Public Immunity: Evolutionary Spandrels for Pathway-Amplifying Protective Antibodies

Abstract

Humoral immunity is seeded by affinity between the B cell receptor (BCR) and cognate antigen. While the BCR is a chimeric display of diverse antigen engagement solutions, we discuss its functional activity as an ‘innate-like’ immune receptor, wherein genetically hardwired antigen complementarity can serve as reproducible templates for pathway-amplifying otherwise immunologically recessive antibody responses. We propose that the capacity for germline reactivity to new antigen emerged as a set of evolutionary spandrels or coupled traits, which can now be exploited by rational vaccine design to focus humoral immunity upon conventionally immune-subdominant antibody targets. Accordingly, we suggest that evolutionary spandrels account for the necessary but unanticipated antigen reactivity of the germline antibody repertoire.

Germline-encoded specificities and the predictability of the B cell response

“…A germline-encoded specificity might have arisen as an evolutionary spandrel, a byproduct of immunoglobulin gene diversification in vertebrates, and then been selected [20][21][22]. For instance, germline alleles with innately high affinity for bacterial antigens might be favored if they protect against commonly encountered pathogens and commensals via broad classes of epitopes shared by these organisms [14,16,23].…”

Germline-encoded specificities and the predictability of the B cell response

“…Affinity maturation can vastly improve binding ( Liao et al, 2013 ; McCarthy et al, 2019 ), yet high affinity for particular epitopes can be “ hardcoded ” on individual germline alleles from the start. These germline-encoded specificities might arise as evolutionary spandrels — byproducts of immunoglobulin gene diversification — ( Gould and Lewontin, 1979 ; Sangesland and Lingwood, 2021 ), but they could be subsequently selected. For instance, germline alleles with innately high affinity for bacterial antigens might arise from long-term selection in vertebrate populations to recognize commonly encountered pathogens and commensals via broad classes of epitopes shared by these organisms ( Yeung et al, 2016 ; Collins and Jackson, 2018 ; Sangesland et al, 2020 ).…”

“…Strains with specific V alleles have higher antibody titers against specific antigens than the other strains ( Sangesland et al, 2019, 2020 ). A third line of evidence comes from sequencing studies, which often show that specific alleles, allele combinations or CDR3 sequences are overrepresented in the response to particular epitopes (reviewed by Dunand and Wilson 2015 and Sangesland and Lingwood 2021 ). Overrepresentation of specific alleles is often interpreted as a consequence of, and as indirect evidence for, the kind of germline-encoded specificity revealed by structural analyses or transgenic mouse experiments.…”

“…Because they do not arise directly from recombination, CDRs 1 and 2 are presumably less affected by epistasis than CDR3 and suggest how some germline V alleles could be reliably selected to respond to particular antigens. A germline-encoded specificity might have arisen as an evolutionary spandrel, a byproduct of immunoglobulin gene diversification in vertebrates, and then been selected ( Gould and Lewontin, 1979 ; Sangesland and Lingwood, 2021 ; Pennell et al, 2023 ). For instance, germline alleles with innately high affinity for bacterial antigens might be favored if they protect against commonly encountered pathogens and commensals via broad classes of epitopes shared by these organisms ( Yeung et al, 2016 ; Collins and Jackson, 2018 ; Sangesland et al, 2020 ).…”