Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation

Abstract

Affinity maturation of the antibody response is a fundamental process in adaptive immunity during which B-cells activated by infection or vaccination undergo rapid proliferation accompanied by the acquisition of point mutations in their rearranged immunoglobulin (Ig) genes and selection for increased affinity for the eliciting antigen. The rate of somatic hypermutation at any position within an Ig gene is known to depend strongly on the local DNA sequence, and Ig genes have region-specific codon biases that influence the local mutation rate within the gene resulting in increased differential mutability in the regions that encode the antigen-binding domains. We have isolated a set of clonally related natural Ig heavy chain–light chain pairs from an experimentally infected influenza patient, inferred the unmutated ancestral rearrangements and the maturation intermediates, and synthesized all the antibodies using recombinant methods. The lineage exhibits a remarkably uniform rate of improvement of the effective affinity to influenza hemagglutinin (HA) over evolutionary time, increasing 1000-fold overall from the unmutated ancestor to the best of the observed antibodies. Furthermore, analysis of selection reveals that selection and mutation bias were concordant even at the level of maturation to a single antigen. Substantial improvement in affinity to HA occurred along mutationally preferred paths in sequence space and was thus strongly facilitated by the underlying local codon biases.

Clonal Characteristics of Circulating B Lymphocyte Repertoire in Primary Biliary Cholangitis

“…Previous research on patients with celiac disease has revealed limited SHMs in autoreactive plasma cells (12), which may be indicative of low-affinity Ag binding (32). In this study, limited SHMs in class-switched isotypes were also observed in PBC patients and their subgroups.…”

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…Similarly, amino acid substitutions in CH235 at these positions were also frequently seen in non-HIV-1 antibodies (16). These commonalities extended to other V H 1-2*02 and V H 1-46 CD4 mimic bnAbs (16) and V H 1-2*02 V3-glycan bnAbs (Bonsignori M. et al, submitted), implying that intrinsic mutability at specific nucleotide sites is a more general biological phenomenon that plays a role in dictating the degree of somatic mutations (16, 32, 65, 66). …”

Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques

“…Isolated Ig genes were analyzed using a Bayesian method (20). The estimated mutation frequency of the heavy chains (HCs) of Env-reactive mAbs was 9.3% ( Figure 4F); this mutation frequency was higher than that observed for Env-reactive antibodies isolated from humans immunized 4 times in the GSK PRO HIV-002 trial (3.8%; ref.…”