Naturally evolvable antibody affinity may be physically limited

Naturally evolving antibodies attain elevated affinity in germinal centers (GCs).[1] In these dynamic open micro-structures, competition between B cell clones and their somatic mutants drives an increase average across individual populations of up to a few thousand cells. Such evolutionary learning the antigenic target (known as maturation), however, eventually saturates. Most notably, saturation is orders magnitude lower than what realizable vitro via directed evolution. What exactly halts vivo evolution sets ceiling remains outstanding puzzle immunology. Three decades after Eisen Siskind discovered maturation 1964, Foote Eisen[2] put forth key insight that constraints extrinsic antibody-antigen interaction may exist limit maturation. This recognition suggests origin compatible with lack improvement despite persistent heterogeneity antibody affinities: Considering soluble antigen, estimated from upper bound on rate conferred by diffusion off set antigen internalization cells.[2] estimate very close observed ceiling, rationale was validated Batista Neuberger.[3] Yet, it has become clear membrane-bound, rather soluble, antigens are most important for B-cell activation vivo. this issue, Desikan et al.,[4]make conceptual step forward extending original tethered surface follicular dendritic cells (FDCs) GCs, modern view uncovered intravital imaging technology. Importantly, GC exert mechanical pulling forces generated actin cytoskeleton receptor (BCR), rupturing membrane-tether order acquire antigen.[5] The authors hypothesize stems physical limits strength chain protein complexes linking FDCs acquisition. Further, weakest link limit. Using known equilibrium binding free energies links involved, al., considering single extraction event. A further taken consider possible configurations multivalent presentation. central idea reached once presenting (in form immune attached FDC) exceeds overall antibody-FDC tether. premise underlying feedback; can return GCs replace current antigen-presenting antibodies, if former had higher antigen. study highlights value process extraction, drawing attention multi-interface linkage proposal invites theoretical developments quantitative analyses lead experimental test. Even phenomenological level, number factors prove consider. First, based constants where cause small change. Given tug-of-war setting implements comparison affinities kinetic rates, might be fruitful describe non-equilibrium bond rupture which tugging modulate effective strengths, potentially altering range distinguishable affinities. Second, stiffness found influence how strongly pull BCR-antigen interaction. predictive theory discrimination must capture mechanosensing behavior. Third, coupling result membrane-mediated interactions or sharing cytoskeletal load. Last but not least, alternative sources maximum evolvable vivo, downstream acquisition, warrant investigations well reveal unexpected underpinning limits. declare no conflict interest.