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Master Thesis

Étude transcriptomique des cellules dendritiques CD103+ CD4+ chez le rat transgénique HLA-B27, modèle de la spondylarthrite

Abstract : Spondyloarthritis (SpA) is one of the most frequent chronic inflammatory joint diseases characterized by articular and extra-articular manifestations. In transgenic rats for HLA-B27 and human β2-microglobulin, the spontaneous development of a SpA-like disease is tightly correlated with dendritic cells (DC) dysfunction. We therefore investigated the factors involved in this dysfunction by performing the transcriptomic analysis of CD103+ CD4+ splenic DC using genome-wide chips. This study has revealed a major defect in the interferon (IFN) signaling pathway in DC from HLA-B27 rats, through the under-expression of many genes in this pathway. We compared our results with those reported in monocytes-derived macrophages from SpA patients. This meta-analysis revealed an reverse IFN signature shared between patients and HLA-B27 rats. In our rat model, the defect was subsequently confirmed and replicated in independent samples by quantitative PCR on selected genes of interest: IFNg, the chemokines Cxcl9, Cxcl10 and Cxcl11, as well as the transcription factors Stat1, Ifit2, Ifit3, Irf1 and Irf7. Moreover, we have highlighted in these DC HLA-B27 an upregulation of Socs3 which could explain the lack of IFN signaling, and a reduced expression of both IL-27 and IL-10 interleukins genes, which could promote the expansion of pathogenic Th17 cells to the detriment of regulatory T cells. Besides, several genes involved in endoplasmic reticulum stress such as Calr, Pdia4 and Pdia6 were overexpressed in DC from HLA-B27 rats. Altogether, these results suggest that the expression of HLA-B27 in CD103+ CD4+ splenic DC could be responsible for the defective IFN signaling, and thus play a role in SpA pathogenesis.
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Master Thesis
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Ingrid Fert. Étude transcriptomique des cellules dendritiques CD103+ CD4+ chez le rat transgénique HLA-B27, modèle de la spondylarthrite. Biologie animale. 2013. ⟨dumas-01473354⟩

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