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Cell Rep. 2019 Oct 29;29(5):1066-1073.e5. doi: 10.1016/j.celrep.2019.09.058.

Injection of Antibodies against Immunodominant Epitopes Tunes Germinal Centers to Generate Broadly Neutralizing Antibodies.

Author information

1
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany; Centre for Individualized Infection Medicine (CIIM), Hannover, Germany; Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Straβe 1, 30625 Hannover, Germany. Electronic address: mmh@theoretical-biology.de.

Abstract

Broadly neutralizing antibodies are crucial for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Their induction is a prime goal in vaccine research. Using computer simulations, we identify strategies to promote the generation of broadly neutralizing antibodies in natural germinal center (GC) reactions. The simulations predict a feedback loop based on antibodies and memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. Memory-derived or injected antibodies specific for immunodominant epitopes control epitope availability, suppress the participation of memory B cells in the GC reaction, and allow for the evolution of other B cells to affinity mature for hidden or rare epitopes. This defines a natural selection mechanism for GC B cells to concentrate on new epitopes rather than refine affinity to already-covered epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.

KEYWORDS:

HIV; broadly neutralizing antibodies; germinal center; hepatitis; influenza; mathematical modeling; memory B cells; original antigenic sin; simulation; targeting hidden epitopes

PMID:
31665624
DOI:
10.1016/j.celrep.2019.09.058
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