. This research focuses on the pivotal role of regulatory T-cells (Tregs), which are essential for maintaining immune tolerance and preventing autoimmune diseases. A case-control study was conducted, including 32 women diagnosed with endometriosis and 22 control subjects. The frequency of peripheral blood CD39+CD73+ suppressor Treg cells was quantified using flow cytometry. No significant differences were observed in the frequency of CD3+CD4+CD25High cells (Median [M]: 10.1; Interquartile Range [IQR]: 6.32â18.3 vs. M: 9.72; IQR: 6.22-19.8) or CD3+CD4+CD25HighCD39+Foxp3+ cells (M: 31.1; IQR: 19.7-44.0 vs. M: 30.55; IQR: 18.5-45.5) between controls and patients. However, a significantly lower frequency of CD3+CD4+CD25HighCD39+CD73+ cells was observed in the endometriosis group compared to controls (M: 1.98; IQR: 0.0377-3.17 vs. M: 2.25; IQR: 0.50-4.08; p = 0.0483), suggesting a reduction in systemic immune tolerance among these patients. This finding highlights the potential role of CD39 and CD73 expression on Treg cells as biomarkers for assessing disease severity and progression. Furthermore, elucidating the mechanisms driving these alterations may unveil new therapeutic strategies to restore immune equilibrium and mitigate endometriosis symptoms.
Assuntos
Apirase , Endometriose , Citometria de Fluxo , Fatores de Transcrição Forkhead , Linfócitos T Reguladores , Humanos , Feminino , Endometriose/imunologia , Endometriose/sangue , Linfócitos T Reguladores/imunologia , Adulto , Estudos de Casos e Controles , Fatores de Transcrição Forkhead/sangue , Fatores de Transcrição Forkhead/análise , Apirase/análise , 5'-Nucleotidase/sangue , Adulto Jovem , Antígenos CD/sangue , Antígenos CD/análise , Estatísticas não Paramétricas , Valores de ReferênciaRESUMO
Abstract Autophagy-related gene (ATG) 5 regulates blood lipids, chronic inflammation, CD4+ T-cell differentiation, and neuronal death and is involved in post-stroke cognitive impairment. This study aimed to explore the correlation of serum ATG5 with CD4+ T cells and cognition impairment in stroke patients. Peripheral blood was collected from 180 stroke patients for serum ATG5 and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cell detection via enzyme-linked immunosorbent assays and flow cytometry. The Mini-Mental State Examination (MMSE) scale was completed at enrollment, year (Y)1, Y2, and Y3 in stroke patients. Serum ATG5 was also measured in 50 healthy controls (HCs). Serum ATG5 was elevated in stroke patients compared to HCs (P<0.001) and was positively correlated to Th2 cells (P=0.022), Th17 cells (P<0.001), and Th17/Treg ratio (P<0.001) in stroke patients but not correlated with Th1 cells, Th1/Th2 ratio, or Treg cells (all P>0.050). Serum ATG5 (P=0.037), Th1 cells (P=0.022), Th17 cells (P=0.002), and Th17/Treg ratio (P=0.018) were elevated in stroke patients with MMSE score-identified cognition impairment vs those without cognition impairment, whereas Th2 cells, Th1/Th2 ratio, and Treg cells were not different between them (all P>0.050). Importantly, serum ATG5 was negatively linked with MMSE score at enrollment (P=0.004), Y1 (P=0.002), Y2 (P=0.014), and Y3 (P=0.001); moreover, it was positively related to 2-year (P=0.024) and 3-year (P=0.012) MMSE score decline in stroke patients. Serum ATG5 was positively correlated with Th2 and Th17 cells and estimated cognitive function decline in stroke patients.
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Abstract Endometriosis's pathophysiology remains incompletely understood, with evidence pointing towards a dysregulated immune response. Regulatory T (Treg) cells, pivotal in maintaining self-tolerance, may facilitate the survival of ectopic endometrial cells within the abdominal cavity, thereby contributing to endometriosis development. This study aimed to assess the prevalence of CD39+CD73+ suppressor Treg cell subsets in the peripheral blood of endometriosis patients. This research focuses on the pivotal role of regulatory T-cells (Tregs), which are essential for maintaining immune tolerance and preventing autoimmune diseases. A case-control study was conducted, including 32 women diagnosed with endometriosis and 22 control subjects. The frequency of peripheral blood CD39+CD73+ suppressor Treg cells was quantified using flow cytometry. No significant differences were observed in the frequency of CD3+CD4+CD25High cells (Median [M]: 10.1; Interquartile Range [IQR]: 6.32‒18.3 vs. M: 9.72; IQR: 6.22-19.8) or CD3+CD4+CD25HighCD39+Foxp3+ cells (M: 31.1; IQR: 19.7-44.0 vs. M: 30.55; IQR: 18.5-45.5) between controls and patients. However, a significantly lower frequency of CD3+CD4+CD25HighCD39+CD73+ cells was observed in the endometriosis group compared to controls (M: 1.98; IQR: 0.0377-3.17 vs. M: 2.25; IQR: 0.50-4.08; p = 0.0483), suggesting a reduction in systemic immune tolerance among these patients. This finding highlights the potential role of CD39 and CD73 expression on Treg cells as biomarkers for assessing disease severity and progression. Furthermore, elucidating the mechanisms driving these alterations may unveil new therapeutic strategies to restore immune equilibrium and mitigate endometriosis symptoms.
RESUMO
Goto-Kakizaki (GK) rats develop a well-defined insulin resistance (IR) andtype 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyteprofile in nonobese diabetic conditions is not yet characterized. Therefore,GK rats were chosen to explore T lymphocyte (TL) dynamics at variousstages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucosetransporter 1 (GLUT1) expression was consistently elevated in GK rats, sug-gesting heightened TL activation. T-regulatory lymphocyte markers dimin-ished at 21 days. However, GK rats showed increased Th1 markers andreduced Gata-3 expression (crucial for Th2 cell differentiation) at 120 days.These findings underscore an early breakdown of anti-inflammatory mecha-nisms in GK rats, indicating a proinflammatory TL profile that may worsenchronic inflammation in T2DM.
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BACKGROUND: Tumor microenvironment is infiltrated by many immune cells, of which Regulatory T (Treg) cells are usually considered as negative regulators of the immune responses. However, the effect of FOXP3+ (forkhead box transcription factor 3) Treg cells infiltrated into the tumor areas on the prognosis of breast cancer is controversial. This meta-analysis aimed to dissect the potential values of FOXP3+ tumor-infiltrating lymphocytes (TILs) as a prognosis predictor of breast cancer. METHODS: After systematic retrieval of all relevant studies, 28 eligible articles were identified for meta-analysis. Odd ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) were obtained for pooled analyses of pathological complete response (pCR), overall survival (OS), and corresponding forest plots and funnel plots were plotted, respectively. RESULTS: Pooled results revealed that patients with higher levels of FOXP3+ TILs experienced better pCR (OR: 1.24, 95% CI 1.09-1.41) and OS (HR: 0.79, 95% CI 0.64-0.97). Subgroup analysis revealed that elevated FOXP3+ TILs were significantly associated with improved pCR (OR: 1.20, 95% CI 1.02-1.40) and OS (HR: 0.22, 95% CI 0.06-0.88) in human epidermal growth factor receptor 2 positive (HER2+) breast cancer patients. Furthermore, FOXP3+ TILs in the stromal area were statistically correlated with the favorable pCR (OR: 1.22, 95% CI 1.08-1.38) and OS (HR: 0.68, 95% CI 0.49-0.96). CONCLUSIONS: The predictive role of FOXP3+ TILs in the prognosis of breast cancer is influenced by various factors such as molecular subtype of breast cancer and the location of Treg. In HER2+ breast cancer and triple-negative breast cancer, FOXP3+ TILs are associated with better pCR and OS. Additionally, FOXP3+ TILs in stromal represent a favourable prognosis.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/patologia , Prognóstico , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Linfócitos T Reguladores/patologia , Fatores de Transcrição Forkhead/metabolismo , Microambiente TumoralRESUMO
Sodium selenite modulates the activity of lymphocytes. It negatively regulates the suppressive activity of cells and increases the immune response. In this study, we evaluated whether the regulatory T cell differentiation was modulated by sodium selenite. The percentages of CD4+CD25+Foxp3+, CD4+CD25+, and CD4+CTLA-4+ cells in CD4+ T cells cultures stimulated with IL-2 and TGF-ß in the presence or absence of selenium, in the form of sodium selenite (2.0×10-6M), were evaluated by flow cytometry. The mRNA expression of TET2/3 enzymes and IL-10 was analyzed by RT-qPCR and the levels of IL-10 were measured by an ELISA. We observed a decrease in CD4+CD25+Foxp3+ and CD4+CTLA-4+ cells in presence of selenium. However, normal percentages were reached again after selenium removal. An increase in CD4+CTL4-4+ cells was detected in selenium-primed cell cultures in absence of IL-2 and TGF-ß. In addition, we observed a decrease in TET3 in presence of selenium. Finally, we observed an augment in IL-10 transcription and protein levels and relative expression of TET2 in cultures exposed to selenium. We suggest that selenium reversibly affects the regulatory T cell differentiation in vitro. Likewise, selenium may modulate Treg percentages promoting optimal immune responses and, at the same time, the expression of specific suppressor molecules.
Assuntos
Interleucina-10 , Selênio , Linfócitos T Reguladores/metabolismo , Selenito de Sódio/farmacologia , Selenito de Sódio/metabolismo , Antígeno CTLA-4/metabolismo , Selênio/farmacologia , Selênio/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Diferenciação Celular , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismoRESUMO
The close relationship between the microbiota and allergic diseases has been known for several years, particularly food allergy. Although the best studied microbiota is that related to bacteria, viruses, parasites and fungi are also constituents of this, although their role is not definitively clarified. The microbial world interacts with the human body constantly, we are in daily contact with an infinite and innumerable number of varieties of microbes in our environment, some of them can pass through the body without causing any harm, while others generate undesirable risk for the body. health. Alteration of the original composition of the microbiota (dysbiosis) is associated with food allergy. This dysbiosis is related to changes in habits, method of termination of pregnancy (birth or cesarean section), replacement of breastfeeding or interruption at an early age; decrease in family size; loss of contact with farm animals or pets; inappropriate prescription or abuse of antibiotics. The transition from a diet based exclusively on milk to one with solid foods is associated with a drastic increase in microbial diversity. Immunomodulatory components of the microbiota (cell surface polysaccharides), dietary factors (vitamin A), and production of secondary metabolites (short-chain fatty acids and secondary bile acid metabolites) promote differentiation of the RORγt+ cell population Treg. ILC3 produces IL-2, which plays a decisive role in maintaining intestinal homeostasis.
La estrecha relación entre la microbiota y las enfermedades alérgicas es conocida desde hace varios años, particularmente la alergia alimentaria. Aunque la microbiota mejor estudiada es la relacionada con las bacterias, también son constitutivas de esta los virus, parásitos y hongos, aun con un rol no definitivamente esclarecido. El mundo microbiano interactúa con el cuerpo humano constantemente, estamos en contacto diario con una cantidad infinita e innumerable de variedades de microbios en nuestro entorno, algunos de ellos pueden pasar a través del cuerpo sin causar ningún daño, mientras que otros generan riesgo indeseable para la salud. La alteración de la composición original de la microbiota (disbiosis) se asocia con alergia alimentaria. Esta disbiosis se relaciona con los cambios de hábito, vía de finalización del embarazo (parto o cesárea), sustitución de la lactancia o interrupción en edades tempranas; disminución del tamaño de las familias; pérdida de contacto con animales de granja o mascotas; prescripción inadecuada o abuso de antibióticos. La transición de una dieta basada exclusivamente en leche a otra con alimentos sólidos se asocia con aumento drástico en la diversidad microbiana. Los componentes inmunomoduladores de la microbiota (polisacáridos de la superficie celular), los factores dietéticos (vitamina A) y la producción de metabolitos secundarios (ácidos grasos de cadena corta y metabolitos secundarios de ácidos biliares) promueven la diferenciación de la población de células RORγt + Treg. La ILC3 produce IL-2, que desempeña un papel decisivo en el mantenimiento de la homeostasis intestinal.
Assuntos
Hipersensibilidade Alimentar , Probióticos , Simbióticos , Feminino , Gravidez , Animais , Humanos , Prebióticos , Cesárea , Disbiose , Probióticos/uso terapêuticoRESUMO
Among the mechanisms of suppression that T regulatory (Treg) cells exert to control the immune responses, the secretion of small extracellular vesicles (sEV) has been recently proposed as a novel contact-independent immunomodulatory mechanism. Previous studies have demonstrated that Treg cells produce sEV, including exosomes, able to modulate the effector function of CD4+ T cells, and antigen presenting cells (APCs) such as dendritic cells (DCs) through the transfer of microRNA, cytokines, the production of adenosine, among others. Previously, we have demonstrated that Neuropilin-1 (Nrp1) is required for Tregs-mediated immunosuppression mainly by impacting on the phenotype and function of effector CD4+ T cells. Here, we show that Foxp3+ Treg cells secrete sEV, which bear Nrp1 in their membrane. These sEV modulate effector CD4+ T cell phenotype and proliferation in vitro in a Nrp1-dependent manner. Proteomic analysis indicated that sEV obtained from wild type (wt) and Nrp1KO Treg cells differed in proteins related to immune tolerance, finding less representation of CD73 and Granzyme B in sEV obtained from Nrp1KO Treg cells. Likewise, we show that Nrp1 is required in Treg cell-derived sEV for inducing skin transplantation tolerance, since a reduction in graft survival and an increase on M1/M2 ratio were found in animals treated with Nrp1KO Treg cell-derived sEV. Altogether, this study describes for the first time that Treg cells secrete sEV containing Nrp1 and that this protein, among others, is necessary to promote transplantation tolerance in vivo via sEV local administration.