B-cell restriction – an alternative piece to the puzzle

Gershoni, Jonathan M.

Curiously, the perfection of antibodies via affinity maturation might be over-doing it in some cases. The evolution of the humoral immune system may not have been able to predict hypervariable pathogens such as HIV-1 as well as shifting and drifting viruses like flu. 64, 65 Thus driving antibodies to perfection by gaining extreme specificity and high affinity ensures the ability to clear pathogens as their concentrations dwindle below the initial KD of the first generation of antibodies. Paradoxically, this is precisely a boon for dynamically changing virus opponents. The natural first generation response is a bit fuzzy in its recognition and more tolerant of epitope variation. There is a need to recognize and handle any virus that may infect us. Therefore, germline responses tend to be more crossreactive, loose-fitting paratopes that bind enough to launch clonal expansion. The multiple rounds of perfection that follow produce the ultimate-fit antibody targeting the initial infectious virus. Gain of specificity and affinity, however, is at the expense of loss of flexibility, tolerance and cross-reactivity. Thus, as the virus accumulates mutations and genetic variants, it gradually morphs to slowly escape the range of recognition of the perfected and high-affinity antibody that matured. [66] [67] [68] If only one could restrict the B-cell response it might prove to be the answer to dynamic genetic drift! If one could stimulate early B-cell lineages yet prevent their further affinity maturation, "fuzzy vaccines" would be possible. Fuzzy-Vaccines would be those that do not train our system to forge ahead and develop antibodies with single variant specificity. Rather, the preferred germline B-cells would be activated but not allowed to affinity mature beyond a certain point, thus gaining the ability to cope not only with the infectious isolate but also with emerging variants yet to appear.