Mécanistique de la commutation de classe des immunoglobulines et production de classes rares (IgE, IgA2 et pseudo-IgG)

Abstract : The process of class switch recombination (CSR) or isotypic switching of immunoglobulin genes characterizes the B cell lineage and primarily involves switch regions preceding the constant genes within the IgH locus. Junctions between donor switch region Sμ and acceptor Sx are generated during this process. Several studies have shown that the fate of B cells is largely modulated according to the class of immunoglobulin they produce and in particular the signals transmitted by their BCR « for example for IgE, BCRs can combine proapoptotic signals. We used several relevant mouse models to study the physiological aspect and the B cell compartment after switching to IgA2 (a dedicated transgenic model expressing IgA2) since IgA2 conveys a membrane signal different from tht of IgA1. In addition, we tested two pharmaceuticals drugs(RHPS4: stabilizer of G-quadruplex structures at the DNA level and JQ1: inhibitor of bromodomain proteins) showed their ability to delay or inhibit class switching towards IgE in vitro but also in vivo in allergic mice. Interestingly, we also demonstrated the existence (till now ignored and maybe masked by the other 4 more abundant IgG subclasses) of a fifth subclass of human IgG, IgG5 which is encoded by a gene classified as a pseudo-gene. We studied the expression modalities of the corresponding gene after a non-canonical switch, the normal IgG5 repertoire, their representation among the monoclonal human IgGs as well as their immune functions through an artificially synthesited IgG5 with human anti-CD20 activity.
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Zeinab Dalloul. Mécanistique de la commutation de classe des immunoglobulines et production de classes rares (IgE, IgA2 et pseudo-IgG). Médecine humaine et pathologie. Université de Limoges, 2018. Français. ⟨NNT : 2018LIMO0048⟩. ⟨tel-02440651⟩

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