Molecular Mechanism of Immunoglobulin V‐Region Diversification Regulated by Transcription and RNA Metabolism in Antigen‐Driven B Cells

The immune system produces specific antibodies (Ab) against any antigens (Ag) of exogenous and endogenous origins with a diverse repertoire of V‐region specificities. The primary V‐region repertoire is created by the rearrangement of immunoglobulin (Ig) V‐region, D‐ and J‐segments with the insertion of N‐ and P‐sequences during early B cell differentiation. Recent studies revealed that secondary diversification of the IgV‐region generated in the peripheral lymphoid organs plays a critical role in the generation of effective Ab production for protection from various pathogens. Naïve B cells that react with Ags initiate proliferation and differentiation in the follicular region and create the germinal centres (GCs), where activation‐induced cytidine deaminase (AID)‐dependent IgV‐region somatic hypermutation (SHM) and class‐switch recombination generate high‐affinity and class‐switched mature Ag‐specific B cells. Our studies have discovered a 210‐kDa nuclear protein, named GC‐associated nuclear protein (GANP) that is up‐regulated in GC B cells during the T cell–dependent (TD) immune responses. By studying mice with mutant forms of the ganp gene, we demonstrated that GANP is essential for the generation of high‐affinity B cells against TD‐Ag by affecting SHM at the IgV‐regions. GANP is associated with AID in the cytoplasm and the GANP/AID complex is recruited to the nucleus, specifically, the chromatin, and targeted selectively to the IgV‐region gene in B cells. GANP augments the access of AID towards IgV‐regions in B cells. Here, we review the role of GANP in acquired immunity through the detailed analysis of the molecular mechanism generating SHM specifically at IgV‐regions in B cells.