Figure 4.

B cell differentiation completion in secondary lymphoid organs. The GC reaction is shown. B cells undergo multiple rounds of SHM in the dark zone (DZ) and then positive selection in the light zone (LZ) until the avidity of their surface BCR is adequate to guarantee them class switching and either the memory B cell or plasma cell fate. Positive (or negative) selection occurs through a mitochondrial-based mechanism that involves Ca⁺² influx due to BCR signaling. If the BCR/Ab does not bind with high avidity to the stimulating Ag, or if there are no costimulatory signals (either T cell-derived or TLR9), mitochondria internalize the cytoplasmic Ca⁺² and the apoptotic cascade described in Figure 1 is initiated. Co-stimulations or high avidity initiate a rescuing cascade, that involves NF-κΒ activation and antiapoptotic protein expression, that rescues the B cell and allows further entry into the DZ for subsequent modifications. Again, energy modulation and bioenergetic swifts regulate proliferation and genomic editing and are depicted in the lower part of the figure (orange—glycolysis, blue—OxPhos). SHM: somatic hypermutation, CSR: class switch recombination, Tfh: T follicular helper cell, TLR9: Toll-like receptor 9. Created with BioRender.com.