The “TIE-Skip” project (36 months, 2 teams) will address scientific issues pertinent to the B-cell-lineage and their implications in immunopathology, with specific focus on antibody-secreting plasma cells. The error-prone V(D)J recombination process generates out-of-frame V(D)J junctions in ~2/3 of cases, leading to the appearance of premature stop codons on immunoglobulin (Ig) transcripts. Whereas the nonsense-mediated mRNA decay (NMD) pathway ensures efficient degradation of nonproductive Ig mRNAs, less is known about the impact of alternative splicing with regard to the production of truncated Ig with internal deletions. In this demand, we seek to determine the impact of truncated-Ig chains produced after exon skipping events eliminating the variable (V) exon. The rationale comes from our recent study showing that the production of aberrant Ig light chains, encoded by alternatively spliced mRNAs lacking V exons, induces ER stress-associated apoptosis in antibody-secreting cells (Srour et al, J Exp Med 2016). Exon skipping events eliminating the V exon can be induced by nonsense codons (physiological nonsense-associated exon skipping) or, by antisense oligonucleotides (AON) hybridizing the donor splice site of V exon on Ig pre-mRNAs (therapeutic AON-mediated Ig exon skipping). Experiments addressing the toxicity of V-domain less Ig chains will be performed in both normal and autoimmune (lupus) conditions. We already obtained a proof of concept for this antisense-mediated Ig exon skipping approach, by using AON hybridizing Ig lambda light chain RNAs in human PC lines. To extend this study, we wish to analyze the extent of exon skipping during splicing of Ig transcripts and, to address whether AON strategies eliminating the V exon could open new therapeutic perspectives for the treatment of PC diseases (Delpy et al., Patent n°PCT/EP2016/078475). Overall, this proposal should have major impact on basic research and public health, and should bring added value for a new therapeutic Ig exon skipping approach. These findings should open new avenues for the treatment of plasma cell disorders.