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Etude par génomique fonctionnelle des conséquences de la surexpression de TRIB1 et FKBP11 dans les lymphocytes B au cours du lupus érythémateux systémique

Abstract : Systemic Lupus Erythematosous (SLE) is an autoimmune disease characterized by an inflammation of various tissues and a high production of autoantibodies (autoAb) (for example: anti-double-stranded(ds)DNA) by B cells, central actors in the physiopathology of lupus. The etiology of SLE includes both genetics and environmental factors. Looking for B cell genetic abnormalities during lupus, our B cell microarray analysis in quiescent SLE patients pointed to the overexpression of TRIB1 and FKBP11 compared to B cells from healthy controls.In order to study the consequences of these expression deregulations on B cell function and autoimmunity development, we generated a B-cell specific Trib1-KI mouse line, overexpressing Trib1 in B cells, starting from a very immature stage (pro-pre B) and a transgenic mouse overexpressing Fkbp11 ubiquitously. Trib1 overexpression induces a normal B cell homeostasis but a decrease in the production of some immunoglobulins (Ig): 1) IgG1 subclass in the serum, at a basal level and after an in vitro stimulation of splenic B cells; 2) Anti-OVA (Ovalbumine) IgM after immunization in vivo with OVA; 3) Anti-dsDNA IgM after immunization with LPS. This abnormal production of Ig seems to be linked to a defect in Ig secretion process. In addition, we developed a murine B cell line overexpressing Trib1 that let us to confirm the Ig production deficiency and to identify potential Trib1’s partners in B cells. In contrast, Fkbp11 overexpression, leads to some features of lupus disease in 8-month-aged-mice, including a tolerance breakdown (characterized by autoantibody production) and the initiation of plasma cell differentiation. In conclusion, Trib1 could exert an immunosuppressive role and its overexpression in SLE could constitute a new mechanism of B cell regulation during remission phases, whereas Fkbp11 seems rather to contribute to lupus physiopathology. Thus, the description of these two biological pathways could bring new insights into the comprehension of lupus disease and could also potentially lead to the development of new therapeutic applications.
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Léa Simoni. Etude par génomique fonctionnelle des conséquences de la surexpression de TRIB1 et FKBP11 dans les lymphocytes B au cours du lupus érythémateux systémique. Immunologie. Université de Strasbourg, 2015. Français. ⟨NNT : 2015STRAJ063⟩. ⟨tel-01681659⟩

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