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Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation.


ABSTRACT: Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, whether stochastic activation of noncognate B cells can generate new affinity to antigen in GCs is unclear. Using a mouse model whose knock-in BCR does not functionally engage with immunizing antigen, we found that chronic immunization induced antigen-specific serological responses with diverse SHM-mediated antibody affinity maturation pathways and divergent epitope targeting. Thus, intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement.

SUBMITTER: Silver J 

PROVIDER: S-EPMC5748855 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation.

Silver Jared J   Zuo Teng T   Chaudhary Neha N   Kumari Rupa R   Tong Pei P   Giguere Sophie S   Granato Alessandra A   Donthula Rakesh R   Devereaux Colby C   Wesemann Duane R DR  

The Journal of experimental medicine 20171215 1


Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of <i>IgH</i> and <i>IgL V</i> region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when <i>Ig V</i> regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the a  ...[more]

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