Previous results obtained from adoptive B cell transfer and immunization experiments in BCR transgenic mouse models (monoclonal antibody knockins) revealed that high affinity BCRs promote early splenic B cells to differentiate to PCs ( 35, 36), a phenomenon that was also reported in a more recent study ( 37). However, it remains unclear whether any deterministic factors, such as antigen affinity or epitope specificity, drive the selection of these highly expanded clones and how deep antigen specificity tracks within the PC repertoire. Previous studies on vaccine-induced PC repertoires (murine- and bone marrow-derived) have found that they are dominated by a few (∼3–5) highly expanded clones that are antigen-specific ( 19, 31), which correlates with the observation that up to 60–90% of the total antigen-specific IgG serum repertoire is comprised of only a few clones (∼4–12) ( 32 – 34). Importantly, most of the studies reporting phenotypic antibody repertoire data were confined to memory B cells or short-lived plasma blasts that express surface BCR, and in contrast to PCs, do not secrete large amounts of antibody proteins (immunoglobulin ) ( 22 – 24, 26 – 30). While there have been numerous studies describing how this process is orchestrated on the genotypic level in several species (e.g., humans, mice, and zebrafish) ( 13 – 21), much less is known about the associated phenotypic antibody repertoire metrics comprising features such as antigen-binding ( 22 – 25), quantitative binding affinity, and epitope specificity, which can physically be measured as a consequence of the antibody amino acid (aa) sequence composition. This dynamic process involves the recombination of germline-encoded genetic elements that encode the antibody (or B cell receptor ) in single B cells ( 6) dogma holds that B cell clonal selection, iterative expansion, and differentiation to PCs occur for clones with increased affinity toward the antigen ( 7 – 12). Humoral immunity and successful vaccination require the generation of sustained levels of circulating serum antibodies, which are produced by clonally expanded plasma cells (PCs), a terminally differentiated subset of B cells that reside in lymphoid organs (e.g., bone marrow) for an extended period of time (up to years for mice and humans) ( 1 – 5). Our results highlight the extent to which clonal expansion can be ascribed to antigen binding, affinity, and epitope specificity, and they have implications for the assessment of effective vaccines. Last, we provide evidence for convergence toward targeting dominant epitopes despite clonal sequence diversity among the most expanded clones. Furthermore, we report both on a polyclonal repertoire and clonal lineage level that antibody-antigen binding affinity does not correlate with clonal expansion or somatic hypermutation. We find that clonal expansion drives antigen specificity of the most expanded clones (top ∼10), whereas among the rest of the clonal repertoire antigen specificity is stochastic. Here, we report on the in-depth genotypic and phenotypic characterization of clonally expanded PC antibody repertoires following protein immunization. However, it remains unclear if clonal selection and expansion of PCs follow any deterministic rules or are stochastic with regards to phenotypic antibody properties (i.e., antigen-binding, affinity, and epitope specificity). Recent studies have started to reveal the balance between deterministic mechanisms and stochasticity of antibody repertoires on a genotypic level (i.e., clonal diversity, somatic hypermutation, and germline gene usage). The capacity of humoral B cell-mediated immunity to effectively respond to and protect against pathogenic infections is largely driven by the presence of a diverse repertoire of polyclonal antibodies in the serum, which are produced by plasma cells (PCs).
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