Related Experiment Video

Updated: Jun 14, 2025

Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches
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Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches

Published on: April 20, 2021

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Somatic hypermutation generates antibody specificities beyond the primary repertoire

Teng Zuo1, Avneesh Gautam1, Shahab Saghaei1

  • 1Department of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.

Immunity
|May 8, 2025
PubMed

B cell somatic hypermutation (SHM) and selection in germinal centers (GCs) enhance antibody affinity for antigen. Here, we investigated whether SHM-based antibody evolution is restricted to specificities established through V(D)J recombination in the primary repertoire. Tracking pre-defined non-specific B cells across multiple immunization models revealed that non-cognate B cells within GCs undergo SHM. Under conditions of limited B cell competition, these B cells generated de novo antigen recognition to multiple epitopes across diverse model antigens. Phylogenetic analyses identified diverse mutational pathways leading to new antigen affinities, and enhanced T cell co-stimulation further promoted new antigen recognition. Our data support a model in which B cell competition-rather than an intrinsic requirement for specific affinity-limits the emergence of new affinities through SHM, highlighting the mammalian adaptive immune system's ability to explore antibody-antigen interactions beyond those encoded by the V(D)J-dependent primary repertoire, demonstrating the flexibility of SHM in not only ripening but also reshaping specificity.

Keywords:
B cellBCR diversificationsaffinity maturationantibodyantibody evolutionantibody specificitycompetitionde novo antigen recognitiongerminal centersomatic hypermutation

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