Marcadores da imunomodulação no sangue materno e fetal e nas placentas de mães diabéticas ou com hiperglicemia gestacional leve
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2016-12-01
Autores
Hara, Cristiane de Castro Pernet [UNESP]
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Universidade Estadual Paulista (Unesp)
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INTRODUÇÃO - Durante a gravidez, a hiperglicemia materna altera a expressão e a transferência de células imunorregulatórias e de imunoglobulinas e o perfil de citocinas na interface materno-fetal. OBJETIVO – Avaliar, em gestações complicadas por hiperglicemia, a expressão de células NK e o perfil de citocinas no sangue, materno e do cordão umbilical, e na placenta (artigo 1); quantificar a produção de anticorpos e a passagem de IgG total, e respectivas subclasses, via receptor FcRn (artigo 2). MÉTODO - Foram avaliadas 120 gestantes, distribuídas nos grupos: não-diabético (ND; N = 30), hiperglicemia gestacional leve (HGL; N = 30), diabetes mellitus gestacional (DMG; N = 30) e diabetes mellitus tipo 2 (DM2; N = 30). Técnicas de citometria de fluxo foram utilizadas para análise de células e citocinas e, de ELISA, para avaliação das concentrações de IgG total e subclasses. A transferência placentária de anticorpos totais, e respectivas subclasses, foi definida pela relação [(concentrações no sangue de cordão umbilical/sangue materno) x 100]. Na análise estatística foram realizadas análises de variância (ANOVA), seguida pelo teste de Tukey, e de correlação de Pearson, com p < 0,05. RESULTADOS - No sangue materno dos grupos hiperglicêmicos, as células NK CD16+CD56– aumentaram, enquanto que CD16+CD56+ foi menor no grupo DMG. No sangue do cordão do grupo DM2 mostrou uma maior proporção de células CD16+CD56– e CD16–CD56+. As camadas extravilosas da placenta dos grupos DMG e DM2 mostraram maior expressão de CD16+CD56– e independente da camada, a proporção de CD16–CD56+ foi maior em HGL e DMG e menor em DM2. Em relação às citocinas, IL-2 foi menor no sangue materno e IFN-y mais elevados no sangue materno e do cordão do grupo DMG. IL-17 foi mais elevada no sangue materno e do cordão do grupo DM2. A camada extravilosa placentária da HGL mostrou níveis elevados de IL-4, IL-6, IL-10, IL-17, e IFN-γ e baixos níveis de IL-1β e IL-8, enquanto que a camada vilosa placentária continha alta níveis de IL-17 e IFN-γ. O grupo HGL, independentemente da região, apresentaram maiores níveis de IL-8. O grupo DM-2, independentemente da região da placenta mostrou níveis elevados de TNF-α, IL-17, e IFN-γ. O sangue materno de DM-2 e o sangue do cordão umbilical de HGL exibiram uma poporção mais elevada de CD19+ expressas por células B. DM2 mostrou a menor proporção de células CD19+na placenta. A expressão de FcRn aumentou nas células do cordão e placenta de HGL. As células do sangue materno, do sangue do cordão e da placenta de DM2 mostraram menor expressão de FcRn. A maior expressão de FcRn, independente do estado hiperglicêmico foi observada nas células da placenta. Houve menores níveis de IgG no sangue materno em DM2 e maiores no sangue do cordão umbilical de HGL. Os níveis mais elevados de IgG4 foi detectado no sangue de mães hiperglicêmicas. Os níveis mais elevados de IgG3 e IgG4 no sangue do cordão foram detectados em HGL, e os menores de IgG2 e IgG3 níveis em DM2. CONCLUSÃO - A hiperglicemia produz ambiente inflamatório com elevada produção de citocinas, apresentando alterações na expressão de células NK, de FcRn na placenta, na produção e taxa de transferência de IgG. Os níveis celulares que expressam CD16+ e de citocinas no sangue materno, sangue do cordão umbilical e tecido placentário são modificados em gestações complicadas pelo diabetes. A hiperglicemia materna compromete a transferência placentária de IgG1, IgG3 e IgG4. Os resultados sugerem que a hiperglicemia materna, diminui a expressão FcRn em células da placenta e sangue e compromete a produção e transferência de anticorpos maternos para os recém-nascidos.
INTRODUCTION - During pregnancy, the immune response associated with diabetes alters the expression and the transfer of immune cells, including regulatory, immunoglobulins and the profile of cytokines in the maternal-fetal interface. OBJECTIVE - To evaluate the expression of NK cells, and the profile of cytokines in maternal blood, umbilical cord and placenta, quantify the production of antibodies, as well as, the passage of IgG and subclasses, via receptors FcRn in pregnancies complicated by diabetes or hyperglycemia. METHOD - were assessed 120 pregnant women, distributed as non-diabetic (ND; n=30), Mild Gestational Hyperglycemia (MGH; n=30), Gestational Diabetes Mellitus (GDM; n=30) and type 2 Diabetes Mellitus (DM2; N=30). The cells and cytokines were evaluated by flow cytometry. The concentrations of total IgG and subclasses were analyzed by ELISA. Placental transfer of the total and subclasses antibodies were defined in each assay by the ratio [(cord concentrations/maternal concentrations) x 100]. In the statistical analysis we used analysis of variance (ANOVA), followed by Tukey test, and Pearson's linear correlation, with p < 0.05. RESULTS - In the maternal blood from the hyperglycemic groups, the CD16+CD56− NK cells increased, whereas that of CD16+CD56+ decreased in GDM group. Cord blood from DM2 showed a higher proportion of CD16+CD56− and CD16−CD56+. The placental extravillous layer of GDM and DM2 showed an increase of CD16+CD56− cells and, irrespective of region, the proportion of CD16−CD56+ cells was higher in MGH and GDM and lower in DM-2. IL-2 was lower in maternal blood and IFN-𝛾����������������������� higher in maternal and cord blood from the GDM group. IL-17 was higher in maternal and cord blood from the DM-2 group. The placental extravillous layer of the MGH showed high levels of IL-4, IL-6, IL-10, IL- 17, and IFN-𝛾����������������������� and low levels of IL-1𝛽����������������������� and IL-8, whereas the placental villous layer contained high levels of IL-17 and IFN-𝛾�����������������������. The GDM group, irrespective of region, showed higher levels of IL-8. The DM-2 group, irrespective of region, placenta showed high levels of TNF-𝛼�����������������������, IL-17, and IFN-𝛾�����������������������. Maternal blood from DM-2 and cord blood from MGH exhibited a higher proportion of CD19+ expression by B cells. DM-2 showed a lower proportion of CD19+ cells in placenta. FcRn expression increased in cells from cord blood and placenta from MGH. Maternal blood, cord blood and placenta cells from DM-2 showed lower FcRn expression. The highest FcRn expression, irrespective of glycemic status, was observed in placenta cells. Maternal blood IgG levels were lower in DM-2, and cord blood IgG levels were higher in MGH. The highest levels of IgG4 were detected in the blood of hyperglycemic mothers. The highest IgG3 and IgG4 levels in cord blood were detected in MGH, and the lowest IgG2 and IgG3 levels in DM-2. CONCLUSIONS - Hyperglycemia produces inflammatory environment with high production of cytokines, presenting changes in expression of NK cells, FcRn in the placenta, in production and rate of transfer of IgG. The levels of cells expressing CD16+ and cytokines in maternal blood, cord blood, and placental tissue are modified in pregnancies complicated by diabetes. Maternal hyperglycemia compromised placental transfer of IgG1, IgG3 and IgG4. The results suggest that regardless of hyperglycemia degree, it decreases FcRn expression in placenta and blood cells and compromises the production and transfer of antibodies from maternal blood to newborns.
INTRODUCTION - During pregnancy, the immune response associated with diabetes alters the expression and the transfer of immune cells, including regulatory, immunoglobulins and the profile of cytokines in the maternal-fetal interface. OBJECTIVE - To evaluate the expression of NK cells, and the profile of cytokines in maternal blood, umbilical cord and placenta, quantify the production of antibodies, as well as, the passage of IgG and subclasses, via receptors FcRn in pregnancies complicated by diabetes or hyperglycemia. METHOD - were assessed 120 pregnant women, distributed as non-diabetic (ND; n=30), Mild Gestational Hyperglycemia (MGH; n=30), Gestational Diabetes Mellitus (GDM; n=30) and type 2 Diabetes Mellitus (DM2; N=30). The cells and cytokines were evaluated by flow cytometry. The concentrations of total IgG and subclasses were analyzed by ELISA. Placental transfer of the total and subclasses antibodies were defined in each assay by the ratio [(cord concentrations/maternal concentrations) x 100]. In the statistical analysis we used analysis of variance (ANOVA), followed by Tukey test, and Pearson's linear correlation, with p < 0.05. RESULTS - In the maternal blood from the hyperglycemic groups, the CD16+CD56− NK cells increased, whereas that of CD16+CD56+ decreased in GDM group. Cord blood from DM2 showed a higher proportion of CD16+CD56− and CD16−CD56+. The placental extravillous layer of GDM and DM2 showed an increase of CD16+CD56− cells and, irrespective of region, the proportion of CD16−CD56+ cells was higher in MGH and GDM and lower in DM-2. IL-2 was lower in maternal blood and IFN-𝛾����������������������� higher in maternal and cord blood from the GDM group. IL-17 was higher in maternal and cord blood from the DM-2 group. The placental extravillous layer of the MGH showed high levels of IL-4, IL-6, IL-10, IL- 17, and IFN-𝛾����������������������� and low levels of IL-1𝛽����������������������� and IL-8, whereas the placental villous layer contained high levels of IL-17 and IFN-𝛾�����������������������. The GDM group, irrespective of region, showed higher levels of IL-8. The DM-2 group, irrespective of region, placenta showed high levels of TNF-𝛼�����������������������, IL-17, and IFN-𝛾�����������������������. Maternal blood from DM-2 and cord blood from MGH exhibited a higher proportion of CD19+ expression by B cells. DM-2 showed a lower proportion of CD19+ cells in placenta. FcRn expression increased in cells from cord blood and placenta from MGH. Maternal blood, cord blood and placenta cells from DM-2 showed lower FcRn expression. The highest FcRn expression, irrespective of glycemic status, was observed in placenta cells. Maternal blood IgG levels were lower in DM-2, and cord blood IgG levels were higher in MGH. The highest levels of IgG4 were detected in the blood of hyperglycemic mothers. The highest IgG3 and IgG4 levels in cord blood were detected in MGH, and the lowest IgG2 and IgG3 levels in DM-2. CONCLUSIONS - Hyperglycemia produces inflammatory environment with high production of cytokines, presenting changes in expression of NK cells, FcRn in the placenta, in production and rate of transfer of IgG. The levels of cells expressing CD16+ and cytokines in maternal blood, cord blood, and placental tissue are modified in pregnancies complicated by diabetes. Maternal hyperglycemia compromised placental transfer of IgG1, IgG3 and IgG4. The results suggest that regardless of hyperglycemia degree, it decreases FcRn expression in placenta and blood cells and compromises the production and transfer of antibodies from maternal blood to newborns.
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Palavras-chave
Hiperglicemia, Imunorreguladoras, IgG, Receptor FcRn, NK, Citocinas, Transferência placentária, Sangue materno e sangue cordão, Hyperglycemia, Immunoregulator, FcRn receptor, Cytokines, Placental transfer, Maternal blood and cord blood