Beyond Hot Spots: Biases in Antibody Somatic Hypermutation and Implications for Vaccine Design

Frontiers in Immunology
Chaim A Schramm, Daniel C Douek

Abstract

The evolution of antibodies in an individual during an immune response by somatic hypermutation (SHM) is essential for the ability of the immune system to recognize and remove the diverse spectrum of antigens that may be encountered. These mutations are not produced at random; nucleotide motifs that result in increased or decreased rates of mutation were first reported in 1992. Newer models that estimate the propensity for mutation for every possible 5- or 7-nucleotide motif have emphasized the complexity of SHM targeting and suggested possible new hot spot motifs. Even with these fine-grained approaches, however, non-local context matters, and the mutations observed at a specific nucleotide motif varies between species and even by locus, gene segment, and position along the gene segment within a single species. An alternative method has been provided to further abstract away the molecular mechanisms underpinning SHM, prompted by evidence that certain stereotypical amino acid substitutions are favored at each position of a particular V gene. These "substitution profiles," whether obtained from a single B cell lineage or an entire repertoire, offer a simplified approach to predict which substitutions will be well-tolerated and w...Continue Reading

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Citations

Feb 26, 2020·MAbs·Anthony R Rees
May 16, 2020·The Journal of Biological Chemistry·Claire Marks, Charlotte M Deane
Aug 9, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Bartlomiej Swiatczak
Nov 15, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Julian Q Zhou, Steven H Kleinstein
May 28, 2021·Frontiers in Immunology·Catherine Tang, Thomas MacCarthy
Nov 23, 2021·Journal of the International AIDS Society·Wilton B WilliamsBarton F Haynes

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Methods Mentioned

BETA
deaminations
transgenic
glycosylation

Software Mentioned

samm
SPURF
Kepler

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