Defining critical roles for RNA helicases in B cells undergoing antibody gene diversification
B cells are crucial to immune defence by producing large quantities of antibodies with pathogen neutralizing capacities. Antibody responses can be made to target a limitless range of antigens with exquisite specificity and affinity, while eliciting different effector functions. This remarkable ability of the adaptive immune system relies on DNA mutation and recombination occurring at immunoglobulin (Ig) loci, that encode for antibody heavy and light chains.
Antibody gene diversification occurs in a step-wise manner during B cell development and differentiation into antibody secreting plasma cells. Early stages of B cell development in the bone marrow are characterized by V(D)J recombination at Ig loci, resulting in the generation of a vast repertoire of antibodies with different antigen specificities. Once a mature B cell encounters its cognate antigen, antibody responses can be further refined through processes known as class switch recombination (CSR) and somatic hypermutation (SHM). As a result, mature B cells differentiating into plasma cells change antibody isotype (or class, which determines different effector functions) and increase antibody affinity towards antigen.
RNA helicases control every step of mRNA metabolism and also play important roles in determining non-coding RNA function. Therefore, these RBPs are ideally suited to coordinate developmental stage transitions and the induction of DNA mutation/recombination at Ig loci, while controlling cell proliferation and the maintenance of genome stability. Our studies on the role of DDX1 in CSR constitute a paradigm of how RNA helicase activity controls non-coding RNA function through modulation of RNA secondary structure. We showed DDX1 is required for sequence-specific targeting of AID to the IgH locus during CSR.