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VH replacement in primary immunoglobulin repertoire diversification

Author:
Sun, Amy, Novobrantseva, Tatiana I., Coffre, Maryaline, Hewitt, Susannah L., Jensen, Kari, Skok, Jane A., Rajewsky, Klaus, Koralov, Sergei B.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.5 pp. E458
ISSN:
0027-8424
Subject:
B-lymphocytes, antibodies, genes, immunoglobulins
Abstract:
The genes encoding the variable (V) region of the B-cell antigen receptor (BCR) are assembled from V, D (diversity), and J (joining) elements through a RAG-mediated recombination process that relies on the recognition of recombination signal sequences (RSSs) flanking the individual elements. Secondary V(D)J rearrangement modifies the original Ig rearrangement if a nonproductive original joint is formed, as a response to inappropriate signaling from a self-reactive BCR, or as part of a stochastic mechanism to further diversify the Ig repertoire. V H replacement represents a RAG-mediated secondary rearrangement in which an upstream V H element recombines with a rearranged V HD HJ H joint to generate a new BCR specificity. The rearrangement occurs between the cryptic RSS of the original V H element and the conventional RSS of the invading V H gene, leaving behind a footprint of up to five base pairs (bps) of the original V H gene that is often further obscured by exonuclease activity and N -nucleotide addition. We have previously demonstrated that V H replacement can efficiently rescue the development of B cells that have acquired two nonproductive heavy chain (IgH) rearrangements. Here we describe a novel knock-in mouse model in which the prerearranged IgH locus resembles an endogenously rearranged productive V HD HJ H allele. Using this mouse model, we characterized the role of V H replacement in the diversification of the primary Ig repertoire through the modification of productive V HD HJ H rearrangements. Our results indicate that V H replacement occurs before Ig light chain rearrangement and thus is not involved in the editing of self-reactive antibodies.
Agid:
2305087