Maturation finale des lymphocytes B : de la commutation de classe aux conséquences pathologiques de la production d'immunoglobulines anormales

Abstract : Class Switch Recombination (CSR) is a key step during the immune response. CSR results in a switch to a more specific Ig isotype in response to a specific antigen. Plasma cells, the ultimate stage of B cell lineage differentiation, will synthesize this Ig. During plasma cell disorders, the production of an abnormal monoclonal Ig can lead to pathogenic situations. The aim of the first part of this study is to determine the minimal requirements for CSR induction with a mouse model in which we inserted a “switch cassette” composed of two transcribed S regions into a kappa locus which is naturally targeted by AID. However, despite efficient transcription and AID targeting of S regions, the “switch cassette” was not sufficient to induce effective CSR. We also developed a mouse model of HCDD (Heavy Chain Deposition Disease) which reproduced typical Randall-type renal lesions due to production of a pathogenic truncated heavy chain. This model demonstrated that the effective response to proteasome inhibitors observed in patients, is the consequence of the presence of a truncated HC that sensitizes plasma cells to this type of therapy through an elevated unfolded protein response (UPR).
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Amélie Bonaud. Maturation finale des lymphocytes B : de la commutation de classe aux conséquences pathologiques de la production d'immunoglobulines anormales. Médecine humaine et pathologie. Université de Limoges, 2015. Français. ⟨NNT : 2015LIMO0017⟩. ⟨tel-01186398⟩

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