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Exploration des mécanismes inflammatoires impliqués dans la physiopathologie de la maladie de Fabry et la réponse à l’enzymothérapie substitutive

Abstract : Fabry disease (FD) is an X-linked disorder due to mutations in the GLA gene that lead to defects in alpha-galactosidase A enzyme activity and subsequent accumulation of glycosphingolipids. A pro-inflammatory condition has been described in FD, but very few studies have investigated the peripheral blood mononuclear cells (PBMCs). Enzyme replacement therapy (ERT) has been the historical treatment of FD and has shown inconstant benefits. In the present work, we investigated the inflammatory mechanisms involved in the response to ERT and in the pathophysiology of the disease. We first developed an ELISA that allows the detection of anti-agalsidase antibodies (Abs) developed against both available ERT. We showed that the prevalence of Abs depends on the clinical phenotype of the patients. The cross-reactivity towards both ERT was complete. Abs, notably the IgG4, had a dose-dependent inhibitory effect on ERT. Abs were not associated with clinical events, but higher lysoGb3 levels suggesting a poorer associated prognosis. In PBMCs, we observed higher percentages of NK cells in Fabry patients under agalsidase beta, suggesting its higher immunogenicity. In Fabry patients, we observed disturbances in T cell maturation with higher percentages of CD27+ and lower percentages of CD57+ cells among the CCR7- populations. The expression of CCR7 was inversely correlated with the concentrations of lysoGb3 and sphingosine-1-phosphate (S1P) in CD4 T cells. We showed that S1P was significantly higher in non-classic patients. Hence we developed essential tools in the perspective of future gene therapies and suggest new topics of research such as the role of S1P or T-cell maturation in FD.
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https://tel.archives-ouvertes.fr/tel-03153269
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Submitted on : Friday, February 26, 2021 - 11:33:26 AM
Last modification on : Friday, March 19, 2021 - 11:20:01 AM
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Wladimir Mauhin. Exploration des mécanismes inflammatoires impliqués dans la physiopathologie de la maladie de Fabry et la réponse à l’enzymothérapie substitutive. Médecine humaine et pathologie. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS610⟩. ⟨tel-03153269⟩

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