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Rôle de la réponse immunitaire de type 2 dans la réparation tissulaire : du concept au modèle pratique de la sclérodermie systémique

Abstract : For many of us, including many immunologists, the role of the immune system is limited to a defense role against different pathogens such as bacteria and viruses. Yet it is becoming increasingly clear that the immune system is involved in many other phenomena such as cancer, obesity and tissue repair.During this thesis, we were interested in the involvement of immune cells, and more particularly innate immune cells, in the tissue repair mechanism. Subsequently, we deepened this work by focusing on the deregulations of tissue repair. These deregulations can lead to "over-repair" phenomena such as fibrosis. Fibrosis is defined as an excessive deposition of extracellular matrix by fibroblasts in response to profibrotic molecules such as TGFβ or IL-13. We therefore focused on the role of the innate immune response in fibrosis by focusing on two types of innate immune cells macrophages and innate lymphoid cells of type 2 (ILC2). We chose systemic scleroderma, an autoimmune disease characterized mainly by fibrosis that can affect the skin and/or internal organs, as our study model. In addition to fibrosis, this pathology is also associated with vascular and immune abnormalities. The mechanisms linking these three characteristics are still poorly defined and poorly understood.It is necessary to understand the physiopathology of this disease and to establish precisely the involvement of the immune response in fibrosis in order to offer therapeutic treatment for scleroderma patients and more generally for all fibrotic diseases.First, we show, in flow cytometry, a decrease of ILC2 in the blood of scleroderma patients compared to controls (0.007 ± 0.007% vs. 0.01 ± 0.01%, p=0.001). In scleroderma subjects, this decrease in the frequency of circulating ILC2 is inversely correlated with skin fibrosis defined by Rodnan's score (R=-0.35, p=0.0062). We observe an increase in these cells in the scleroderma skin compared to controls (5.015 ± 2.8% vs. 2.816 ± 1.8%). This result is positively correlated to Rodnan's score (r=0.58, p=0.01). We obtain similar results in immunofluorescence. In collaboration with Prof. Batteux's team, we studied the role of ILC2 in a mouse model of scleroderma. We observe an increase in cutaneous ILC2 even before fibrosis is established in the skin of scleroderma mice (16677 ± 3068 vs. 9091 ± 474). Then, we show, in vitro, that ILC2 stimulated by TGFb lose the expression of KLRG1. Upon contact with TGFb-stimulated ILC2, fibroblasts become pro-fibrotic compared to incubation with unstimulated ILC2.These results bring new knowledge in the physiopathology of systemic scleroderma and more particularly in the fibrosis characterizing this disease, which offers potential therapeutic prospects.The conceptual approach to the role of the immune system in tissue repair proposed in this thesis renews our vision of immunity and potentially opens up a new and still underestimated field of therapies targeting the immune system.STAR
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Paôline Laurent. Rôle de la réponse immunitaire de type 2 dans la réparation tissulaire : du concept au modèle pratique de la sclérodermie systémique. Médecine humaine et pathologie. Université de Bordeaux, 2018. Français. ⟨NNT : 2018BORD0229⟩. ⟨tel-02157267⟩

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