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https://www.arca.fiocruz.br/handle/icict/6859
A SHIFT TOWARDS A T CELL CYTOKINE DEFICIENCY ALONG WITH AN ANTI-INFLAMMATORY/REGULATORY MICROENVIRONMENT MAY ENABLE THE SYNTHESIS OF ANTI-FVIII INHIBITORS IN HAEMOPHILIA A PATIENTS
Flow Cytometry/FACS
Haematology
Immune Regulation
Intracellular Cytokine Staining
Author
Affilliation
Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil/Fundação HEMOMINAS. Laboratório de Pesquisa. Belo Horizonte, MG, Brasil/Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, Brasil
Fundação HEMOMINAS. Laboratório de Pesquisa. Belo Horizonte, MG, Brasil /Pontifícia Universidade Católica de Minas Gerais. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil
Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil
Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, Brasil
Fundação HEMOMINAS. Laboratório de Pesquisa. Belo Horizonte, MG, Brasil /Pontifícia Universidade Católica de Minas Gerais. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil
Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, Brasil
Universidade Federal de Minas Gerais. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil
Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, Brasil
Abstract
Despite the clinical relevance of anti-factor VIII (FVIII) antibodies (anti-FVIII inhibitors) impairing haemostatic activity of haemophilia A (HA) patients, the immunological mechanisms underlying their production are unknown. Aiming to understand more clearly the immune response in patients with [HAa-FVIII(+)] and without [HAa-FVIII(-)] anti-FVIII inhibitors, we have characterized the cytokine pattern of peripheral blood leucocytes, using anin vitrostimulation of whole blood samples with plasma-derived (pFVIII) or recombinant FVIII (rFVIII). The results highlighted decreased levels of tumour necrosis factor (TNF)-a + neutrophils with higher interleukin (IL)-5/TNF-aratioinHAa-FVIII(+). All HA samples displayed decreased levels of IL-10 + monocytes when compared to the blood donor (BD) samples. HAa-FVIII(+) showed lower levels of TNF-a + monocytes and increased IL-10/TNF-a ratio. Analysis of adaptive immunity revealed increased levels of interferon (IFN)-g +, TNF-a + and IL-4 + T-cells, from both CD4 + and CD8 + T cells, in HAa-FVIII(-) when compared to BD. Moreover, increased frequency of IL-10 + B cells and higher levels ofa-FVIII IgG1 were observed in HAa-FVIII(-). Basal levels of cytokine + B-cells, similar to BD, and higher levels ofa-FVIII IgG4 are major features in HAa-FVIII(+). The global cytokine profile demonstrated a major anti-inflammatory/regulatory pattern in HAa-FVIII(+), confirmed by thein vitrostimuli with pFVIII or rFVIII. The polarized anti-inflammatory/regulatory immune response in HAa-FVIII(+) and the mixed pattern with a bias towards an inflammatory cytokine profile, modulated by IL-4 in HAa-FVIII(-), may be the key element to drive the development of distinct subclasses of anti-FVIII antibodies. These finding have implications for the design of safe and effective therapeutic protocols to control inhibitors synthesis in HA patients.
Keywords
Antibody ResponsesFlow Cytometry/FACS
Haematology
Immune Regulation
Intracellular Cytokine Staining
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