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Etude des dysfonctions lymphocitaires T dans le syndrome néphrotique idiopathique

Abstract : The pathogenesis of minimal-change nephrotic syndrom (MCNS) is unknown, but, supported by many clinical and experimental arguments, it was suggested that MCNS is a dys-immune disorder with immunogical and renal expression, during which T-cell alteration would be observed. However, the exact mechanism remains unknown. Recently, Rituximab, a B-cell depleting agent, is effctive in inducing mid- and long-term remission suggesting involvement of B-cell dysfunction and/or lack of T-B cooperation. Our laboratory identified a new gene: C-MIP. We have shown that C-MIP abundance is increased in some T and B lymphocyte subpopulations, as well as in podocytes of MCNS patients during relapse phase but undetectable in healthy subjects.In this work, ancillary to the NEPHRUTIX PHRC, we studied T-cell disturbances before and during the relapse or during the remission time in MCNS and the effect of Rituximab therapy. In this study, we found that relapses were associated with significant decrease in regulatory T cell and interleukin-2 expression, while C-MIP abundance was significantly increased. These changes are restored during remission time. Finally, remission after Rituximab therapy leads to a decrease in follicular T cells (Tfh), iNKT and double-negative (CD4- CD8-) T cells expressing the invariant Vα24 chain, suggesting that MCNS involves a disorder of innate and adaptative immune response, which can be stabilized by Rituximab treatment.In order to study the C-MIP role, we generated transgenic mice overexpressing this gene in the peripheral mature T-cells. This overexpression leads to an altered lymphocyte phenotype with an accumulation of naive T lymphocytes, a significant decrease of Th1 and Th2 activating cytokines and accumulation of inactive Src kinases. These results suggest that, by inhibiting Src kinases, C-MIP is a negative regulator of activation T involved in proximal signalling and may be responsable of the lymphocyte T hypo-reactivity observed in patients with active MCNS.
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https://tel.archives-ouvertes.fr/tel-01945257
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Submitted on : Wednesday, December 5, 2018 - 11:12:38 AM
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  • HAL Id : tel-01945257, version 1

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Pauline Vachin. Etude des dysfonctions lymphocitaires T dans le syndrome néphrotique idiopathique. Médecine humaine et pathologie. Université Paris-Est, 2018. Français. ⟨NNT : 2018PESC0044⟩. ⟨tel-01945257⟩

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