B-cell restriction – an alternative piece to the puzzle

Gershoni, Jonathan M.

The dynamic dialogue between pathogens and our immune defenses leads to serial rounds of co-evolution. Our B-cells encounter vast repertoires of epitopes presented by a virus. The virus evolves to best conceal its most vulnerable targets while in turn presents multiple distracting non-neutralizing epitopes; banking on the fact that B-cells indiscriminately bind and respond to everything. 39 Multiple antibodies are produced, most of which, do not hit critical neutralizing epitopes. Those that do, however, initiate rounds of somatic hypermutations and go on to optimize their affinity to precisely target and complement the founder infectious strain of virus. 14,40-42 As affinitymaturation proceeds, the antibodies focus and gain perfection for that specific strain initially encountered, all the while losing ability to bind divergent viral genetic variants yet to emerge. 14 Perfection of highly target-specific neutralizing affinity-matured antibodies goes hand in hand with loss of broad cross-reactivity that allows recognition of ever variant members of the evolving viral swarm. Perfection of potent exquisitely specific neutralizing antibodies opens the back door for viral mutations to escape scrutiny and go on to spread infection and havoc. 43 Curiously, two strong points of B-cells physiology, the ability to (i) bind and react to everything and (ii) affinityperfect their antibodies, provide some advantage for the most challenging virus targets, those that are hypervariable, constantly changing while luring B-cells in false directions. Paradoxically, what might prove to be the best strategy for production of vaccines towards hyper-variant viruses like HIV and influenza is to restrict the B-cell response!