Evidence map›Paper›PMID 40339575›Full record

ArticleImmunity2025

Somatic hypermutation generates antibody specificities beyond the primary repertoire.

Teng Zuo, Avneesh Gautam, Shahab Saghaei, Sweta N Khobragade, Rahaman Ahmed, Azadeh Mahdavinia, Mehrdad Zarghami, Gaspar A Pacheco, Kenneth Green, Meghan Travers and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Immunity, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

  1. Article
  2. Article
  3. A Synthetic Platform for Antibody Junctional Diversification Beyond Natural Constraints.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Teng ZuoDepartment 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.
Avneesh GautamDepartment 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.
Shahab SaghaeiDepartment 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.
Sweta N KhobragadeDepartment 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.
Rahaman AhmedDepartment 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.
Azadeh MahdaviniaDepartment 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.
Mehrdad ZarghamiDepartment 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.
Gaspar A PachecoDepartment 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.
Kenneth GreenDepartment 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.
Meghan TraversDepartment 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.
Nicholas GarciaDepartment 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.
Zahra AllahyariDepartment 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.
Vishal RaoDepartment 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.
Sachin KumarDepartment 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.
Robert NovakDepartment 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.
Joyce K HwangDepartment 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.
Duane R WesemannDepartment 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. Electronic address: dwesemann@bwh.harvard.edu.

Funding

Technology and Computational CoreP01AI165072 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI WESEMANN, DUANE R. · 2021 to 2023
$19.6M
Computational Bioscience Program Training GrantT15LM009451 · NLM · UNIVERSITY OF COLORADO DENVER · PI Katherina Kechris-Mays, Arjun Krishnan · 2007 to 2026
$11.7M
Flipped Germinal CentersR01AI169619 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI WESEMANN, DUANE R. · 2021 to 2025
$3.7M
Antibody Durability DynamicsR01AI170715 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI Duane R. Wesemann · 2022 to 2026
$3.4M
Understanding IgE BiologyR01AI158811 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI WESEMANN, DUANE R. · 2022 to 2025
$3.0M
Elucidating Germinal Center-Mediated Antibody EvolutionR01AI139538 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI WESEMANN, DUANE R. · 2019 to 2022
$2.4M
NIAID NIH HHS P01 AI165072NIAID NIH HHS R01 AI139538NIAID NIH HHS R01 AI158811NIAID NIH HHS R01 AI169619NIAID NIH HHS R01 AI170715NLM NIH HHS T15 LM009451
6 · The paper itself

Abstract

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.

Indexed as

Antibody SpecificityB-LymphocytesSomatic Hypermutation, ImmunoglobulinAnimalsAntibody AffinityAntigensGerminal CenterMiceMice, Inbred C57BLT-LymphocytesV(D)J RecombinationAntigensaffinity maturationantibodyantibody evolutionantibody specificityB cellBCR diversificationscompetitionde novo antigen recognitiongerminal centersomatic hypermutation

Identifiers

PMID40339575
PMCPMC12158646

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.