20 | Chapter 2 Figure 1. Schematic depiction of B-cell development in the bone marrow. B cells develop from common lymphoid progenitor (CLP). At this stage, both the heavy and the light chains are present in their germline configurations. Subsequently, at the pro-B cell stage, RAG1/2 is expressed (here depicted in red) and gene recombination at the Ig heavy chain locus is initiated. First, a D to J segment recombination takes place, followed by V to DJ recombination. Successful recombination at the early pre-B cell stage leads to the expression of pre-BCR, composed of the recombined heavy chain – m-Igh, and the surrogate light chain, composed of l5 and VpreB. At the late pre-B cell stage, the RAG1/2 recombinase is expressed for the second time and the recombination of Ig light chain genes is initiated. Following the successful Ig light chain recombination, the B-cell receptor (BCR/IgM) is expressed at the immature B-cell stage. Created with BioRender.com RAG1 and RAG2 proteins are essential for V(D)J recombination and normal B-cell development, this has been clearly illustrated in mice where the biallelic disruption of Rag1 and Rag2 genes resulted in a complete developmental block of B and T cells at their progenitor stage due to the inability to initiate V(D)J recombination18,19. Biallelic RAG1 or RAG2 null mutations in human result in severe combined immunodeficiency (SCID) presented with absent B- and T-cell lymphocytes20. Recent advances in genetic engineering allowed successful replacement of the RAG1 or RAG2 null mutations using CRISPR-Cas9 editing of the hematopoietic stem cells in mice and patients, which led to successful production of mature B and T cells with diverse antigen receptor repertoires21,22. Omenn syndrome (OS) presents as an additional clinical phenotype linked to hypomorphic mutations in RAG1 and RAG2, where only residual enzymatic RAG activity is observed. This condition is characterized by the presence of oligoclonal lymphocytes and infiltrating activated T cells, which cause damage to target tissues. Atypical SCID (AS) and delayed onset combined immunodeficiency with granulomas or autoimmunity (CID-G/AI) are some of the other clinical phenotypes associated with RAG1/2 mutations23.
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