Regulatory T cells isolated from endometriotic peritoneal fluid express a different number of Toll-like receptors / Células T reguladoras isoladas do fluido peritoneal de mulheres com endometriose expressam um número diferente de receptores do tipo Toll

ABSTRACT Objective To analyze and compare the expression of Toll-like receptors by regulatory T cells present in the peritoneal fluid of patients with and without endometriosis. Methods Regulatory T cells were isolated from peritoneal fluid of women with and without endometriosis, collected during surgery, and mRNA was extracted for analysis of Toll-like receptors expression by reverse-transcriptase polymerase chain reaction. Results Patients with endometriosis presented regulatory T cells expressing a larger number and variety of Toll-like receptors when compared to regulatory T cells from patients in the Control Group. Toll-like receptor-1 and Toll-like receptor-2 in regulatory T cells were expressed in both groups. All other expressed Toll-like receptors types were only found in regulatory T cells from the Endometriosis Group. Conclusion Patients with endometriosis had peritoneal regulatory T cells expressing various Toll-like receptors types.

RESUMO Objetivo Analisar e comparar a expressão de receptores do tipo Toll por células T reguladoras presentes no líquido peritoneal de pacientes com endometriose. Métodos Células T reguladoras foram isoladas do líquido peritoneal de mulheres com e sem endometriose, coletadas durante a cirurgia, e o RNAm foi extraído para análise da expressão de receptores do tipo Toll por reação em cadeia da polimerase com transcriptase reversa. Resultados Pacientes com endometriose apresentaram células T reguladoras expressando maior número e variedade de Toll por células quando comparadas com T reguladoras de pacientes do Grupo Controle. Receptores do tipo Toll-1 e receptores do tipo Toll-2 foram expressos em ambos os grupos. Todos os outros tipos de receptores Toll foram encontrados expressos apenas em células T reguladoras do grupo com endometriose. Conclusão Pacientes com endometriose apresentaram células T reguladoras peritoneais expressando vários tipos de receptores tipo Toll.

Células T reguladoras en lupus eritematoso generalizado / Regulatory T cells in systemic lupus erythematosus

Resumen El lupus eritematoso generalizado (LEG) es una enfermedad autoinmune crónica caracterizada por la pérdida de la tolerancia a los antígenos propios y la síntesis de diferentes autoanticuerpos con la formación y depósito de complejos inmunes y el daño de múltiples órganos. Las células T reguladoras (Treg) desempeñan un papel esencial en el mantenimiento de la tolerancia periférica, controlan el estado de activación del sistema inmune y limitan las respuestas autoinmunes. El estudio del número y la función de las diferentes subpoblaciones de células Treg en LEG ha sido objeto de una intensa investigación. Dependiendo del fenotipo de las células Treg analizado se ha reportado que la frecuencia de estas células en pacientes con LEG se encuentra disminuida, aumentada o sin alteraciones. Además, diferentes grupos han descrito que la función supresora de las células Treg de los pacientes con LEG se encuentra reducida o no se ve afectada. En conjunto, lo datos reportados sugieren que las células Treg desempeñan un papel relevante en la patogénesis del LEG y que estos linfocitos pueden ser considerados blancos potenciales para el diseño de nuevas estrategias terapéuticas para esta enfermedad.

Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a loss of tolerance to self-antigens and synthesis of different autoantibodies, with the formation and deposition of immune complexes and damage to multiple organs. T regulatory cells (Tregs) play a crucial role in maintaining peripheral tolerance, controlling the state of activation of the immune system and limiting autoimmune responses. The study of the number and function of the different Treg cell subpopulations in SLE has been the subject of intense research. Depending on the analyzed Treg cell phenotype, the frequency of these cells has been reported to be reduced, increased or unaltered in patients with SLE. In addition, different groups have described that Treg cells suppressive function is reduced or unaffected in patients with SLE. Taken together, the reported data suggest that Treg cells play a relevant role in the pathogenesis of SLE and that these lymphocytes can be considered potential targets for the design of new therapeutic strategies for this condition.

Low frequency of regulatory B-cells and increased CD4+ and CD8+ interferon-γ-producing cells in patients with tropical spastic paraparesis associated with human T-cell lymphotropic virus type

Abstract INTRODUCTION: Tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) is a disease caused by human T-cell lymphotropic virus type 1 (HTLV-I) that mainly infects CD4 T cells-for example, those of the CD4+CD25hiFOXP3+ [Treg] phenotype-where it inhibits forkhead box protein P3 (FOXP3) expression and promotes interferon-γ (IFN-γ) expression. However, the role it exerts on regulatory B cells (CD19+CD24hiCD38hi; Breg) is unknown. METHODS: The frequencies of Treg and Breg cells was evaluated and the Th1 profiles were assessed in TSP/HAM patients and healthy control subjects. RESULTS: Low percentages of Breg cells and high production of IFN-γ were observed in patients compared to those in healthy control subjects. CONCLUSIONS: The low percentage of Breg cells in patients and the increase in the frequency of Th1 cells suggest an imbalance in the control of the inflammatory response that contributes to the immunopathogenesis of TSP/HAM.

Cytokines and chemokines associated with Treg/Th17 response in chronic inflammatory periapical disease

Abstract Cytokines and chemokines have a fundamental role in the maintenance of inflammation and bone response, which culminate in the development of chronic periapical lesions. Regulatory (Treg) and Th17 cytokines play a key role in regulating the immune response involved in this process. The aim of this study was to investigate the role of Treg and Th17 cells in chronic inflammatory periapical disease, by comparing the expression of the immunoregulatory mediators TGF-β, IL-10, CCL4, and the proinflammatory IL-17 and CCL20 in the periapical tissue of teeth with pulp necrosis, with and without associated chronic lesions. Eighty-six periapical tissue samples were obtained from human teeth. The samples were divided into three groups: pulp necrosis with a periapical lesion (n=26); pulp necrosis without a periapical lesion (n=30), and control (n=30). All samples were submitted to histopathological analysis and cytokine and chemokine measurement through ELISA. Statistical analyses were done with Kruskal-Wallis and Mann-Whitney tests and Spearman correlation. The group with pulp necrosis and a periapical lesion showed a higher expression of CCL4 and TGF-β in comparison with pulp necrosis without a lesion. CCL20 was higher in the group with a periapical lesion when compared to the control. In all groups there was a weak positive correlation between IL-17/CCL20, IL-10/CCL4, and IL-17/TGF-β. Both types of cytokines, pro-inflammatory and immunoregulatory, occur simultaneously in periapical tissue. However, a rise in immunosuppressive cytokines and chemokines (CCL4 and TGF-β) in periapical lesions suggests a role of these cytokines in stable periapical disease.

Altered Tregs and oxidative stress in pregnancy associated lupus

Abstract Aim SLE is a systemic autoimmune disease generally affecting woman in the reproductive age. It is associated with an altered level of Tregs and oxidative stress while an increase in Tregs, and different antioxidant mechanisms to combat oxidative stress are essential for successful pregnancy. Hence, this study aims to determine the level of CD4+ and CD8+ Tregs and oxidative stress in pregnant lupus patients. Methods Ten healthy and 10 pregnant lupus volunteers from the North Indian population, within the age group of 20-30 years were enrolled in the study. All the patients were non-smokers, non-alcoholics and were not associated or undergoing therapy for any other disease. They had a SLEDAI of 37.4 ± 7.32 with 5.2 ± 1.93 years of disease duration. Oxidative stress was determined by measuring the enzyme activity of anti-oxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) and the level of reduced glutathione and lipids peroxidised, spectrophotometrically. Flowcytometry was performed for immunophenotyping to determine CD8+ and CD4+ Tregs. Results Elevated CD8+ Tregs and diminished CD4+ Tregs were observed in pregnant lupus patients. Oxidative stress was significantly increased as the activities of anti-oxidant enzymes and level of reduced glutathione was considerably diminished. There was a substantial increase in the amount of lipids peroxidised. Conclusion Pregnant lupus patients undergo considerable level of oxidative stress in comparison to healthy pregnant woman. The decreased level of CD4+ Tregs and an increase in CD8+ Tregs might be another important factor responsible for pregnancy associated complications. Hence, lupus leads to alterations in the necessary conditions for a successful pregnancy, which might eventually cause higher mortality, morbidity and associated complications.

CD4+CD69+ T cells and CD4+CD25+FoxP3+ Treg cells imbalance in peripheral blood, spleen and peritoneal lavage from pristane-induced systemic lupus erythematosus (SLE) mice

Abstract Background: Adaptive immune cells, including CD4+CD69+ and CD4+CD25+FoxP3+ regulatory T (Treg) cells, are important for maintaining immunological tolerance. In human systemic lupus erythematosus (SLE), CD4+CD25+FoxP3+ Treg cells are reduced, whereas CD69 expression is increased, resulting in a homeostatic immune imbalance that may intensify autoreactive T cell activity. To analyze the mechanisms implicated in autotolerance failure, we evaluated CD4+CD69+ and CD4+CD25+FoxP3+ T cells and interleukin profiles in a pristane-induced SLE experimental model. Methods: For lupus induction, 26 female Balb/c mice received a single intraperitoneal 0.5 ml dose of pristane, and 16 mice received the same dose of saline. Blood and spleen samples were collected from euthanized mice 90 and 120 days after pristane or saline inoculation. Mononuclear cells from peripheral blood (PBMC), peritoneal lavage (PL) and splenocytes were obtained by erythrocyte lysis and cryopreserved for further evaluation by flow cytometry using the GuavaEasyCyte TM HT. After thawing, cells were washed and stained with monoclonal antibodies against CD3, CD4, CD8, CD25, CD28, CD69, FoxP3, CD14 and Ly6C (BD Pharmingen TM). Interleukins were quantified using Multiplex® MAP. The Mann-Whitney test and the Pearson coefficient were used for statistical analysis, and p < 0.05 considered significant. Results: Compared with the controls, SLE-induced animals presented increased numbers of CD4+CD69+ T cells in the blood on T90 and T120 (p = 0.022 and p = 0.008) and in the spleen on T120 (p = 0.049), but there were decreased numbers in the PL (p = 0.049) on T120. The percentage of Treg was lower in blood (p < 0.005 and p < 0.012) on T90 and T120, in spleen (p = 0.043) on T120 and in PL (p = 0.001) on T90. Increased numbers of CD4+ CD69+ T cells in the PL were positively associated with high IL-2 (p = 0.486) and IFN-γ (p = 0.017) levels, whereas reduced Treg cells in the blood were negatively correlated with TNFα levels (p = 0.043) and positively correlated with TGFβ1 (p = 0.038). Conclusion: Increased numbers of CD4+CD69+ T cells and reduced numbers of CD4+CD25+FoxP3+ Treg cells with an altered interleukin profile suggests loss of autotolerance in pristane-induced lupus mice, which is similar to human lupus. Therefore, this model is useful in evaluating mechanisms of cellular activation, peripheral tolerance and homeostatic immune imbalance involved in human SLE.

Ultrasound inflammatory parameters and Treg/Th17 cell profiles in established rheumatoid arthritis

Abstract Background: Imbalance and disfuntion in regulatory T-cells (Tregs) and IL-17 producer lymphocytes (Th17) have been implicated in the pathogenesis of rheumatoid arthritis (RA). Gray scale synovial proliferation (GS), power Doppler signal (pD) and bone erosions seen on high resolution muskuloskeletal ultrasound (MSUS) are hallmarks of destructive articular disease. Objective: To evaluate the association of peripheral Tregs and Th17 with MSUS findings in RA. Methods: RA patients (1987 ACR criteria) treated with disease-modifying antirheumatic drugs (DMARDs) were included. Lymphocytes were isolated and immunophenotyped by flow cytometry to investigate regulatory FoxP3+ T cells and IL-17+ cells. MSUS (MyLab 60, Esaote, Genova, Italy, linear probe 6-18 MHz) was performed on hand joints, and a 10-joint US score was calculated for each patient. Results: Data on lymphocytes subsets were avaiable for 90 patients. The majority of patients were Caucasian women with a median disease duration of 6 years (interquartile range: 2-13 years). Mean DAS28 was 4.28 (SD ± 1.64) and mean HAQ score was 1.11 (SD ± 0.83). There was no significant correlation of 10-joint GS score (rS = 0.122, 95% CI: - 0.124 to 0.336, P = 0.254) and 10-joint pD score (rS = 0.056, 95% CI: - 0.180 to 0.273, P = 0.602) with the mean percentage of peripheral Treg cells. Also, 10-joint GS score (rS = 0.083, 95% CI: - 0.125 to 0.302, P = 0.438) and 10-joint pD score 10 (rS = - 0.060, 95% CI: - 0.271 to 0.150, P = 0.575); did not correlate to Th17 profile. No association of bone erosions on MSUS with Treg and Th17 profiles (P = 0.831 and P = 0.632, respectively) was observed. Conclusion: In this first study addressing MSUS features and lymphocytes subtypes in established RA, data did not support an association of circulating Tregs and Th17 lymphocytes with inflammatory and structural damage findings on MSUS.

Maternal schistosomiasis: IL-2, IL-10 and regulatory T lymphocytes to unrelated antigen in adult offspring mice

Abstract INTRODUCTION: We evaluated IL-10, IL-2 and regulatory T cells (Treg), in response to ovalbumin (OA), in offspring from schistosomotic mouse mothers. METHODS: We used animals born (BIM) or suckled (SIM) from infected mothers; and mice born/suckled from infected (BSIM) or non-infected mothers (CONTROL). After OA+adjuvant immunization, spleen cells were cultured, with or without OA, and doubly marked for cytometry. RESULTS: BIM showed fewer CD4+/IL-2+ and more B220+/IL-10+ cells, whereas the SIM group showed increased Treg frequency. BSIM had fewer B220+/IL-10+ and Treg cells. CONCLUSIONS: Separately, gestation or nursing induced immunosuppressive cells in infected mothers, but improved anti-OA immunity when combined.

Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis

Abstract: Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation.

Immunotherapy and gene therapy as novel treatments for cancer / Inmunoterapia y terapia génica como nuevos tratamientos contra el cáncer

Abstract The immune system interacts closely with tumors during the disease development and progression to metastasis. The complex communication between the immune system and the tumor cells can prevent or promote tumor growth. New therapeutic approaches harnessing protective immunological mechanisms have recently shown very promising results. This is performed by blocking inhibitory signals or by activating immunological effector cells directly. Immune checkpoint blockade with monoclonal antibodies directed against the inhibitory immune receptors CTLA-4 and PD-1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is an anti-CTLA-4 antibody which demonstrated good results when administered to patients with melanoma. Gene therapy has also shown promising results in clinical trials. Particularly, Herpes simplex virus (HSV)-mediated delivery of the HSV thymidine kinase (TK) gene to tumor cells in combination with ganciclovir (GCV) may provide an effective suicide gene therapy for destruction of glioblastomas, prostate tumors and other neoplasias by recruiting tumor-infiltrating lymphocytes into the tumor. The development of new treatment strategies or combination of available innovative therapies to improve cell cytotoxic T lymphocytes trafficking into the tumor mass and the production of inhibitory molecules blocking tumor tissue immune-tolerance are crucial to improve the efficacy of cancer therapy.

Resumen El sistema inmune interactúa íntimamente con los tumores durante el proceso del desarrollo de la enfermedad y su progresión a metástasis. Esta compleja comunicación entre el sistema inmune y las células tumorales puede prevenir o promover el crecimiento del tumor. Los nuevos enfoques terapéuticos que aprovechan los mecanismos inmunológicos, ya sea por el bloqueo de señales inhibitorias o por la activación directa de células efectoras, han mostrado resultados prometedores. El bloqueo de puntos de control inmunológicos (immune-checkpoints) con anticuerpos monoclonales dirigidos contra receptores que normalmente inhiben el sistema inmune, como CTLA-4 o PD-1, ha resultado ser un tratamiento exitoso para pacientes con melanoma avanzado. El fármaco ipilimumab es un anticuerpo anti-CTLA-4 que ha demostrado buenos resultados terapéuticos en pacientes con melanoma. Por otro lado, la terapia génica también ha mostrado resultados prometedores en ensayos clínicos. En especial, la administración de la enzima timidina quinasa del virus Herpes simplex (HSV-TK) en combinación con el fármaco ganciclovir (GCV) ha mostrado ser una terapia suicida muy efectiva para la destrucción de diferentes neoplasias incluyendo glioblastomas y tumores prostáticos, por un mecanismo que involucra el reclutamiento de linfocitos infiltrantes de tumor. Es importante la búsqueda de nuevas estrategias o la combinación de terapias innovadoras, con el fin de involucrar tanto la atracción de linfocitos citotóxicos así como el empleo de moléculas que inhiban la inmunotolerancia del tejido tumoral para mejorar la eficiencia de los tratamientos contra el cáncer.

Relación entre linfocitos T reguladores (T regs) y anticuerpos anti-receptores de TSH (TRab) y el riesgo de cáncer de tiroides en enfermedad de Graves / Relationship between T regulatory lymphocytes (Tregs) and TSH receptor antibodies (TRab) on risk of thyroid cancer in Graves disease

Durante los últimos años se ha estudiado la relación entre enfermedad de Graves (EG), TSH, TRAb y cáncer de tiroides, existiendo estudios que demuestran mayor prevalencia y agresividad del cáncer de tiroides en pacientes con EG, mientras otros refutan estos hallazgos sugiriendo que serían producto del sesgo de selección. Aquellos estudios que plantean una relación causal entre EG y el desarrollo de cáncer de tiroides, la atribuyen a la presencia de autoanticuerpos TSI, que estimularían el foco de malignidad. Se cree que las citoquinas producidas localmente en pacientes con EG trabajarían en conjunto con los TRAb para determinar la agresividad del cáncer papilar de tiroides en estos pacientes. Dentro de las células reclutadas por el tumor para evadir la respuesta inmune se encuentran los linfocitos Treg, que estarían elevados en paciente con EG, llevando a la disminución de la respuesta inmune y creando un ambiente permisivo para la proliferación celular. Por tratarse de una línea de investigación reciente, no existe consenso sobre el tema y sus implicancias en el tratamiento de los pacientes con EG. La finalidad de este artículo es realizar una revisión de la literatura que exponga y contraste la información disponible a la fecha.

In recent years the relationship between Graves’ disease (GD), TSH, TRAb and thyroid carcinoma has been studied. Research studies show a higher prevalence and aggressiveness of thyroid carcinoma in patients with GD, however other researchers refute these findings suggesting it’s due to selection bias. Increasing evidence suggests a causal relationship between GD and the development of thyroid carcinoma, mainly because of the existence of TSI autoantibodies that could stimulate the focus of malignancy. It is believed that cytokines produced locally in patients with GD work alongside with TRAb regulating the aggressiveness of papillary thyroid carcinoma in these patients. Within the cells recruited by the tumor to elude the immune system we find Treg lymphocytes, which have been found to be increased in patients with GD, leading to a diminished immune response, creating a permissive environment for cell proliferation. Since this is a relatively new line of research, there is no consensus on the subject and its relevance for the treatment of patients with GD. The aim of this article is to show recent literature available on the subject.

Circulating myeloid-derived suppressor cells predict disease activity and treatment response in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is a disease characterized by isolated thrombocytopenia. Abnormal effector T cell activation is an important mechanism in the pathogenesis of ITP. Regulatory T cells (Treg) have a strong immunosuppressive function for T cell activation and their importance in the pathophysiology and clinical treatment of ITP has been confirmed. Myeloid-derived suppressor cells (MDSCs) are other immunosuppressive cells, which can also suppress T cell activation by secreting arginase, iNOS and ROS, and are essential for Treg cells’ differentiation and maturation. Therefore, we speculate that MDSCs might also be involved in the immune-dysregulation mechanism of ITP. In this study, we tested MDSCs and Treg cells in peripheral blood samples of twenty-five ITP patients and ten healthy donors. We found that MDSCs and Treg cells decreased simultaneously in active ITP patients. Relapsed ITP patients showed lower MDSCs levels compared with new patients. All patients received immunosuppressive treatment including dexamethasone alone or in combination with intravenous immune globulin. We found that MDSCs’ level after treatment correlated with platelet recovery. Our study is the first that focused on MDSCs’ role in ITP. Based on our results, we concluded that circulating MDSCs could predict disease activity and treatment response in ITP patients. This preliminary conclusion indicates a substantial significance of MDSCs in the pathophysiology and clinical treatment of ITP, which deserves further investigation.

Influence of Treg cells and HBV genotype on sustained response and drug resistance in the treatment with nucleoside drugs

We aimed to investigate the influence of regulatory T cells including CD4+CD25+, CD8+CD28- and hepatitis B virus (HBV) genotype on sustained virological response and tolerance of nucleoside drugs. One hundred and thirty-seven patients were enrolled. Lamivudine was administered to 84 patients. Entecavir was administered to the other 53 patients. Before treatment, biochemical tests, HBV DNA load, HBV serum level, HBV genotype, PB CD3+, CD4+, CD8+, CD4+CD25+/CD3+, and CD8+CD28-/CD3+ frequencies were measured. Based on HBV DNA loads after 4 weeks of therapy, patients were divided into response group and suboptimal response group. The lamivudine group received treatment continuously, and then patients were categorized into non-resistance group and resistance group. Compared with the suboptimal response and resistance groups for lamivudine, CD4+CD25+/CD3+ levels were higher in the response and non-resistance groups (t=4.372, P=0.046; t=7.262, P=0.017). In the non-resistance group, CD8+CD28-/CD3+ frequency was lower than in the resistance group (t=5.527, P=0.037). Virus load and hepatitis B E antigen (HBeAg)-positive rate were significantly lower than in the response and resistance group (t=2.164, P=0.038; X2=4.239, P=0.040; t=2.015, P=0.044; X2=16.2, P=0.000). Incidence of drug resistance was high in patients with virogene type C. For the virological response to entecavir, CD8+CD28-/CD3+ level was significantly lower than that of the suboptimal response group (t=6.283, P=0.036). Response and suboptimal response groups were compared in CD3+, CD4+, CD8+, CD4+CD25+/CD3+ and virus genotype, and differences were not statistically significant (P>0.05). Baseline regulatory T cells including CD4+CD25+/CD3+ and CD8+CD28-/CD3+ frequencies have a relationship with the incidence of rapid virological response and the resistance to nucleoside drugs. Patients with HBV genotype C receiving lamivudine more often underwent drug resistance. Antiviral efficacy and the resistance to lamivudine were closely correlated with baseline factors; the same cannot be found for entecavir.

Treg and Th17 cells in inflammatory periapical disease: a systematic review

Abstract: The process involved in periapical lesions, which occur as an outcome of pulpal necrosis, is regulated by the immune system including regulatory T cells (Treg) and T helper 17 cell (Th17) responses. The objective of this study was to conduct a frequency systematic review to determine the presence of Treg/Th17 responses and the influence of these cells in the progression of chronic inflammatory periapical lesions in humans. A systematic computerized search was carried out in Pubmed, Medline, Web of Science and Scopus electronic databases from their date of inception through the first week of May 2017. In addition, the reference lists of the included articles and the grey literature were hand-searched. Articles that evaluated the presence and influence of Treg/Th17 in the progression of human periapical lesions were included. Study selection and the quality assessment of the included articles (using the Newcastle-Ottawa scale) were carried out by two authors. Fifty-seven titles/abstracts were screened and eight studies met the eligibility criteria and were included in this systematic review. The included studies showed large variation in the type of periapical lesion assessed, mean age, age range, type of experiment and findings regarding the participation of Th17 and Treg in the status of inflammatory periapical lesions. The studies showed the involvement of Treg in the modulation of the inflammatory response in radicular cysts and periapical granulomas. This systematic review highlights the relationship between Treg and Th17 acting in a subtle balance inhibiting or promoting the progression of human periapical lesions.

Rol de la microbiota gastrointestinal en la regulación de la respuesta inmune / The role of gut microbiota in the regulation of the immune response

The gastrointestinal tract hosts around 10(14) bacterial microorganisms, in a constantly growing density from the stomach to the distal colon. This microbiota is composed by more than 500 species of bacteria, which are quickly acquired after birth, fairly stable during the host’s life, and essential for human homeostasis. These bacteria have important functions, such as stimulating the immune system, protecting the host from invading bacteria and viruses, and improving digestion, especially of complex carbohydrates. Also, the gut microbiota interacts directly with the immune system. However, the interaction of the intestinal epithelium and its microbiota with the immune system has yet to be fully understood. Secretory immunoglobulin A, produced by the plasma cells in Peyer’s patches and in the lamina propria, maintains non-invasive commensal bacteria and neutralize invasive pathogens. Dendritic cells migrate from the lamina propria of the secondary lymphoid organs to regulate gut immunity. They also have a key role maintaining luminal IgA and inducing the growth of regulatory T cells. Dendritic cells supervise the gut microenvironment too, keeping an immunological equilibrium and tolerance. The importance of the gut microbiota in regulating the immune system lies mostly in the homeostasis-or positive equilibrium. Thus, many diseases are a consequence of poor interactions or a loss of this equilibrium.

Inducción de células T reguladoras por estatinas: alternativa terapéutica para el control del asma extrínseca / Induction of regulatory T cells by statins: alternative therapy for the control of extrinsic asthma

El asma bronquial extrínseca se origina por una reacción inmunológica de hipersensibilidad tipo I, desencadenada principalmente por alérgenos ambientales. Clásicamente, la respuesta inmune mediada por células T CD4+ con perfil Th2 determina las principales características de esta enfermedad, con la infiltración de eosinófilos y basófilos que median la inflamación crónica de las vías aéreas. Se ha observado que las células T reguladoras pueden actuar como moduladores endógenos durante los procesos asmáticos, controlando la exacerbación de las crisis y disminuyendo el daño tisular. Aunque los glucocorticoides son el principal tratamiento para el asma, solo alivian temporalmente los síntomas y se asocian con efectos adversos y aparición de resistencia, lo cual ha incentivado el desarrollo de alternativas terapéuticas que modulen la respuesta inmune y controlen la inflamación crónica. Recientemente, se ha postulado que las estatinas podrían ser una alternativa promisoria para disminuir la respuesta inflamatoria y disminuir la morbilidad asociada a esta enfermedad, debido a su gran potencial inmunomodulador, entre los que se destaca la inducción de células T reguladoras(AU)

Extrinsic asthma is caused by an immunological type I hypersensitivity reaction triggered mainly by environmental allergens. Usually, immune response mediated mainly by CD4 + T cells with Th2 profile determines the main features of extrinsic asthma, including infiltration of eosinophils and basophils that mediate chronic inflammation of the airways. It has been observed that regulatory T cells may act as endogenous modulators during asthmatic processes, controlling crisis exacerbation and decreasing tissue damage. Although glucocorticoids are the main treatment for asthma, these only relieve symptoms temporarily and are associated with adverse effects and development of resistance, which has encouraged the development of alternative therapies that modulate the immune response and control chronic inflammation. Recently, it has been postulated that statins may be a promising alternative to reduce the inflammatory response and decrease the morbidity associated with this disease, due to its great immunomodulator potential, especially in the induction of regulatory T cells(AU)

Abnormal phenotypic distribution of regulatory and effector T cells in octogenarian and nonagenarian women / Distribuição fenotípica anormal das células T reguladoras e efetoras em mulheres octogenárias e nonagenárias

SummaryIntroduction:aging is associated with several immunologic changes. Regulatory (Treg) and effector T cells are involved in the pathogenesis of infectious, neoplastic, and autoimmune diseases. Little is known about the effects of aging on the frequency and function of these T cell subpopulations.Methods:peripheral blood mononuclear cells (PBMC) were obtained from 26 young (under 44 years old) and 18 elderly (above 80 years old) healthy women. T cell subpopulations were analyzed by flow cytometry.Results:elderly individuals had lower frequency of several activated effector T cell phenotypes as compared with young individuals: CD3+CD4+CD25+ (3.82±1.93 versus 9.53±4.49; p<0.0001); CD3+CD4+CD25+CD127+(2.39±1.19 versus 7.26±3.84; p<0.0001); CD3+CD4+CD25+ (0.41±0.22 versus 1.86±0.85, p<0.0001); and CD3+CD4+CD25highCD127+(0.06±0.038 versus 0.94±0.64, p<0.0001). Treg (CD3+CD4+CD25+CD127øFoxp3+) presented lower frequency in elderly individuals as compared to young adults (0.34±0.18 versus 0.76±0.48; p=0.0004) and its frequency was inversely correlated with age in the whole group (r=-0.439; p=0.013). The elderly group showed higher frequency of two undefined CD25øFoxp3+ phenotypes: CD3+CD4+CD25øFoxp3+(15.05±7.34 versus 1.65±1.71; p<0.0001) and CD3+CD4+CD25øCD127øFoxp3+(13.0±5.52 versus 3.51±2.87; p<0.0001).Conclusions:the altered proportion of different T cell subsets herein documented in healthy elderly women may be relevant to the understanding of the immunologic behavior and disease susceptibility patterns observed in geriatric patients.

ResumoIntrodução:o envelhecimento está associado a diversas alterações imunológicas. Células T reguladoras e efetoras estão envolvidas na patogênese de enfermidades infecciosas, neoplásicas e autoimunes. Pouco se sabe acerca dos efeitos da idade sobre a frequência e a função dessas populações celulares.Métodos:células mononucleares do sangue periférico foram obtidas de participantes saudáveis (26 com idade inferior a 44 anos e 18 acima de 80 anos). As subpopulações celulares foram analisadas por citometria de fluxo.Resultados:o grupo constituído por idosas apresentou menor frequência de vários fenótipos de células T efetoras ativadas em comparação com jovens: CD3+CD4+CD25+ (3,82±1,93 versus 9,53±4,49, p<0,0001); CD3+CD4+ CD25+CD127+ (2,39±1,19 versus7,26±3,84, p<0,0001); CD3+CD4+CD25high(0,41±0,22 versus 1,86±0,85, p<0,0001); CD3+CD4+CD25highCD127+(0,06±0,038 versus 0,94±0,64, p<0,0001). As células T reguladoras CD3+CD4+CD25highCD127øFoxP3+ apresentaram menor frequência em indivíduos idosos em comparação com adultos jovens (0,34±0,18 versus0,76±0,48, p=0,0004) e sua frequência foi inversamente correlacionada com a idade em todo o grupo (r=-0,439; p=0,013). O grupo de idosas apresentou maior frequência de dois fenótipos indefinidos (CD25øFoxP3+), células CD3+CD4+CD25øFoxP3+ (15,05±7,34 versus 1,65±1,71, p<0,0001) e células CD3+CD4+CD25øCD127øFoxP3+(13,0±5,52 versus 3,51±2,87, p<0,0001).Conclusão:as proporções alteradas de diferentes subpopulações de células T em idosas saudáveis contribuem para a compreensão dos padrões de comportamento e suscetibilidade a doenças imunológicas evidenciadas em pacientes geriátricos.

Risk behaviors for sexually transmitted diseases among crack users / Comportamentos de risco para doenças sexualmente transmissíveis em usuários de crack / Conductas de riesgo para enfermedades de transmisión sexual entre usuarios de crack

AbstractObjectives: to investigate the prevalence and risk behaviors by means of reporting of sexually transmitted diseases among crack users.Method: cross-sectional study carried out with 588 crack users in a referral care unit for the treatment of chemical dependency. Data were collected by means of face-to-face interview and analyzed using Stata statistical software, version 8.0.Results: of the total participants, 154 (26.2%; 95% CI: 22.8-29.9) reported antecedents of sexually transmitted diseases. Ages between 25 and 30 years (RP: 2.1; 95% CI: 1.0-4.0) and over 30 years (RP: 3.8; 95% CI: 2.1-6.8), alcohol consumption (RP: 1.9; 95% CI: 1.1-3.3), antecedents of prostitution (RP: 1.9; 95% CI: 1.3-2.9) and sexual intercourse with person living with human immunodeficiency virus/AIDS (RP: 2.7; 95% CI: 1.8-4.2) were independently associated with reporting of sexually transmitted diseases.Conclusion: the results of this study suggest high risk and vulnerability of crack users for sexually transmitted diseases.

ResumoObjetivos:investigar a prevalência e comportamentos de risco através do relato de doenças sexualmente transmissíveis em usuários de crack.Método:estudo transversal, realizado com 588 usuários de crack, de uma unidade de referência para tratamento de dependência química. Os dados foram obtidos por meio de entrevista face a face e analisados em programa estatístico Stata, versão 8.0.Resultados:do total de participantes, 154 (26,2%; IC 95%: 22,8-29,9) referiram antecedentes de doenças sexualmente transmissíveis. Idade entre 25 e 30 anos (RP: 2,1; IC 95%: 1,0-4,0) e superior a 30 anos (RP: 3,8; IC 95%: 2,1-6,8), consumo de álcool (RP: 1,9; IC 95%: 1,1-3,3), antecedentes de prostituição (RP: 1,9; IC 95%: 1,3-2,9) e relação sexual com pessoa vivendo com o vírus da imunodeficiência humana/aids (RP: 2,7; IC 95%: 1,84,2) foram independentemente associados ao relato de doenças sexualmente transmissíveis.Conclusão:os resultados deste estudo sugerem elevado risco e vulnerabilidade dos usuários de crackpara as doenças sexualmente transmissíveis.

ResumenObjetivos:investigar la prevalencia y las conductas de riesgo a través del informe de las enfermedades de transmisión sexual entre los usuarios de crack.Método:estudio transversal con 588 usuarios de crack, de una unidad de referencia para el tratamiento de la dependencia química. Los datos fueron obtenidos a través de entrevista cara a cara y se analizaron utilizando el programa estadístico Stata, versión 8.0.Resultados:del total de participantes, 154 (26,2%; IC 95%: 22,8-29,9) informaron antecedentes de enfermedades de transmisión sexual. Edad entre 25 y 30 años (RP: 2,1; IC9 5%: 1,0-4,0) y superior a 30 años (RP: 3,8; IC 95%: 2,1-6,8), consumo de alcohol (OR: 1,9; IC 95%: 1,1-3,3), antecedentes de prostitución (RP: 1,9; IC 95%: 1,3-2,9) y relaciones sexuales con persona viviendo con el virus de inmunodeficiencia humana/ SIDA (RP: 2,7; IC 95%: 1,8-4,2) se asociaron de forma independiente con la notificación de las enfermedades de transmisión sexual.Conclusión:los resultados de este estudio sugieren alto riesgo y la vulnerabilidad de los usuarios de crackpara las enfermedades de transmisión sexual.

Consumo de cafeína durante a gestação e transtorno de déficit de atenção e hiperatividade (TDAH): uma revisão sistemática da literatura / Caffeine consumption during pregnancy and attention deficit hyperactivity disorder (ADHD): a systematic literature review / Consumo de cafeína durante el embarazo y trastorno por déficit de atención e hiperactividad (TDAH): una revisión sistemática de la literatura

O objetivo do presente estudo foi avaliar, mediante revisão sistemática da literatura, as evidências acerca da associação entre consumo materno de cafeína durante a gestação e transtorno de déficit de atenção e hiperatividade (TDAH) na infância. A busca na literatura ocorreu de forma sistemática, em múltiplas etapas, nas bases PubMed, LILACS, BIREME e PsycINFO, com limites para artigos publicados em português, inglês e espanhol, realizados em humanos. Foram encontradas 373 referências. Dessas, somente cinco foram mantidas, por atenderem ao objetivo deste estudo. Os cinco trabalhos foram realizados em países desenvolvidos; a maioria utilizou delineamento longitudinal e foi publicada nos últimos cinco anos. Apenas um estudo encontrou associação positiva. Estudos sobre o consumo de cafeína na gestação e TDAH são escassos, com resultados controversos e se deparam com várias dificuldades metodológicas, como falta de padronização na definição do desfecho.

This aim of this study was to conduct a systematic literature review on the association between maternal caffeine intake during pregnancy and attention deficit hyperactivity disorder (ADHD) in childhood. The systematic multiple-stage literature search in PubMed, LILACS, BIREME, and PsycINFO was limited to research in human subjects and published in Portuguese, English, and Spanish. A total of 373 references were retrieved. Of these, only five met the study's objectives and were kept in the review. Most of the studies employed a longitudinal design, were conducted in developed countries, and were published in the last five years. Only one study found a positive association. Studies on caffeine consumption during pregnancy and ADHD are scarce, with conflicting results and several methodological difficulties such as lack of standardized outcome measures.

El objetivo de este estudio fue evaluar, a través de una revisión sistemática de la literatura, evidencias sobre la asociación entre el consumo de cafeína durante el embarazo y el trastorno por déficit de atención e hiperactividad (TDAH) en la infancia. Se realizó una búsqueda sistemática en la literatura, por etapas múltiples, en PubMed, LILACS BIREME y PsycINFO, limitándose a artículos publicados en portugués, inglés y español, realizados en estudios sobre humanos. Fueron localizadas 373 referencias. De ellas, apenas se mantuvieron cinco, por cumplir el objetivo de este estudio. Los estudios se realizaron en países desarrollados; el diseño longitudinal fue el más utilizado y se trata de publicaciones de los últimos cinco años. Sólo un estudio encontró asociación positiva. Los estudios sobre el consumo de cafeína durante el embarazo y el TDAH son escasos, con resultados controvertidos, y enfrentan varias dificultades metodológicas, como la no estandarización de la evaluación del resultado.

Use of positive pressure in preoperative and intraoperative of bariatric surgery and its effect on the time of extubation / Utilização da pressão positiva no pré e no intraoperatório de cirurgia bariátrica e seus efeitos sobre o tempo de extubação / Utilización de la presión positiva en el pre- y en el intraoperatorio de cirugía bariátrica y sus efectos sobre el tiempo de extubación

BACKGROUND AND OBJECTIVE: To investigate the influence of intraoperative and preoperative positive pressure in the time of extubation in patients undergoing bariatric surgery. METHOD: Randomized clinical trial, in which 40 individuals with a body mass index between 40 and 55 kg/m2, age between 25 and 55 years, nonsmokers, underwent bariatric surgery type Roux-en-Y gastric bypass by laparotomy and with normal preoperative pulmonary function were randomized into the following groups: G-pre (n = 10): individuals who received treatment with noninvasive positive pressure before surgery for 1 h; G-intra (n = 10): individuals who received positive end-expiratory pressure of 10 cm H2O throughout the surgical procedure; and G-control (n = 20): not received any preoperative or intraoperative intervention. Following were recorded: time between induction of anesthesia and extubation, between the end of anesthesia and extubation, duration of mechanical ventilation, and time between extubation and discharge from the post-anesthetic recovery. RESULTS: There was no statistical difference between groups. However, when applied to the Cohen coefficient, the use of positive end-expiratory pressure of 10 cm H2O during surgery showed a large effect on the time between the end of anesthesia and extubation. About this same time, the treatment performed preoperatively showed moderate effect. CONCLUSION: The use of positive end-expiratory pressure of 10 cm H2O in the intraoperative and positive pressure preoperatively, influenced the time of extubation of patients undergoing bariatric surgery. .

JUSTIFICATIVA E OBJETIVO: investigar a influência do uso da pressão positiva nas vias aéreas intraoperatória e pré-operatória no tempo de extubação de pacientes submetidos à cirurgia bariátrica. MÉTODO: Trata-se de ensaio clínico randomizado, no qual 40 indivíduos com índice de massa corporal entre 40 e 55 kg/m2, idade entre 25 e 55 anos, não tabagistas, submetidos à cirurgia bariátrica do tipo derivação gástrica em Y de Roux por laparotomia e com prova de função pulmonar pré-operatória dentro da normalidade foram randomizados nos seguintes grupos: G-pré (n = 10): indivíduos que receberam tratamento com pressão positiva não invasiva antes da cirurgia, durante uma hora, G-intra (n = 10): indivíduos que receberam Positive End-expiratory Pressure de 10 cm H2O durante todo o procedimento cirúrgico e G-controle (n = 20): não receberam qualquer tipo de intervenção pré ou intraoperatória. foram anotados os seguintes tempos: tempo decorrido entre a indução anestésica e a extubação, entre o término da anestesia e extubação, tempo de ventilação mecânica, e tempo entre a extubação e a alta da Recuperação Pós-Anestésica. RESULTADOS: Não houve diferença estatística entre os grupos, porém quando aplicado ao Coeficiente de Cohen, o uso da Positive End-expiratory Pressure de 10 cm H2O no intraoperatório mostrou um efeito grande sobre o tempo entre o término da anestesia e a extubação. Sobre este mesmo tempo, o tratamento realizado no pré-operatório apresentou efeito moderado. CONCLUSÃO: O uso da Positive End-expiratory Pressure de 10 cm H2O no intraoperatório e da pressão positiva no pré-operatório, pode influenciar o tempo de extubação de pacientes submetidos à cirurgia bariátrica. .

JUSTIFICACIÓN Y OBJETIVO: Investigar la influencia del uso de la presión positiva en las vías aéreas intraoperatoria y preoperatoria en el tiempo de extubación de pacientes sometidos a la cirugía bariátrica. MÉTODO: Se trata de un ensayo clínico aleatorizado, en el cual 40 individuos con IMC entre 40 y 55 kg/m2, edad entre 25 y 55 años, no fumadores, sometidos a cirugía bariátrica del tipo derivación gástrica en Y de Roux por laparotomía y con prueba de función pulmonar preoperatoria dentro de la normalidad fueron aleatorizados en los siguientes grupos: G-pre (n = 10): individuos que recibieron tratamiento con presión positiva no invasiva antes de la cirugía durante una hora; G-intra (n = 10): individuos que recibieron PEEP de 10 cm H2O durante todo el procedimiento quirúrgico y G-control (n = 20): no recibieron ningún tipo de intervención pre- o intraoperatoria. Fueron anotados los siguientes tiempos: tiempo trascurrido entre la inducción anestésica y la extubación, entre el fin de la anestesia y la extubación, tiempo de ventilación mecánica, y tiempo entre la extubación y el alta de la sala de recuperación postanestésica. RESULTADOS: No hubo diferencia estadística entre los grupos, sin embargo cuando se aplicó el coeficiente de Cohen, el uso de la PEEP de 10 cm H2O en el intraoperatorio mostró un efecto importante sobre el tiempo entre el término de la anestesia y la extubación. Sobre ese mismo tiempo, el tratamiento realizado en el preoperatorio presentó un efecto moderado. CONCLUSIÓN: El uso de la PEEP de 10 cm H2O en el intraoperatorio y de la presión positiva en el preoperatorio puede influir en el tiempo de extubación de pacientes sometidos a cirugía bariátrica. .