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. 2014 Apr 22:5:170.
doi: 10.3389/fimmu.2014.00170. eCollection 2014.

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

Thomas B Kepler  1 , Supriya Munshaw  2 , Kevin Wiehe  3 , Ruijun Zhang  3 , Jae-Sung Yu  4 , Christopher W Woods  5 , Thomas N Denny  4 , Georgia D Tomaras  6 , S Munir Alam  4 , M Anthony Moody  7 , Garnett Kelsoe  8 , Hua-Xin Liao  4 , Barton F Haynes  4
Affiliations

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

Thomas B Kepler et al. Front Immunol. .

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.

Keywords: antibody affinity maturation; antibody selection; experimental influenza infection; phylogenetics; somatic hypermutation.

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Figures

Figure 1
Figure 1
The profile of the probable error in the modal heavy chain UA.
Figure 2
Figure 2
(A) Maximum-likelihood clonal tree showing observed (o), intermediate (i), and ancestral (a) sequences. The tree was inferred using both heavy and light chains. (B) Regression analysis of log10 Kd vs. evolutionary distance.
Figure 3
Figure 3
Lower: mutability by position for heavy (left) and light (right) chains. Mutability at CDR nucleotides is shown in red. Upper: histogram by position of accumulated non-synonymous mutations; evolutionary distance vs. position for each synonymous (open disks), and non-synonymous (closed disks) mutation.
Figure 4
Figure 4
Simplified illustration of genotype space with preferred directions. Each node is a DNA sequence, and neighbors differ by one nucleotide. The dark arrows show preferred directions, meaning the mutation along the direction of the arrow occurs at a higher rate than mutations along the regular paths. The nodes labeled 2, 3, and 4 are all six steps from node 1, but differ in the number of non-preferred steps that must be taken to arrive there from 1.
Figure 5
Figure 5
Cumulative distribution function (CDF) of mutability among observed mutations (black), and corresponding to three models: order 0 (no effect of mutability at all, blue), order 1 (consistent with selection random with respect to mutability, magenta), second order (selection proportional to mutability, red). Note that the observed CDF for synonymous mutations is approximately consistent with the order one model, and falls between the order zero and order one curves in any case. The CDF for non-synonymous mutations falls between the order one and order two curves.
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References

    1. Yoshida T, Mei H, Dörner T, Hiepe F, Radbruch A, Fillatreau S, et al. Memory B and memory plasma cells. Immunol Rev (2010) 237:117–3910.1111/j.1600-065X.2010.00938.x - DOI - PubMed
    1. Di Noia JM, Neuberger MS. Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem (2007) 76:1–2210.1146/annurev.biochem.76.061705.090740 - DOI - PubMed
    1. Brown LE, Murray JM, White DO, Jackson DC. An analysis of the properties of monoclonal antibodies directed to epitopes on influenza virus hemagglutinin. Arch Virol (1990) 114:1–2610.1007/BF01311008 - DOI - PubMed
    1. Usinger WR, Lucas AH. Avidity as a determinant of the protective efficacy of human antibodies to pneumococcal capsular polysaccharides. Infect Immun (1999) 67:2366–70 - PMC - PubMed
    1. Lambert P-H, Liu M, Siegrist C-A. Can successful vaccines teach us how to induce efficient protective immune responses? Nat Med (2005) 11(4 Suppl):S54–6210.1038/nm1216 - DOI - PubMed