Trial reportProceedings of the National Academy of Sciences of the United States of America2014
Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity.
Trial report in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 162 papers, 1 of them a synthesis that pooled it.
What it found
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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.
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.
Who cites it
162 citing papers in PubMed, 1 synthesis or guideline pooled it, 236 citations in OpenAlex.
- Organ-based characterization of B cells in patients with systemic lupus erythematosus.Frontiers in immunology · 2025Pooled it
- Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses.The Journal of allergy and clinical immunology · 2019Trial
- Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation.The Journal of allergy and clinical immunology · 2018Trial
- Article
- Epigenetic regulation of B cell tolerance and dysfunction in autoimmune disease.Nature reviews. Immunology · 2026Review
- Novel human monoclonal antibodies with enhanced sensitivity for lipoarabinomannan antigens present in urines of TB patients.bioRxiv : the preprint server for biology · 2026Article
- Non-PF4/heparin-binding, platelet-activating antibodies in heparin-induced thrombocytopenia.Blood · 2026Article
- Longitudinal evolution of rheumatoid factor-expressing lymphoma precursors in a patient with Sjögren's disease.Journal of translational autoimmunity · 2026Article
- Article
- Dysregulation of anti-Ro60 B cell autoreactivity in systemic lupus erythematosus.bioRxiv : the preprint server for biology · 2026Article
- Germinal-centre and extrafollicular B cell pathways in systemic lupus erythematosus.Nature reviews. Rheumatology · 2026Review
- Virus-like antigen display delivers a stand-alone danger signal through the BCR that circumvents tolerance.bioRxiv : the preprint server for biology · 2026Article
- Lyn governs the establishment and maintenance of B cell anergy by suppressing PI3K signaling.Nature communications · 2026Article
- Framework-mediated binding of foreign and self-glycans by IGHV4-34 antibodies.Frontiers in immunology · 2026Review
- Convergent mutation trajectories convert functional self-tolerance in IGHV4-34 B cells to genetic tolerance encoded in the antibody.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- IL-33 expands plasma cells, disrupts germinal centers, and increases autoantibody production in mice.Nature communications · 2025Article
- Article
- Chronic lymphocytic leukemia specificity analyses unveil bacterial lipopolysaccharides as the cognate ligands of established stereotyped BCR subsets.Blood cancer journal · 2025Article
- B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements.Blood cancer discovery · 2025Article
- Signaling Activation and Modulation in Extrafollicular B Cell Responses.Immunological reviews · 2025Review
102 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
The best-understood mechanisms for achieving antibody self/non-self discrimination discard self-reactive antibodies before they can be tested for binding microbial antigens, potentially creating holes in the repertoire. Here we provide evidence for a complementary mechanism: retaining autoantibodies in the repertoire displayed as low levels of IgM and high IgD on anergic B cells, masking a varying proportion of autoantibody-binding sites with carbohydrates, and removing their self-reactivity by somatic hypermutation and selection in germinal centers (GCs). Analysis of human antibody sequences by deep sequencing of isotype-switched memory B cells or in IgG antibodies elicited against allogeneic RhD+ erythrocytes, vaccinia virus, rotavirus, or tetanus toxoid provides evidence for reactivation of anergic IgM(low) IgD+ IGHV4-34+ B cells and removal of cold agglutinin self-reactivity by hypermutation, often accompanied by mutations that inactivated an N-linked glycosylation sequon in complementarity-determining region 2 (CDR2). In a Hy10 antibody transgenic model where anergic B cells respond to a biophysically defined lysozyme epitope displayed on both foreign and self-antigens, cell transfers revealed that anergic IgM(low) IgD+ B cells form twice as many GC progeny as naïve IgM(hi) IgD+ counterparts. Their GC progeny were rapidly selected for CDR2 mutations that blocked 72% of antigen-binding sites with N-linked glycan, decreased affinity 100-fold, and then cleared the binding sites of blocking glycan. These results provide evidence for a mechanism to acquire self/non-self discrimination by somatic mutation away from self-reactivity, and reveal how varying the efficiency of N-glycosylation provides a mechanism to modulate antibody avidity.
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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.