Stochasticity intrinsic to B cell responses permits antibody diversification and affinity maturation

Immunoglobulins (Igs) diversify by two distinct mechanisms to protect from a vast array of pathogenic threats. Combinatorial assembly of Ig heavy and light chain variable (V) region exons from various gene segments generates a diverse, naïve, pre-immune Ig repertoire initially expressed as B cell surface receptors (BCRs). Upon activation, B cell V regions can undergo somatic hypermutation (SHM) and affinity-based selection toward antigen within germinal centers (GCs) to produce high affinity antibodies. Whether BCR engagement due to antigen recognition within the anticipatory pre-immune BCR repertoire is required for the GC SHM and affinity maturation process to begin is not well defined. To examine this, we used a mouse model whose knock-in BCR does not bind to, or engage with, immunizing antigen. Chronic immunization induced delayed, but reliable serologic responses with stochastic kinetics. Divergent Ig V region mutation patterns resulted in diverse epitope targeting. These results indicate that the GC SHM and selection system harbors sufficient intrinsic flexibility to permit de novo antigen recognition and subsequent maturation toward high affinity antibodies without the need for initial pre-immune BCR recognition or engagement.