ABSTRACT
Antigen-mediated cross-linking of Immunoglobulin E (IgE) bound to mast cells/basophils via FcÉRI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FcÉRI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FcÉRI signals for DC function remain poorly understood. We show that humanized mice that express FcÉRI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FcÉRI cross-linking fails to induce maturation or production of inflammatory mediators in human DCs and FcÉRI-humanized DCs. Furthermore, conferring expression of FcÉRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcÉRI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcÉRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast cell-dependent allergic phenotype observed in FcÉRI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.
Subject(s)
Asthma/immunology , Dendritic Cells/immunology , Egg Hypersensitivity/immunology , Immunoglobulin E/immunology , Mast Cells/immunology , Receptors, IgE/immunology , Allergens/immunology , Animals , Asthma/genetics , Asthma/pathology , Cell Migration Assays , Cell Movement/drug effects , Cross-Linking Reagents/chemistry , Cytokines/biosynthesis , Cytokines/metabolism , Dendritic Cells/drug effects , Dendritic Cells/pathology , Egg Hypersensitivity/genetics , Egg Hypersensitivity/pathology , Feedback, Physiological , Gene Expression Regulation , Humans , Immunity, Mucosal , Immunoglobulin E/chemistry , Immunoglobulin E/genetics , Lipopolysaccharides/pharmacology , Mast Cells/drug effects , Mast Cells/pathology , Mice , Mice, Transgenic , Ovalbumin/immunology , Papain/pharmacology , Primary Cell Culture , Protein Binding , Receptors, IgE/chemistry , Receptors, IgE/genetics , Signal TransductionABSTRACT
Objetivo: Identificar los factores de riesgo sociodemográficos, obstétricos y perinatales que con más frecuencia se asocian a muerte fetal en embarazos mayores de 27 semanas. Método: De enero de 2004 a junio de 2009 en el Hospital Civil de Guadalajara, se realizó un estudio de casos y controles con 528 casos de muerte fetal de más de 27 semanas de gestación y 528 neonatos vivos cuyo nacimiento ocurrió inmediatamente después. Se comparó la frecuencia de diferentes variables maternas y fetales que en forma previa se han reportado asociadas a muerte fetal, por medio de Chi2 y prueba exacta de Fisher; se estimó la fuerza de asociación entre estas variables y muerte fetal con la razón de momios, con un intervalo de confianza del 95 por ciento. Resultados: De los factores de riesgo estudiados se asociaron con muerte fetal: edad materna mayor de 35 años, escolaridad baja, multiparidad, antecedente de aborto y de muerte fetal, atención prenatal deficiente, complicaciones en el embarazo, líquido amniótico anormal, doble circular de cordón umbilical al cuello del producto y malformaciones congénitas mayores del recién nacido. No se asoció con muerte fetal, el estado civil soltero, ser primigesta, tabaquismo, sexo masculino del feto, circular simple al cuello y macrosomía fetal. Conclusiones: De los factores de riesgo asociados con muerte fetal, resalta la atención prenatal deficiente que de ser mejorada, podría disminuir la fuerza de asociación de algunas de las otras variables que se asociaron a muerte fetal.
Objective: To identify sociodemographic, obstetric and perinatal factors most frequently associated with fetal death in pregnancies over 27 weeks. Methods: From January 2004 to June 2009 at the Civil Hospital of Guadalajara, we performed a case-control study of 528 stillbirths over 27 weeks gestation and 528 living infants whose birth occurred immediately afterwards. We compared the frequency of maternal and fetal variables that previously have been reported associated with fetal death by means of Chi2 and Fisher exact test, we estimated the strength of association between these variables and fetal death with odds ratios with a confidence level of 95 percent. Results: The studied risk factors associated with fetal death was: maternal age older than 35 years, low schooling, multiparity, history of abortion and stillbirth, poor prenatal care, pregnancy complications, abnormal amniotic fluid, circular double umbilical cord around the neck of product and major congenital malformations of the newborn. Single marital status, primiparity, smoking, male fetus, simple circular neck and fetal macrosomia, was not associated with fetal death. Conclusions: Risk factors associated with fetal death, like poor prenatal care emphasizes that, if improved, could decrease the strength of association of some of the other variables associated with fetal death.
