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BACKGROUND: Obesity and metabolic syndrome (MetS) are key risk factors for type 2 diabetes and cardiovascular disease. Little information exists on the prevalence of obesity and MetS in Latin America and specifically in Ecuador. We aimed to estimate the prevalence of overweight, obesity, and MetS among adults in Ecuador. METHODS: We analyzed data from a nation-wide population-based survey in Ecuador (ENSANUT-ECU) among 10,318 participants (3684 men, 6634 women; age range: 18-59 years) conducted in 2012. Data related to residential location (urban versus rural), altitude (< 500, 500-1500 or > 1500 m above sea level (MASL)), region (highland, coast, amazon, or Galápagos), and socioeconomic status were collected. BMI, waist circumference, blood lipids, glucose, and blood pressure were measured by trained fieldworkers following standardized procedures. RESULTS: The age-standardized prevalence of overweight was 39.5%; 22.3% was obese; and 31.2% had MetS. The prevalence of obesity, low HDL-cholesterol, and abdominal obesity were higher in women than in men, whereas men had a higher prevalence of hypertension (p < 0.05). Sex differences were not observed regarding the prevalence of combined MetS. Prevalence of both obesity and MetS was higher in urban areas, at low altitude regions (coast and Galapagos), and at high socioeconomic status (all p < 0.05). CONCLUSIONS: Prevalence of obesity and MetS in Ecuador are high. There are important demographic differences in the prevalence of MetS between Ecuadorian subpopulations that requires targeted research and prevention efforts, to hold and reduce the current public health problem of metabolic disorders.
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Demografia , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Fatores Socioeconômicos , Adolescente , Adulto , Estudos Transversais , Equador/epidemiologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prevalência , Prognóstico , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: Psychotic disorders are characterized by a deranged immune system, including altered number and function of Natural Killer (NK) and T cells. Psychotic disorders arise from an interaction between genetic vulnerability and exposure to environmental risk factors. Exposure to social adversity during early life is particularly relevant to psychosis risk and is thought to increase reactivity to subsequent minor daily social stressors. Virtual reality allows controlled experimental exposure to virtual social stressors. AIM: To investigate the interplay between social adversity during early life, cell numbers of NK cells and T helper subsets and social stress reactivity in relation to psychosis liability. METHODS: Circulating numbers of Th1, Th2, Th17, T regulator and NK cells were determined using flow cytometry in 80 participants with low psychosis liability (46 healthy controls and 34 siblings) and 53 participants with high psychosis liability (14 ultra-high risk (UHR) patients and 39 recent-onset psychosis patients), with and without the experience of childhood trauma. We examined if cell numbers predicted subjective stress when participants were exposed to social stressors (crowdedness, hostility and being part of an ethnic minority) in a virtual reality environment. RESULTS: There were no significant group differences in Th1, Th2, Th17, T regulator and NK cell numbers between groups with a high or low liability for psychosis. However, in the high psychosis liability group, childhood trauma was associated with increased Th17 cell numbers (pâ¯=â¯0.028). Moreover, in the high psychosis liability group increased T regulator and decreased NK cell numbers predicted stress experience during exposure to virtual social stressors (pâ¯=â¯0.015 and pâ¯=â¯0.009 for T regulator and NK cells, respectively). CONCLUSION: A deranged Th17/T regulator balance and a reduced NK cell number are associated intermediate biological factors in the relation childhood trauma, psychosis liability and social stress reactivity.
Assuntos
Células Matadoras Naturais/citologia , Transtornos Psicóticos/sangue , Estresse Psicológico/sangue , Linfócitos T Reguladores/citologia , Células Th17/citologia , Adulto , Feminino , Humanos , Masculino , Meio Social , Adulto JovemRESUMO
BACKGROUND: Despite the existence of several pathophysiological theories about bipolar disorder, it has so far been difficult to find diagnostic biomarkers and to develop new pharmacologic treatments based on the more novel theories. AIM: To reflect on the causes and consequences of problems that beset pathophysiological research into psychiatric disorders in general and bipolar disorder in particular. METHOD: In this essay we address the problems facing professionals engaged in research into bipolar disorder and we interpret these problem in the light of brain complexity. RESULTS: The complexity of the brain can be divided into two types: spatial complexity, which reflects the various physiological levels of the central nervous system (genetic, molecular, cellular, neuronal circuits and phenomenological levels), and temporal complexity, i.e. neurodevelopment. We discuss the consequences of these two types of complexity and make suggestions relating to clinical practice and pathophysiological psychiatric research. CONCLUSION: To achieve further progress in the field of brain research, we need to acquire a deeper understanding of the spatial and temporal complexity of the brain and consider the possible consequences of such knowledge for the pathophysiology and treatment of psychiatric illnesses such as bipolar disorder.
Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/fisiopatologia , Encéfalo/fisiopatologia , Biomarcadores , Humanos , PsicopatologiaRESUMO
Immune dysregulation plays a role in the vulnerability for mood disorders. Immune growth factors, such as Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein-2 (IGF-BP2), Epidermal Growth Factor (EGF), IL-7 and sCD25 have repeatedly been reported altered in patients with mood disorders. The aim of this study was to investigate levels of these factors in serum of adolescent bipolar offspring, who have a heightened risk for mood disorder development and to also analyze the data combined with previously published data. Growth factors were assessed by CBA/ELISA in adolescent bipolar offspring (n=96, mean age=16years) and in age- and gender-matched healthy controls (n=50). EGF belonged to a mutually correlating cluster of mainly neurotrophic compounds including S100B and BDNF, which were in general decreased in serum. IL-7, SCF, IGF-BP2 and sCD25, belonged to a different mutually correlating cluster of immune growth factors, which were in general increased: IGF-BP2 significantly in serum of offspring without a mood disorder, IL-7 and SCF in serum of offspring who had experienced a mood episode. This pattern of de- and increases was not different between bipolar offspring that developed or did not develop a mood disorder over time, apart from the IGF-BP2 level, which was near significantly higher in offspring later developing a mood disorder. Correlations with the previously published immune-cellular abnormalities were not found. In conclusion non-affected adolescents at familial mood disorder development risk were characterized by a distinct pattern of a series of compounds operating in a network of hematopoiesis, neurogenesis and inflammation.
Assuntos
Transtorno Bipolar/sangue , Transtorno Bipolar/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Adolescente , Transtorno Bipolar/complicações , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/imunologia , Filho de Pais com Deficiência , Fator de Crescimento Epidérmico/sangue , Fator de Crescimento Epidérmico/imunologia , Feminino , Humanos , Inflamação/complicações , Inflamação/imunologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/imunologia , Interleucina-7/sangue , Interleucina-7/imunologia , Masculino , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Fator de Células-Tronco/sangue , Fator de Células-Tronco/imunologiaRESUMO
OBJECTIVES: T cell abnormalities have been repeatedly reported in adult patients with mood disorders, suggesting a role of these cells in the pathogenesis of these disorders. In the present study, we explored the dynamics of circulating T cell subsets over time in a population at high familial risk for developing a mood disorder. METHODS: Children of a parent with bipolar disorder (bipolar offspring, N=140) were assessed at three time-points: adolescence, young adulthood and adulthood. We carried out a detailed fluorescence-activated cell sorting (FACS) analysis to determine various T cell subsets from frozen stored peripheral blood mononuclear cells of bipolar offspring and age- and gender-matched healthy controls at each time-point. RESULTS: Throughout the period of observation reduced levels of CD3+ and CD3+ CD4+ T cells were observed. In bipolar offspring Th1, Th2, Th17 and natural T regulatory cells (Tregs) followed a dynamic course over time with reduced levels of Tregs in adolescence and a reduced relative number of Th1, Th17 cells in young adulthood. In post hoc analysis Tregs were inversely associated with the pro-inflammatory monocyte state determined previously (rs=-0.220, p=0.001). Significant associations between T cell subset abnormalities and psychopathology such as mood disorders were not found. CONCLUSIONS: A subtle partial T cell defect was present in bipolar offspring from adolescence through adulthood. Within this defect the dynamic change of inflammatory and regulatory T cell subsets suggests a high inflammatory state during adolescence, a reduced inflammatory state during young adulthood and a virtually normalized state at adulthood.
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Transtornos do Humor/genética , Transtornos do Humor/imunologia , Subpopulações de Linfócitos T/metabolismo , Adolescente , Transtorno Bipolar/genética , Criança , Feminino , Expressão Gênica , Predisposição Genética para Doença , Humanos , Inflamação/complicações , Inflamação/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Monócitos/metabolismo , Transtornos do Humor/complicações , Adulto JovemRESUMO
OBJECTIVES: In the salivary glands of patients with primary Sjögren Syndrome (pSjS) an accumulation of dendritic cells (DCs) is seen, which is thought to play a role in stimulating local inflammation. Aberrancies in subsets of monocytes, generally considered the blood precursors for DCs, may play a role in this accumulation of DCs. This study is aimed at determining the level of mature CD14lowCD16+ monocytes in pSjS and their contribution to the accumulation of DCs in pSjS. METHODS: Levels of mature and immature monocytes in patients with pSjS (n = 19) and controls (n = 15) were analysed by flow cytometry. The reverse transmigration system was used for generation of DCs generated from monocyte subsets. The phenotype of DCs in pSjS salivary glands was analysed using immunohistochemistry. In vivo tracking of monocyte subsets was performed in a mouse model. RESULTS: Increased levels of mature CD14lowCD16+ monocytes were found in patients with pSjS (mean (SD) 14.5 (5.5)% vs 11.4 (3.4)%). These cells showed normal expression of chemokine receptor and adhesion molecules. Mature monocytes partly developed into DC-lysosome-associated membrane glycoprotein (LAMP)+ (19.6 (7.5)%) and CD83+ (16 (9)%) DCs, markers also expressed by DCs in pSjS salivary glands. Monocyte tracking in the non-obese diabetic (NOD) mouse showed that the homologue population of mature mouse monocytes migrated to the salivary glands, and preferentially developed into CD11c+ DCs in vivo. CONCLUSIONS: Mature monocytes are increased in pSjS and patient and mouse data support a model where this mature monocyte subset migrates to the salivary glands and develops into DCs.
Assuntos
Células Dendríticas/imunologia , Monócitos/imunologia , Receptores de IgG/sangue , Glândulas Salivares/imunologia , Síndrome de Sjogren/imunologia , Adulto , Idoso , Animais , Antígenos CD/sangue , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/sangue , Proteínas Ligadas por GPI , Humanos , Imunoglobulinas/sangue , Imunofenotipagem , Proteínas de Membrana Lisossomal/sangue , Glicoproteínas de Membrana/sangue , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Antígeno CD83RESUMO
BACKGROUND: In previous studies we found mild deficiencies of circulating T cells in patients with bipolar disorder (BD) and children at risk for BD, correlating to a higher inflammatory state. The genetic and environmental influences on these T cell deficiencies in association with BD development are unknown. OBJECTIVES: The aim is to quantify genetic and environmental factors that contribute to the association between the liability to develop BD and T cell deficiencies. METHODS: Participants of a Dutch bipolar twin study (11 monozygotic BD twin pairs, 15 dizygotic BD twin pairs, 15 monozygotic and 12 dizygotic healthy twin pairs) were included. A detailed FACS analysis of frozen stored leukocytes was carried out to determine the percentages of T cells and various other leukocyte and lymphocyte subsets. A bivariate liability threshold twin model was used to determine genetic and environmental (common and unique) influences on the correlation between BD and the various subsets. RESULTS: Lower percentages of T cells and higher percentages of NK cells were associated with the familial liability to develop BD. Neither genetic nor shared or unique environmental factors could explain the associations. Lithium usage explained part of the association for T cells, smoking in part that for NK cells. CONCLUSIONS: Our results confirm that BD is the result of a complex interaction between various genetic and environmental risk factors, in which T and NK cells act as important intermediate immune players.
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Premature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heterogeneous disorder with a multicausal pathogenesis involving chromosomal, genetic, enzymatic, infectious, and iatrogenic causes. There remains, however, a group of POF patients without a known etiology, the so-called "idiopathic" form. An autoimmune etiology is hypothesized for the POF cases with a concomitant Addison's disease and/or oöphoritis. It is concluded in this review that POF in association with adrenal autoimmunity and/or Addison's disease (2-10% of the idiopathic POF patients) is indeed an autoimmune disease. The following evidence warrants this view: 1) The presence of autoantibodies to steroid-producing cells in these patients; 2) The characterization of shared autoantigens between adrenal and ovarian steroid-producing cells; 3) The histological picture of the ovaries of such cases (lymphoplasmacellular infiltrate around steroid-producing cells); 4) The existence of various autoimmune animal models for this syndrome, which underlines the autoimmune nature of the disease. There is some circumstantial evidence for an autoimmune pathogenesis in idiopathic POF patients in the absence of adrenal autoimmunity or Addison's disease. Arguments in support of this are: 1) The presence of cellular immune abnormalities in this POF patient group reminiscent of endocrine autoimmune diseases such as IDDM, Graves' disease, and Addison's disease; 2) The more than normal association with IDDM and myasthenia gravis. Data on the presence of various ovarian autoantibodies and anti-receptor antibodies in these patients are, however, inconclusive and need further evaluation. A strong argument against an autoimmune pathogenesis of POF in these patients is the nearly absent histological confirmation (the presence of an oöphoritis) in these cases (< 3%). However, in animal models using ZP immunization, similar follicular depletion and fibrosis (as in the POF women) can be detected. Accepting the concept that POF is a heterogenous disorder in which some of the idiopathic forms are based on an abnormal self-recognition by the immune system will lead to new approaches in the treatment of infertility of these patients. There are already a few reports on a successful ovulation-inducing treatment of selected POF patients (those with other autoimmune phenomena) with immunomodulating therapies, such as high dosages of corticosteroids (288-292).
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Autoimunidade/fisiologia , Insuficiência Ovariana Primária/imunologia , Tolerância a Antígenos Próprios/imunologia , Doença de Addison/fisiopatologia , Apresentação de Antígeno/fisiologia , Células Apresentadoras de Antígenos/fisiologia , Doenças Autoimunes/genética , Doenças Autoimunes/fisiopatologia , Linfócitos B/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Linfócitos T/fisiologiaRESUMO
Postpartum thyroiditis is a syndrome of transient or permanent thyroid dysfunction occurring in the first year after delivery and based on an autoimmune inflammation of the thyroid. The prevalence ranges from 5-7%. We discuss the role of antibodies (especially thyroid peroxidase antibodies), complement, activated T cells, and apoptosis in the outbreak of postpartum thyroiditis. Postpartum thyroiditis is conceptualized as an acute phase of autoimmune thyroid destruction in the context of an existing and ongoing process of thyroid autosensitization. From pregnancy an enhanced state of immune tolerance ensues. A rebound reaction to this pregnancy-associated immune suppression after delivery explains the aggravation of autoimmune syndromes in the puerperal period, e.g., the occurrence of clinically overt postpartum thyroiditis. Low thyroid reserve due to autoimmune thyroiditis is increasingly recognized as a serious health problem. 1) Thyroid autoimmunity increases the probability of spontaneous fetal loss. 2) Thyroid failure due to autoimmune thyroiditis-often mild and subclinical-can lead to permanent and significant impairment in neuropsychological performance of the offspring. 3) Evidence is emerging that as women age subclinical hypothyroidism-as a sequel of postpartum thyroiditis-predisposes them to cardiovascular disease. Hence, postpartum thyroiditis is no longer considered a mild and transient disorder. Screening is considered.
Assuntos
Transtornos Puerperais/terapia , Tireoidite Autoimune/terapia , Tireoidite/terapia , Adulto , Feminino , Humanos , Cuidado Pós-Natal , Gravidez , Complicações na Gravidez/fisiopatologia , Cuidado Pré-Natal , Transtornos Puerperais/fisiopatologia , Tireoidite/fisiopatologia , Tireoidite Autoimune/fisiopatologiaRESUMO
OBJECTIVE: Endothelial progenitor cells (EPCs) contribute to postnatal neovascularization and are therefore of great interest for autologous cell therapies to treat ischemic vascular disease. However, the origin and functional properties of these EPCs are still in debate. METHODS AND RESULTS: Here, ex vivo expanded murine EPCs were characterized in terms of phenotype, lineage potential, differentiation from bone marrow (BM) precursors, and their functional properties using endothelial NO synthase (eNOS)-green fluorescent protein transgenic mice. Despite high phenotypic overlap with macrophages and dendritic cells, EPCs displayed unique eNOS expression, endothelial lineage potential in colony assays, and angiogenic characteristics, but also immunologic properties such as interleukin-12p70 production and low levels of T-cell stimulation. The majority of EPCs developed from an immature, CD31(+)Ly6C+ myeloid progenitor fraction in the BM. Addition of myeloid growth factors such as macrophage-colony-stimulating factor (M-CSF) and granulocyte/macrophage (GM)-CSF stimulated the expansion of spleen-derived EPCs but not BM-derived EPCs. CONCLUSIONS: The close relationship between EPCs and other myeloid lineages may add to the complexity of using them in cell therapy. Our mouse model could be a highly useful tool to characterize EPCs functionally and phenotypically, to explore the origin and optimize the isolation of EPC fractions for therapeutic neovascularization.
Assuntos
Células da Medula Óssea/citologia , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Neovascularização Fisiológica/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Células-Tronco/citologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células Dendríticas/citologia , Células Endoteliais/enzimologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Proteínas de Fluorescência Verde/genética , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo III/genética , Fenótipo , Proteínas Recombinantes de Fusão/metabolismo , Especificidade da Espécie , Baço/citologia , Células-Tronco/fisiologiaRESUMO
INTRODUCTION: Bipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter (GM) volumes reduction. Neurotrophic factors have been suggested to play a role in the neuroprogressive changes during the illness course. In particular peripheral brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in BD. The aim of our study was to investigate if serum levels of BDNF are associated with GM volumes in BD patients and healthy controls (HC). METHODS: We studied 36 inpatients affected by a major depressive episode in course of BD type I and 17 HC. Analysis of variance was performed to investigate the effect of diagnosis on GM volumes in the whole brain. Threshold for significance was P<0.05, Family Wise Error (FWE) corrected for multiple comparisons. All the analyses were controlled for the effect of nuisance covariates known to influence GM volumes, such as age, gender and lithium treatment. RESULTS: BD patients showed significantly higher serum BDNF levels compared with HC. Reduced GM volumes in BD patients compared to HC were observed in several brain areas, encompassing the caudate head, superior temporal gyrus, insula, fusiform gyrus, parahippocampal gyrus, and anterior cingulate cortex. The interaction analysis between BDNF levels and diagnosis showed a significant effect in the middle frontal gyrus. HC reported higher BDNF levels associated with higher GM volumes, whereas no association between BDNF and GM volumes was observed in BD. DISCUSSION: Our study seems to suggest that although the production of BDNF is increased in BD possibly to prevent and repair neural damage, its effects could be hampered by underlying neuroinflammatory processes interfering with the neurodevelopmental role of BDNF.
Assuntos
Transtorno Bipolar/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Transtorno Depressivo Maior/metabolismo , Substância Cinzenta/metabolismo , Adulto , Biomarcadores/sangue , Transtorno Bipolar/complicações , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Estudos de Casos e Controles , Córtex Cerebral/efeitos dos fármacos , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Giro do Cíngulo/metabolismo , Humanos , Lítio/administração & dosagem , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Previous studies of our group among bipolar offspring and bipolar twins showed significant higher prevalence's and levels of antithyroid peroxidase antibodies (TPO-Abs) in offspring and co-twins (without a mood disorder) compared to controls, suggesting that TPO-Abs might be considered as vulnerability factor (trait marker) for BD development. OBJECTIVES: Here we elucidate, in the same cohorts, but now after 12- and 6-year follow-up, whether TPO-abs should be considered as a 'trait' marker for BD. The present study aims to investigate whether TPO-Abs (1) are stable over time, (2) are associated with lithium-exposure, (3) share a common genetic background with BD and are related to psychopathology. RESULTS: In bipolar offspring and twins, the prevalence of TPO-Abs is stable over time (r s = .72 p < .001 resp. r s = .82, p < .001) and not associated with lithium use. At follow-up, an increased prevalence of TPO-abs was again observed in bipolar offspring (10,4% versus 4%) and higher TPO-abs titers were still present in co-twins of bipolar cases compared to control twins [mean 1.06 IU/ml (SD .82) versus mean .82 IU/ml (SD .67)], although statistical significance was lost. CONCLUSIONS: Although our results show a trend toward an increased inherited risk of the co-occurrence of BD and thyroid autoimmunity, large-scale studies can only draw final conclusions. Nationwide epidemiological and GWAS studies reach such numbers and support the view of a possible common (autoimmune) etiology of severe mood disorders and chronic recurrent infections and autoimmunity, including thyroid autoimmunity.
RESUMO
There is room for immune markers other than TPO-Abs to identify an increased risk to develop autoimmune thyroid disease (AITD). Our aim was to test the hypothesis that activation of CD4+ T cells is such marker in relatives of AITD patients, who have an increased risk to develop AITD. We established a controlled study on 20 TPO-Ab positive and 20 TPO-Ab negative euthyroid female relatives. All these cases had at least one 1st or 2nd degree relative with a documented autoimmune hyper- or hypothyroidism in whom we studied the percentages of circulating subsets of activated (MHC class-II, CD25 (IL-2R), CD71 or CD69+) CD4+ T cells and the level of the soluble (s)-IL2R in serum. We found that euthyroid female relatives did not show an activation of their T cell system, but a reduced expression of CD25 on CD4+ T cells. The level of the shed IL2R in serum was also lower in comparison with levels found in healthy control females. A reduced T cell activity was found in both TPO-Ab positive and negative relatives. In conclusion, female relatives with at least one 1st or 2nd degree relative with an AITD show signs of a reduced expansion capability of their T cell pool. It is hypothesized that this reduced expansion capability may affect T cell tolerance mechanisms more than T effector mechanisms.
Assuntos
Receptores de Interleucina-2/sangue , Tireoidite Autoimune/genética , Tireoidite Autoimune/imunologia , Adulto , Autoanticorpos/sangue , Autoantígenos/imunologia , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Ativação Linfocitária , Pessoa de Meia-Idade , Fatores de Risco , Tolerância a Antígenos Próprios , Subpopulações de Linfócitos T/imunologiaRESUMO
Macrophages are a heterogeneous population of cells that belong to the mononuclear phagocyte system. They play an important role in tissue homeostasis and remodeling and are also potent immune regulators. Pancreatic macrophages are critically involved in the development and pathogenesis of autoimmune diabetes. To elucidate the ontogeny of pancreatic macrophages, we characterized in this study the macrophages present in the adult and developing fetal pancreas of normal mice. We additionally examined the presence of local macrophage precursors and the involvement of macrophages in the growth of endocrine tissue in the fetal pancreas. We identified two phenotypically distinct macrophage subsets in the adult pancreas. The majority of macrophages was CD45(+)ER-MP23(+)MOMA-1(+). Under noninflammatory conditions, only a minority ( approximately 5%) of the pancreatic macrophages additionally expressed the macrophage marker F4/80. In contrast, in the fetal pancreas, phenotypically, mature macrophages were identified exclusively by their expression of F4/80 and lacked detectable staining with ER-MP23 and MOMA-1 antibodies. In fetal pancreas organ cultures, we could show that macrophages develop from pre-existing precursors, which are present in the fetal pancreas at embryonic age 12.5. Moreover, the number of macrophages increased significantly when macrophage-colony stimulating factor was added to these cultures. It is important that this increase of F4/80-positive cells was paralleled by an increase in the number of insulin-producing cells, suggesting that macrophages support the growth of these endocrine cells.
Assuntos
Sistema Endócrino/embriologia , Macrófagos/citologia , Macrófagos/imunologia , Pâncreas/citologia , Pâncreas/crescimento & desenvolvimento , Animais , Antígenos de Diferenciação/imunologia , Linhagem da Célula/imunologia , Sistema Endócrino/imunologia , Feminino , Técnicas In Vitro , Células Secretoras de Insulina/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pâncreas/imunologia , FenótipoRESUMO
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease whose notorious pathologic feature is insulitis accompanied by destruction of beta-cells. In this morphological study, we examined the pancreatic events during the onset of diabetes in spontaneously diabetic BB/Organon rats. Dendritic cells were the first cells to accumulate around the islets, followed by lymphocytes. Scavenger macrophages and MHC class II-positive beta-cells were only seen late in the disease. These observations suggest a role for antigen-presenting dendritic cells in the onset of the beta-cell-specific autoimmune reaction and emphasize the necessity to distinguish between the several monocyte-macrophage subtypes in studies on the pathogenesis of IDDM.
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Células Dendríticas/patologia , Ilhotas Pancreáticas/patologia , Macrófagos/patologia , Estado Pré-Diabético/patologia , Animais , Anticorpos Monoclonais , Diabetes Mellitus Experimental/patologia , Feminino , Linfócitos/patologia , Masculino , Ratos , Ratos Endogâmicos BBRESUMO
This immunohistochemical study describes the infiltration pattern of monocytes-macrophages and dendritic cells during the development of insulitis and diabetes in the NOD mouse. A panel of monoclonal antibodies (MoAbs) was used to analyze pancreases of nondiabetic (glucosuria negative) male and female NOD mice at 3, 7, 10, and 17 weeks of age. BALB/c female mice 17-weeks-old, diabetic NOD female mice 20- to 30-weeks-old, and nondiabetic NOD male mice 22-weeks-old were used as controls. Three MoAbs (viz., ER-MP23, MOMA1, and BM8) were special and appeared to identify macrophage/dendritic cell subsets that either had a characteristic infiltration pattern in the initial phases of the autoimmune reaction before T-cell infiltration or were typical for the later beta-cell destructive insulitis process. 1) Raised numbers of ER-MP23+ and MOMA-1+ dendritic cells/macrophages were characteristic for the initial phases of the NOD insulitis in 3-week-old mice. The cells were found in and near swollen para-insular vessels. In 7-week-old mice, these ER-MP23+ and MOMA-1+ cells had accumulated around the islets and were the first hematopoietic cells detectable at these spots. 2) From 7 weeks of age onward, BM8+ macrophages could be found in the para- and peri-insulitis processes. However, only in females were these BM8+ macrophages found to infiltrate into the islets. In lymphoid tissues, ER-MP23 predominantly reacts with macrophages/dendritic cells present in the subcapsular and interfollicular sinuses of lymph nodes and the T-cell zones of these lymph nodes. ER-MP23 also reacts with tissue macrophages/dendritic cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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Células Dendríticas/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Ilhotas Pancreáticas/patologia , Macrófagos/patologia , Monócitos/patologia , Pancreatopatias/patologia , Linfócitos T/patologia , Animais , Anticorpos Monoclonais , Antígenos/análise , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Feminino , Imuno-Histoquímica/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Pancreatopatias/genética , Pancreatopatias/imunologia , Linfócitos T/imunologiaRESUMO
Aggregation of dendritic cells (DCs) in homotypic clusters has been described in vivo in lymph and skin, and here we report studies on homotypic clustering of rat splenic (s) DCs in vitro. Wistar rat sDCs readily formed homotypic clusters in culture, which increased in number and size over time (with a peak at t = 3 h). Keeping the cells at higher densities or treatment with anti-CD43 induced more and larger homotypic clusters. After such enhanced clustering the DCs had increased their T cell stimulating capabilities in syngeneic mixed lymphocyte reaction, and had a higher expression of CD80 and CD86 (signs of maturation). Ag transfer from bovine serum albumin-fluorescein isothiocyanate-pulsed to unpulsed DCs was observed during clustering. Here we also show that sDCs of the biobreeding diabetes-prone (BB-DP) rat, a model of autoimmune diabetes/thyroiditis, formed fewer and smaller clusters than Wistar sDCs, and that DC-DC clustering resulted in only a modest maturation of the cells (as determined in syn MLR and by phenotyping). Anti-CD43 completely restored the clustering defect BB-DP DCs in vitro, yet T cell-stimulating capability was only restored to a limited extent. Ag transfer in BB-DP DC clusters was similar.
Assuntos
Antígenos CD , Células Dendríticas/citologia , Células Dendríticas/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Apresentação de Antígeno/imunologia , Antígenos/imunologia , Antígenos/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Agregação Celular/imunologia , Diferenciação Celular/imunologia , Feminino , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Leucossialina , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Masculino , Ratos , Ratos Endogâmicos BB , Soroalbumina Bovina/imunologia , Soroalbumina Bovina/metabolismo , Sialoglicoproteínas/imunologia , Baço/citologia , Linfócitos T/imunologiaRESUMO
We hypothesized that the relatively low immunogenicity of liver grafts might be related to a special maturation program of hepatic myeloid dendritic cells (MDC), yielding relatively immature effector MDC with weak allogeneic T-cell stimulatory capacity. To investigate whether maturation of human liver-derived MDC in vivo differs from maturation of MDC at another anatomical location, we compared the immunophenotypes and allogeneic T-cell stimulatory capacity of MDC from hepatic with those from inguinal lymph nodes (LN). MDC were purified by immunomagnetic selection from hepatic LN obtained from multi-organ donors (n = 8) and from inguinal LN of kidney transplant recipients (n = 7). MDC from hepatic LN had a significantly reduced capacity to stimulate allogeneic T-cell proliferation compared to MDC from inguinal LN. However, this was not due to an immaturity, since MDC from hepatic LN had significantly higher expressions of HLA-DR, CD80, and CD86 compared to MDC from inguinal LN. Hepatic MDC maturate in vivo to a mature type of effector MDC with relatively poor allogeneic T-cell stimulatory capacity.
Assuntos
Células Dendríticas/citologia , Células Dendríticas/imunologia , Fígado/citologia , Linfócitos T/imunologia , Antígenos HLA-DR/análise , Humanos , Isoantígenos/imunologia , Fígado/imunologia , Ativação LinfocitáriaRESUMO
BACKGROUND: This study aimed to examine whether inflammatory gene expression was a trait or a state marker in patients with bipolar disorder (BD). METHODS: 69 healthy controls (HC), 82 euthymic BD patients and 8 BD patients with a mood episode (7 depressed, 1 manic) were included from the MOODINFLAME study. Six of the eight patients who had a mood episode were also investigated when they were euthymic (6 of the 82 euthymic patients). Of these participants the expression of 35 inflammatory genes was determined in monocytes using quantitative-polymerase chain reaction, of which a total gene expression score was calculated as well as a gene expression score per sub-cluster. RESULTS: There were no significant differences in inflammatory monocyte gene expression between healthy controls and euthymic patients. Patients experiencing a mood episode, however, had a significantly higher total gene expression score (10.63 ± 2.58) compared to healthy controls (p = .004) and euthymic patients (p = .009), as well as when compared to their own scores when they were euthymic (p = .02). This applied in particular for the sub-cluster 1 gene expression score, but not for the sub-cluster 2 gene expression score. CONCLUSIONS: Our study indicates that in BD inflammatory monocyte, gene expression is especially elevated while in a mood episode compared to being euthymic.
RESUMO
An accumulation of antigen-presenting dendritic cells (DC) in the thyroid gland, followed by thyroid autoimmune reactivity, occurs in normal Wistar rats during iodine deficiency, and spontaneously in diabetic-prone Biobreeding rats. This intrathyroidal DC accumulation coincides with an enhanced growth rate and metabolism of the thyrocytes, suggesting that both phenomena are related. Because DC are known to regulate the hormone synthesis and growth in other endocrine systems (i.e. the pituitary, the ovary, and the testis), we tested the hypothesis that DC, known for their superb accessory cell function in T cell stimulation, act as regulators of thyrocyte proliferation (and hormone secretion). We investigated the effect of (Nycodenz density gradient) purified splenic DC from Wistar rats on the growth rate of and thyroid hormone secretion by Wistar thyroid follicles (collagenase dispersion) in culture. Various numbers of DC and follicles were cocultured during 24 h. The proliferative capacity of thyrocytes was measured by adding tritiated thymidine (3H-TdR) and bromodeoxyuridine, the hormone secretion into the culture fluid was measured by using a conventional T3 RIA. Furthermore, antibodies directed against interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were added to these cocultures to determine the role of these cytokines in a possible DC regulation of thyrocyte growth. Cocultures were also carried out in the presence of antimajor histocompatibility complex-class I (MHC I), anti-MHC II, antiintercellular adhesion molecule-1 (ICAM-1), and antilymphocyte function-associated antigen-1alpha (LFA-1alpha) antibodies to possibly interfere with DC-thyrocyte interactions. The addition of DC to thyroid follicles clearly inhibited their 3H-TdR uptake, particularly at a 10:1 ratio, in comparison to follicle cultures alone, both under basal conditions and after TSH stimulation (75 +/- 7% and 49 +/- 11% reduction, respectively, n = 4). The follicle T3 secretion (after TSH stimulation) was also suppressed by DC in this system, but to a lesser extent (at best at an 1:1 ratio, 25 +/- 7% reduction, n = 4). The DC-induced inhibition of thyroid follicle growth was totally abrogated after addition of anti-IL-1beta antibodies; anti-IL-6 only had effect on the DC inhibition of non-TSH-stimulated thyrocytes, whereas anti-TNF-alpha demonstrated no effect at all. The antibodies to MHC and to adhesion molecules had also no effect on this DC-induced growth inhibition. The effect of the different anti-cytokine and anti-adhesion antibodies on the T3 secretion from thyroid follicles was not investigated. The clear inhibition of thyrocyte growth by splenic DC (classical antigen-presenting cells) again demonstrates the regulatory role of DC in endocrine systems. Proinflammatory cytokines such as IL-1beta and IL-6 are important mediators in this regulation. The here shown dual role of DC represents a link between the immune and endocrine system, which may form the gateway to the understanding of the initiation of thyroid autoimmune reactions and the thyroid autoimmune phenomena seen in iodine deficiency.