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The phenomenon of autoimmunity develops as a result of the triggering factor released by damaged cells. This leads to an infiltration of CD4+ cells involved in stimulating the effector cells cytotoxicity and stimulating the humoral response. One of the most common autoimmune disorders are autoimmune thyroid diseases, including Hashimoto's thyroiditis and Graves's diseases. Helper T lymphocytes, which are divided into Th1, Th2, Tregs, and the relatively new groups Th17, Th22, and Th9, are involved in the pathogenesis of AITD. CD4+ cell subtypes mature and differentiate by specific transcription factors and in a specific interleukin environment. Not only are Th1 and Th2 cells involved in the development of AITD, but also Th17, Th22, and Th9 lymphocytes and their correlation to Tregs lymphocytes. The plasticity of the CD4+ cells is very important, affecting the balance between these cells, as well the factors modulating their phenotypic variability. Patients with AITD have an increased percentage of Th17, Th22, and Th9 cells as well as defective function of Tregs lymphocytes. The balance between Th17 cells (and also other cytotoxic T cells) and Treg cells is also very important. Understanding the role of CD4 cells in the pathogenesis of AITD may be important not only for the development of the knowledge, but also for determining therapeutic targets.
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Enfermedades Autoinmunes , Linfocitos T CD4-Positivos , Linfocitos T Colaboradores-Inductores , Enfermedad de Graves , Enfermedad de Hashimoto , HumanosRESUMEN
Chronic lung allograft dysfunction (CLAD) is the main cause of poor survival and low quality of life of lung transplanted patients. Several studies have addressed the role of dendritic cells, macrophages, T cells, donor specific as well as anti-HLA antibodies, and interleukins in CLAD, but the expression and function of immune checkpoint molecules has not yet been analyzed, especially in the two CLAD subtypes: BOS (bronchiolitis obliterans syndrome) and RAS (restrictive allograft syndrome). To shed light on this topic, we conducted an observational study on eight consecutive grafts explanted from patients who received lung re-transplantation for CLAD. The expression of a panel of immune molecules (PD1/CD279, PDL1/CD274, CTLA4/CD152, CD4, CD8, hFoxp3, TIGIT, TOX, B-Cell-Specific Activator Protein) was analyzed by immunohistochemistry in these grafts and in six control lungs. Results showed that RAS compared to BOS grafts were characterized by 1) the inversion of the CD4/CD8 ratio; 2) a higher percentage of T lymphocytes expressing the PD-1, PD-L1, and CTLA4 checkpoint molecules; and 3) a significant reduction of exhausted PD-1-expressing T lymphocytes (PD-1pos/TOXpos) and of exhausted Treg (PD-1pos/FOXP3pos) T lymphocytes. Results herein, although being based on a limited number of cases, suggest a role for checkpoint molecules in the development of graft rejection and offer a possible immunological explanation for the worst prognosis of RAS. Our data, which will need to be validated in ampler cohorts of patients, raise the possibility that the evaluation of immune checkpoints during follow-up offers a prognostic advantage in monitoring the onset of rejection, and suggest that the use of compounds that modulate the function of checkpoint molecules could be evaluated in the management of chronic rejection in LTx patients.
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Aloinjertos , Regulación de la Expresión Génica , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Proteínas de Punto de Control Inmunitario/genética , Trasplante de Pulmón , Adulto , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores , Susceptibilidad a Enfermedades , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Proteínas de Punto de Control Inmunitario/metabolismo , Inmunohistoquímica , Trasplante de Pulmón/efectos adversos , Masculino , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: The aim: To evaluate the relationship of certain alleles of HLA class II leukocyte antigens and the profile of antibodies to various subunits of nicotinic acetylcholine receptors (nAChR), the level of Treg lymphocytes and the serum concentration of anti-inflammatory IL-10 for various clinical myasthenia gravis phenotypes. PATIENTS AND METHODS: Materials and methods: We examined 217 patients with thymus-independent myasthenia (n = 42) and thymus-dependent myasthenia, among them patients with thymus hyperplasia (n = 108) and thymoma (n = 67). We used the following methods: ELISA, flow cytometry, light and fluorescence microscopy. RESULTS: Results: Certain genomic (polymorphism of leukocyte HLA-DR antigens) and epigenomic (antibodies to α1 and α7 nAChR subunits, expression of Treg lymphocytes and concentration of cytokines) predictors were identified for various myasthenia phenotypes. The presence of HLA haplotypes DR2 and DR7 in some young patients with M with disease progression led to the development of myasthenia gravis with thymoma (MT) at an older age. The presence of α7 nAChR subunit on thymocyte mitochondria was revealed, which is an additional autoimmune target for autoantibodies in patients with myasthenia gravis. An increase in the concentration of cytokines (IL-4, IL-8, IFN-γ) in all patients with myasthenia gravis was revealed. CONCLUSION: Conclusions: Estimate the features of the formation of various variants of the immune response in thymus-independent and thymus-dependent myasthenia gravis is a necessary condition for targeted immunocorrection or surgery.
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Miastenia Gravis , Neoplasias del Timo , Anciano , Autoanticuerpos , Epigenómica , Genómica , Humanos , Miastenia Gravis/genética , FenotipoRESUMEN
High-salt intake and high-fructose intake are risk factors for hypertension via oxidative stress and inflammation. T helper (Th)17 lymphocytes play an important role in the development of hypertension. Here, we tested the hypothesis that activation of pathogenic Th17 lymphocytes induces hypertension after high-fructose intake in Dahl salt-sensitive (SS) but not Dahl salt-resistant (SR) rats. Eight-week-old male SS and SR rats were offered 20% fructose solution or tap water only for 4â weeks. Systolic blood pressure was measured by the tail-cuff method. T lymphocyte [Th17 and T regulatory (Treg)] profiling was determined via flow cytometry. The expression of Th17-related (IL-17A, IL-17RA, IL-23R and RORγt) and Treg-related (IL-10, CD25, FOXP3 and TGFß) factors were measured via ELISA or qRT-PCR. Th17 lymphocytes isolated from high-fructose-fed SS rats were intraperitoneally injected into recipient SS and SR rats, and recombinant IL-23 protein was subcutaneously injected into SS and SR rats to induce hypertension.High-fructose intake induced hypertension via the activation of pathogenic Th17 lymphocytes in SS but not SR rats. Injection of activated Th17 lymphocytes isolated from fructose-fed SS rats induced hypertension via increase of serum IL-17A only in recipient SS rats. In addition, injection of IL-23 induced hypertension via activation of pathogenic Th17 lymphocytes only in SS rats.Thus, activation of pathogenic Th17 lymphocytes induces hypertension after high-fructose intake in SS but not SR rats. These results indicate that immunologic tolerance plays an important role in protection against hypertension in SR rats.
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Hipertensión/inmunología , Activación de Linfocitos/inmunología , Células Th17/inmunología , Animales , Presión Sanguínea , Peso Corporal , Citocinas/sangre , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Fructosa , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/inmunología , Hipertensión/sangre , Hipertensión/complicaciones , Proteínas Inmediatas-Precoces/metabolismo , Interleucina-23/metabolismo , Masculino , Modelos Biológicos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas Endogámicas Dahl , Transducción de Señal , Sístole , Linfocitos T Reguladores/inmunologíaRESUMEN
We aimed in this study to investigate a possible involvement of Th17/Treg cells imbalance in autism spectrum disorders (ASD). Using flowcytometry to determine circulating Th17 and Treg cells percentages, RT- PCR and ELISA for cytokine expression, we demonstrated that Th17/Treg balance in ASD children was significantly skewed toward a Th17 response compared to their control. Th17 cells and the ratio of Th17/Treg cells had a significantly positive correlation with disease severity whereas Treg cells had a negative correlation. The imbalance of Th17, Treg cells and their related cytokines may play a vital role in the progression of the disease.
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Trastorno del Espectro Autista/sangre , Interleucina-10/sangre , Interleucina-17/sangre , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Factor de Crecimiento Transformador beta/sangre , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/inmunología , Biomarcadores/sangre , Niño , Preescolar , Femenino , Citometría de Flujo/métodos , Humanos , Interleucina-10/inmunología , Interleucina-17/inmunología , Masculino , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
Background and Rationale: Among the key players in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), microglia and T regulatory lymphocytes (Treg) are candidate cells for modifying the course of the disease. The gut microbiota (GM) acts by shaping immune tolerance and regulating the Treg number and suppressive function, besides circulating neuropeptides, and other immune cells that play in concert through the gut-brain axis. Previous mouse models have shown an altered enteric flora in early stage ALS, pointing to a possible GM role in ALS pathogenesis. Fecal Microbial Transplantation (FMT) is a well-known therapeutic intervention used to re-establish the proper microenvironment and to modulate enteric and systemic immunity. Methods: We are going to perform a multicenter randomized double-blind clinical trial employing FMT as a therapeutic intervention for ALS patients (NCT0376632). Forty-two ALS patients, at an early stage, will be enrolled with a 2:1 allocation ratio (28 FMT-treated patients vs. 14 controls). Study duration will be 12 months per patient. Three endoscopic procedures for intestinal biopsies in FMT and control groups are predicted at baseline, month 6 and month 12; at baseline and at month 6 fresh feces from healthy donors will be infused at patients in the intervention arm. The primary outcome is a significant change in Treg number between FMT-treated patients and control arm from baseline to month 6. Secondary outcomes include specific biological aims, involving in-depth analysis of immune cells and inflammatory status changes, central and peripheral biomarkers of ALS, besides comprehensive analysis of the gut, saliva and fecal microbiota. Other secondary aims include validated clinical outcomes of ALS (survival, forced vital capacity, and modifications in ALSFRS-R), besides safety and quality of life. Expected Results: We await FMT to increase Treg number and suppressive functionality, switching the immune system surrounding motorneurons to an anti-inflammatory, neuroprotective status. Extensive analysis on immune cell populations, cytokines levels, and microbiota (gut, fecal and saliva) will shed light on early processes possibly leading the degenerative ALS course. Conclusions: This is the first trial with FMT as a potential intervention to modify immunological response to ALS and disease progression at an early stage.
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Systemic and local chronic inflammation might enhance the risk of pancreatic ductal adenocarcinoma (PDAC), and PDAC-associated inflammatory infiltrate in the tumor microenvironment concurs in enhancing tumor growth and metastasis. Inflammation is closely correlated with immunity, the same immune cell populations contributing to both inflammation and immune response. In the PDAC microenvironment, the inflammatory cell infiltrate is unbalanced towards an immunosuppressive phenotype, with a prevalence of myeloid derived suppressor cells (MDSC), M2 polarized macrophages, and Treg, over M1 macrophages, dendritic cells, and effector CD4⺠and CD8⺠T lymphocytes. The dynamic and continuously evolving cross-talk between inflammatory and cancer cells might be direct and contact-dependent, but it is mainly mediated by soluble and exosomes-carried cytokines. Among these, tumor necrosis factor alpha (TNFα) plays a relevant role in enhancing cancer risk, cancer growth, and cancer-associated cachexia. In this review, we describe the inflammatory cell types, the cytokines, and the mechanisms underlying PDAC risk, growth, and progression, with particular attention on TNFα, also in the light of the potential risks or benefits associated with anti-TNFα treatments.
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Inmunidad , Inflamación/inmunología , Neoplasias Pancreáticas/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Citocinas/análisis , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Inflamación/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Páncreas/inmunología , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Microambiente TumoralRESUMEN
Background: Fibroblast proliferation is a critical feature during heart failure development. Previous studies reported regulatory T-lymphocytes (Tregs)' protective role against myocardial fibrosis. However, notably, Tregs also secrete fibrogenic cytokine TGF-ß when activated. This study aimed to clarify the intriguing link between Tregs and fibrosis, the role of Tregs Kv1.3 potassium channel (regulating T-lymphocytes activation) in the fibrosis process, and how selective aldosterone receptor antagonist Eplerenone affects Tregs and fibrosis through its action on Kv1.3 channel. Methods and Results: After co-incubation with Tregs, cardiac fibroblast proliferation (CCK-8 assay) and levels of collagen I, III, and Matrix metalloproteinase2 (ELISA) significantly elevated. Cell viability assays, Kv1.3 channel mRNA (RT-qPCR), and protein expression (In-Cell Western Blotting) revealed Tregs were activated/proliferated when co-cultured with fibroblasts. Treg intracellular TGF-ß level increased by 5.8-fold, far more than that of intracellular IL-10, extracellular TGF-ß and IL-10 (ELISA). And 30 µM eplerenone suppressed Tregs proliferation by 82.77% and furthermore, suppressed intracellular TGF-ß level to a significantly greater extent than that of intracellular IL-10, extracellular TGF-ß and IL-10. Moreover, the Kv1.3 current (whole-cell patch clamp) of Tregs in congestive heart failure patients and rats (induced by coronary artery ligation and exhaustive exercise) elevated by >4-fold than that of healthy volunteers and control rats, whereas 30 µM eplerenone suppressed the current by >60% in control Tregs. In addition, docking calculations (AutoDock software 4.0 suite) showed eplerenone has higher H-bond energy with Kv1.3 channel than other selective blockers. Conclusion: Immuno-regulation in the late stage of CHF activates Tregs proliferation via the upregulation of Kv1.3 channels, which promotes cardiac fibrosis by primarily secreting TGF-ß. Taken together, eplerenone's high affinity to Kv1.3 channel enables it to antagonize the Kv1.3 channels directly to suppress Tregs proliferation, which in turn may play an immuno-regulatory role during CHF.
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Breast cancer is the most frequently diagnosed type of cancer in women worldwide. Both the development and progression of breast cancer are related to tumour evasion of the immune system through a process called cancer immune-editing, in which regulatory lymphocytes play an important role. The infiltration of Treg cells in patients with breast cancer has been proposed as an independent unfavourable prognostic factor. In the present study, we aimed to evaluate the percentages of the Treg cell populations in the peripheral blood of patients with breast cancer with respect to progesterone receptor expression. Peripheral blood samples were collected from 27 patients with breast cancer treated in the Clinical Department of Breast Cancer and Reconstructive Surgery of the Professor Franciszek Lukaszczyk Oncological Centre, Bydgoszcz. Flow cytometry was used to evaluate the percentage of CD25+/FOXP3+/CD127 (-/low) T cells within CD3+/CD4+ T cells. The presence of CD25+/FOXP3+/CD127 (-/low) T cells within CD3+/CD4+ T cells was identified in all the examined blood samples. A statistically significantly higher percentage of CD25+/FOXP3+/CD127 (-/low) T cells within CD3+/CD4+ T cells was observed in progesterone receptor (PR)-negative breast cancer patients when compared to PR-positive breast cancer patients. The observed high percentage of CD25+/FOXP3+/CD127 (-/low) T cells within CD3+/CD4+ T cells in PR (-) breast cancer patients when compared to PR (+) breast cancer patients seems to confirm the unfavourable prognostic significance of these cells in breast cancer patients. This may indicate a rationale for combining standard oncological treatment in breast cancer patients with Treg-depleting therapy.
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Childhood eczema or atopic dermatitis (AD) is a distressing disease associated with pruritus, sleep disturbance, impaired quality of life and Staphylococcus aureus isolation. The pathophysiology of AD is complex and various seromarkers of immunity are involved. We investigated if anti-staphylococcal enterotoxin IgE (anti-SE), selected seromarkers of T regulatory (Treg), T helper (Th) and antigen-presenting cells (APC) are associated with clinical signs of disease severity and quality of life. Disease severity was assessed with the Scoring Atopic Dermatitis (SCORAD) index, and quality of life with the Children's Dermatology Life Quality Index (CDLQI) in AD patients ≤18 years old. Concentrations of anti-staphylococcus enterotoxin A and B immunoglobulin E (anti-SEA and anti-SEB), selected Treg/Th/APC chemokines, skin hydration and transepidermal water loss (TEWL) were measured in these patients. Forty patients with AD [median (interquartile range) age of 13.1 (7.9) years) were recruited. Backward stepwise linear regression (controlling for age, personal allergic rhinitis and asthma, and other blood markers) showed the serum anti-SEB level was positively associated with S. aureus and S. epidermidis isolations, objective SCORAD, clinical signs and CDLQI. TNF-α (a Th1 cytokine) was positively associated with objective SCORAD (B = 4.935, p = 0.010), TGF-ß (a Treg cytokine) negatively with disease extent (B = -0.015, p = 0.001), IL-18 (an APC cytokine) positively with disease extent (B = 0.438, p = 0.001) and with TEWL (B = 0.040, p = 0.010), and IL-23 (an APC cytokine) negatively with disease extent (B = -2.812, p = 0.006) and positively with pruritus (B = 0.387, p = 0.007). CONCLUSIONS: Blood levels of anti-SEB, Th1, Treg and APC cytokines are correlated with various clinical signs of AD. AD is a systemic immunologic disease involving Staphylococcus aureus, cellular, humoral, cytokine and chemokine pathophysiology.
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Dermatitis Atópica/diagnóstico , Inmunoglobulina E/sangre , Prurito/diagnóstico , Staphylococcus aureus , Adolescente , Células Presentadoras de Antígenos/inmunología , Biomarcadores/sangre , Quimiocinas/sangre , Niño , Preescolar , Dermatitis Atópica/sangre , Enterotoxinas/sangre , Femenino , Humanos , Masculino , Prurito/sangre , Calidad de Vida , Piel/microbiología , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Factor de Crecimiento Transformador beta/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
OBJECTIVES: Classically, immune thrombocytopenia (ITP) was thought to be caused by the destruction and insufficient production of platelets, as mediated by autoantibodies. More recently other immune mechanisms that contribute to the disease have been discovered. This review attempts to address the main unresolved questions in ITP. METHODS: We review the most current knowledge of the pathophysiology of ITP. Immunological effects of available therapies are also described. DISCUSSION: The trigger may be a loss of tolerance due to molecular mimicry with cross-reaction of antibodies arising from infectious agents or drugs, genetic factors, and/or platelet Toll receptors. This loss of tolerance activates autoreactive effector B and T lymphocytes, which in turn initiates platelet destruction, mediated by cytotoxic T lymphocytes and the release of pro-inflammatory cytokines (IL-2/IL-17) by T helper (Th) cells (Th1/Th17). Th2 (anti-inflammatory) and regulatory B (Breg) and Treg cells are also inhibited (with decrease in IL-10/TGF-ß), which leads to the disease becoming chronic. Some isotypes of autoantibodies may increase the bleeding risk. Corticosteroids, rituximab, and thrombopoietin receptor agonists (A-TPOs) all increase levels of Tregs and TGF-ß. The A-TPOs also increase Breg levels, which could explain why complete remission has been seen in some cases. CONCLUSION: A better understanding of the immunomodulatory effects of each ITP therapy is needed to best manage the disease.
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Púrpura Trombocitopénica Idiopática/fisiopatología , HumanosRESUMEN
We have shown that cholera toxin (CT) and other cyclic AMP (cAMP)-elevating agents induce upregulation of the inhibitory molecule CTLA-4 in human resting CD4+ T lymphocytes, which following the treatment acquired suppressive functions. In this study, we evaluated the effect of cAMP-elevating agents on human CD4+CD25+ T cells, which include the T regulatory cells (Tregs) that play a pivotal role in the maintenance of immunological tolerance. We found that cAMP-elevating agents induce upregulation of CTLA-4 in CD4+CD25- and further enhance its expression in CD4+CD25+ T cells. We observed an increase of two isoforms of mRNA coding for the membrane and the soluble CTLA-4 molecules, suggesting that the regulation of CTLA-4 expression by cAMP is at the transcriptional level. In addition, we found that the increase of cAMP in CD4+CD25+ T cells converts the CD4+CD25+Foxp3- T cells in CD4+CD25+Foxp3+ T cells, whereas the increase of cAMP in CD4+CD25- T cells did not upregulate Foxp3 in the absence of activation stimuli. To investigate the function of these cells, we performed an in vitro suppression assay by culturing CD4+CD25+ T cells untreated or pre-treated with CT with anti-CD3 mAbs-stimulated autologous peripheral blood mononuclear cell. We found that CT enhances the inhibitory function of CD4+CD25+ T cells, CD4+, and CD8+ T cell proliferation and IFNγ production are strongly inhibited by CD4+CD25+ T cells pre-treated with cAMP-elevating agents. Furthermore, we found that CD4+CD25+ T lymphocytes pre-treated with cAMP-elevating agents induce the upregulation of CD80 and CD86 co-stimulatory molecules on immature dendritic cells (DCs) in the absence of antigenic stimulation, however without leading to full DC maturation. These data show that the increase of intracellular cAMP modulates the phenotype and function of human CD4+CD25+ T cells.
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Early studies described CD69 as a leukocyte activation marker, and suggested its involvement in the activation of different leukocyte subsets as well as in the pathogenesis of chronic inflammation. However, recent investigations have showed that CD69 knockout mice exhibit an enhanced or reduced susceptibility to different experimental models of inflammatory diseases, including those mediated by T helper 17 (Th17) lymphocytes. In this regard, the expression of CD69, both in Th17 lymphocytes and by a subset of regulatory T cells, has an important role in the control of the immune response and the inflammatory phenomenon. Therefore, different evidence indicates that CD69 exerts a complex immunoregulatory role in humans, and that it could be considered as a target molecule for the therapy of immune-mediated diseases.