RESUMO
Children born by Caesarean Section have a higher risk for type 1 diabetes. We aimed to investigate whether Caesarean Section leads to alterations of the immune response in children with familial risk for type 1 diabetes. We examined measures of innate and adaptive immune responses in 94 prospectively followed children, including 40 born by Caesarean Section. Proinflammatory serum cytokine concentrations were determined at age 6 months. As a measure of vaccine response, IgG1, IgG2, and IgG4 tetanus antibody titers and CD4(+) T cell proliferation against tetanus toxoid were quantified. Compared to infants born by vaginal delivery, infants born by Caesarean Section had lower concentrations of the cytokines IFN-É£ (p=0.014) and IL-8 (p=0.005), and weaker CD4(+) T cell responses to tetanus measured in the first (p=0.007) and second year (p=0.047) of life. Overall, our findings provide evidence that the mode of delivery influences the immune status and responsiveness during childhood.
Assuntos
Imunidade Adaptativa/imunologia , Cesárea , Diabetes Mellitus Tipo 1/imunologia , Interferon gama/imunologia , Interleucina-8/imunologia , Toxoide Tetânico/imunologia , Anticorpos Antibacterianos/imunologia , Linfócitos T CD4-Positivos , Estudos de Casos e Controles , Parto Obstétrico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunoglobulina G , Lactente , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-1beta/imunologia , Interleucina-2/imunologia , Interleucina-6/imunologia , Masculino , Estudos Prospectivos , Toxina Tetânica/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Fms-like tyrosine kinase-3 is a commonly mutated gene in acute myeloid leukemia, with about one-third of patients carrying an internal-tandem duplication of the juxtamembrane domain in the receptor (FLT3-ITD). FLT3-ITD exhibits altered signaling quality, including aberrant activation of STAT5. To identify genes affecting FLT3-ITD-mediated STAT5 signaling, we performed an esiRNA-based RNAi screen utilizing a STAT5-driven reporter assay. Knockdowns that caused reduced FLT3-ITD-mediated STAT5 signaling were enriched for genes encoding proteins involved in protein secretion and intracellular protein transport, indicating that modulation of protein transport processes could potentially be used to reduce constitutive STAT5 signaling in FLT3-ITD-positive cells. The relevance of KDELR1, a component involved in the Golgi-ER retrograde transport, was further analyzed. In FLT3-ITD-expressing leukemic MV4-11 cells, downregulation of KDELR1 resulted in reduced STAT5 activation, proliferation and colony-forming capacity. Stable shRNA-mediated depletion of KDELR1 in FLT3-ITD-expressing 32D cells likewise resulted in reduced STAT5 signaling and cell proliferation. Importantly, these cells also showed a reduced capacity to generate a leukemia-like disease in syngeneic C3H/HeJ mice. Together our data suggest intracellular protein transport as a potential target for FLT3-ITD driven leukemias, with KDELR1 emerging as a positive modulator of oncogenic FLT3-ITD activity.
Assuntos
Genoma , Proteínas/fisiologia , Interferência de RNA , Transdução de Sinais/fisiologia , Tirosina Quinase 3 Semelhante a fms/metabolismo , Animais , Sequência de Bases , Primers do DNA , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT5/metabolismoRESUMO
Insulin autoantibodies (IAA) can appear in children within months of introducing solid foods to the diet and before clinical type 1 diabetes. The aim of this study was to determine whether infant dietary antigens could be immunizing agents of IAA. To this end, IAA binding to [(125) I]insulin was competed with food preparations and extracts of foods encountered in the infant diet (milk formulas, bovine milk, wheat flour, fowl meal). Bovine milk powder extracts inhibited IAA-positive samples from six of 53 children (age 0·3-14·0 years) participating in German prospective cohorts. Inhibition in these sera ranged from 23 to 100%. Competition was abolished when hydrolyzed milk powder was used. Competition with protein components of bovine milk found that two of the six milk-reactive sera were inhibited strongly by alpha- and beta-casein; none were inhibited by the milk proteins bovine serum albumin or lactoglobulins. The two casein-reactive sera had high affinity to alpha-casein (1·7×10(9) ; 3·1×10(9) l/mol), and lesser affinity to beta-casein (4·0×10(8) ; 7·0×10(7) l/mol) and insulin (2·6×10(8) ; 1·6×10(8) l/mol). No children with milk-reactive IAA developed autoantibodies to other islet autoantigens or diabetes (median follow-up 9·8 years). These results suggest that autoimmunity to insulin can occur infrequently via cross-reactivity to food proteins, but this form of IAA immunization does not appear to be associated with progression to diabetes.
Assuntos
Autoanticorpos/imunologia , Caseínas/imunologia , Anticorpos Anti-Insulina/imunologia , Insulina/imunologia , Adolescente , Animais , Autoanticorpos/metabolismo , Ligação Competitiva , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Caseínas/metabolismo , Caseínas/farmacologia , Bovinos , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Citometria de Fluxo , Humanos , Lactente , Alimentos Infantis , Insulina/metabolismo , Insulina/farmacologia , Anticorpos Anti-Insulina/metabolismo , Radioisótopos do Iodo , Proteínas do Leite/imunologia , Proteínas do Leite/metabolismo , Proteínas do Leite/farmacologia , Ligação Proteica , Soroalbumina BovinaRESUMO
Allograft rejection is mainly driven by the production of IL-2, which expands T cells by linking the IL-2 receptor (IL-2R) composed of three subunits: CD25, CD122 and CD132. Daclizumab, widely used in immunosuppression, is a humanized anti-CD25 antibody that disrupts IL-2 signaling by binding to CD25 and preventing the assembly of the high-affinity IL-2R. Here we show that Daclizumab, while blocking the T-cell response to IL-2, increases CD4(+) and CD8(+) T-cell proliferative response to the homeostatic cytokine IL-7. The IL-7R shares CD132 with the IL-2R and blocking of CD25 by Daclizumab results in the enhanced formation of the IL-7R that in turn allows IL-7 to bind more efficiently on the cell surface. The consequently increased IL-7R signaling boosts intracellular phosphorylated STAT5 and T-cell proliferation. In addition, treatment with Daclizumab delays the internalization of CD127 upon IL-7 treatment, retaining T-cell sensitivity to IL-7 for a prolonged time. This effect of Daclizumab highlights the redundancy of the cytokine system, which may influence T-cell proliferation in transplanted patients, and provides information to improve future immunosuppressive strategies.