# Elucidating Germinal Center-Mediated Antibody Evolution

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $610,560

## Abstract

PROJECT SUMMARY
Antibodies diversify through two distinct pathways. The first involves combinatorial assembly of
Immunoglobulin (Ig) variable region (V) exons during B cell development. The second involves V exon somatic
hypermutation (SHM) and affinity-based selection in germinal centers (GCs). There are fundamental gaps in
understanding how these systems collaborate to recognize, adapt, and neutralize diverse pathogenic threats.
The long-term goal is to shed light onto fundamental GC B cell biology and elucidate underlying mechanisms
of protective antibody development. The objective for this proposal is to elucidate mechanisms underlying GC
plasticity—in particular, the extent of GC diversification, and the parameters that allow B cell GC entry and
continued antibody evolution. The central hypothesis is that the GC system provides dual function with regard
to antibody development. On one hand, the GC reaction intensifies affinities readily available from the primary
repertoire. On the other hand, GC plasticity is flexible enough to allow for the recruitment of extremely low
affinity/non-cognate B cell clones whose BCR is not initially of sufficient affinity to compete well in the GC, but
which may have unique potential (given a few needed mutations) to recognize critical epitopes not otherwise
targeted well by the primary repertoire. A deeper understanding of how these GC functions are regulated
promises to reveal new insights into how to more effectively recruit low frequency/low affinity B cells with
potential to become broadly neutralizing, and shepherd them toward protective efficacy. This hypothesis will be
explored with two specific aims: 1) Characterize the capacity and limitations of diversity mediated by the GC
SHM diversification system; and 2) Define features that regulate B cell participation in germinal centers. Under
the first aim, the flexibility of affinity development and specificity potential by the GC diversification system will
be examined using an extremely low BCR/antigen affinity (Ka<102 M-1), and BCR-negative model systems in
the physiologic context of competitive settings. Under the second aim, modifiable factors that regulate the
flexibility of SHM-mediated Ig evolution in physiologic contexts will be defined. The approach is innovative,
because the applicant's recent published work and preliminary data indicate that GC-mediated diversification
can provide specificities to new epitopes not otherwise present in the primary Ig repertoire within a physiologic,
competitive environment of a diverse primary Ig repertoire. Innovative mouse models will be used to probe the
parameters and mechanistic aspects of the roles of affinity and Ig frequency on participation in GC maturation
and contribution to protective antibody responses in the context of an animal model expressing a diverse
human Ig repertoire. Discovering how extremely low affinity B cell clones gain access to the GC and continue
to mature in the highly competitive...

## Key facts

- **NIH application ID:** 9897485
- **Project number:** 5R01AI139538-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Duane R. Wesemann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $610,560
- **Award type:** 5
- **Project period:** 2019-03-20 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897485

## Citation

> US National Institutes of Health, RePORTER application 9897485, Elucidating Germinal Center-Mediated Antibody Evolution (5R01AI139538-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9897485. Licensed CC0.

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