Impact de la production des immunoglobulines tronquées sur le développement lymphocytaire B normal et tumoral

Abstract : The recombination process V(D)J of immunoglobulin (Ig) genes is characterized by random junctions between the variable (V), diversity (D) and joining (J) segments. A frameshift mutation appears in two-third of cases, generating a non-productive or « out of frame » junction. Several studies have shown that both productive and non-productive alleles are actively transcribed. The mature transcripts from nonproductive alleles are usually considered sterile and innocuous as a result of an mRNA surveillance mechanism called NMD « Nonsense-Mediated mRNA Decay ». By degrading aberrant mRNA, this mechanism prevents the appearance of truncated Ig during B cell ontogeny. However, less is known about the impact of alternative splicing on non-productive Ig transcripts. This mechanism, called NAS « Nonsense-associated Altered Splicing » can lead to the production of truncated Ig with internal deletions of variable domain (V). During my thesis, we have shown that the presence of a stop codon, within the variable exon (VJ) of Igκ transcripts, promotes exon skipping and synthesis of V domain-less κ light chains (ΔV-κLCs). Interestingly, such truncated Ig causes cellular stress and leads to plasma cells apoptosis (Article 1). These findings have identified a new checkpoint acting late during plasma cell differentiation: TIE « Truncated-Ig Exclusion » checkpoint. This process ensures counter-selection of plasma cells producing truncated-Ig. We also studied the alternative splicing of non-productive Ig transcripts in the absence of TIE-checkpoint (Article 2). We found that hypertranscription of Ig genes in plasma cells promote alternative splicing of non-productive Ig transcripts. Using a model forcing the expression of truncated Ig, we identified a cooperative action between mRNA surveillance mechanisms (NMD) and those of protein surveillance (UPR « Unfolded Protein Response », autophagy) (Article 3). Based on these results, we have developed a new therapeutic approach by increasing the production of truncated Ig using antisense oligonucleotides (AON) that leads to the elimination of the variable exon during splicing. This invention could open new avenues for the treatment of Multiple Myeloma patients and other pathologies affecting plasma cells.
Document type :
Theses
Complete list of metadatas

https://tel.archives-ouvertes.fr/tel-01760588
Contributor : Abes Star <>
Submitted on : Friday, April 6, 2018 - 2:49:07 PM
Last modification on : Thursday, July 5, 2018 - 3:22:10 PM

File

2016LIMO0011.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-01760588, version 1

Collections

Citation

Nivine Srour. Impact de la production des immunoglobulines tronquées sur le développement lymphocytaire B normal et tumoral. Médecine humaine et pathologie. Université de Limoges, 2016. Français. ⟨NNT : 2016LIMO0011⟩. ⟨tel-01760588⟩

Share

Metrics

Record views

302

Files downloads

269