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Article
| Open Access
Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states
Follicular helper T cells play critical roles in the formation of high affinity antibody responses, but the signals involved in the development of these cells after initial differentiation are poorly understood. Here Podestà, Cavazzoni and colleagues characterise transitionary phases of follicular helper T cell development and how progression through these stages is linked to humoral immunity.
- Manuel A. Podestà
- , Cecilia B. Cavazzoni
- & Peter T. Sage
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Article
| Open Access
Engaging an HIV vaccine target through the acquisition of low B cell affinity
Broadly neutralizing antibodies (bnAbs) for HIV have been difficult to elicit with one issue being the low B cell affinity required. Here the authors use a transgenic mouse bearing human-like antibody repertoires to show that low affinity B cells persist which enables vaccine expansion of antibodies against the CD4 binding site, a conserved HIV bnAb target.
- Larance Ronsard
- , Ashraf S. Yousif
- & Daniel Lingwood
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| Open Access
Somatically hypermutated antibodies isolated from SARS-CoV-2 Delta infected patients cross-neutralize heterologous variants
In this study, authors identified neutralizing antibodies by isolating B cells from SARS-CoV-2 Delta infected patients and detect altered structural features, likely introduced by somatic hypermutation, that are involved in epitope binding and increase neutralization breadth against virus variants.
- Haisheng Yu
- , Banghui Liu
- & Xiaoping Tang
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Article
| Open Access
B cell analyses after SARS-CoV-2 mRNA third vaccination reveals a hybrid immunity like antibody response
SARS-CoV-2 vaccines and infection induce antibody responses but the evolution of subsequent variants has resulted in the development of escape mutants. Here the authors characterise, at single cell level, the antibody response in donors after a third dose of SARS-CoV-2 mRNA vaccination and show difference in breadth, neutralisation and molecular signature according to the vaccination regimen used.
- Emanuele Andreano
- , Ida Paciello
- & Rino Rappuoli
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Article
| Open Access
Machine learning analyses of antibody somatic mutations predict immunoglobulin light chain toxicity
Systemic light chain amyloidosis (AL) is caused by the production of toxic light chains and can be fatal, yet effective treatments are often not possible due to delayed diagnosis. Here the authors show that a machine learning platform analyzing light chain somatic mutations allows the prediction of light chain toxicity to serve as a possible tool for early diagnosis of AL.
- Maura Garofalo
- , Luca Piccoli
- & Andrea Cavalli
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Article
| Open Access
REV7 is required for processing AID initiated DNA lesions in activated B cells
REV7 has emerged as a critical regulator of DNA double-strand breaks repair. Here, the authors show that REV7 is crucial for both antibody class switch recombination and somatic hypermutation in activated B cells, in addition to their survival upon AID-deamination.
- Dingpeng Yang
- , Ying Sun
- & Fei-Long Meng
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Article
| Open Access
B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids
Dietary fiber-derived short-chain fatty acids (SCFA) act as histone deacetylase (HDAC) inhibitors on Tregs and innate immune cells, promoting immune tolerance by altering gene expression. Here the authors show that SCFA HDAC inhibitor activity impacts B cell differentiation, antibody responses and antibody-driven autoimmunity.
- Helia N. Sanchez
- , Justin B. Moroney
- & Paolo Casali
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Article
| Open Access
Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage
Development of broadly neutralizing antibodies (bnAb) against HIV-1 in infected adults is a multi-step process unachievable by current vaccine approaches. Here the authors reconstruct the ontogeny of an infant bnAb, which develops in fewer steps, and identify its unique features that may shorten the path to HIV vaccines.
- Cassandra A. Simonich
- , Laura Doepker
- & Julie Overbaugh
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Article
| Open Access
Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation
Knowledge on how antibody responses have evolved is critical for the induction of protective immunity. Here the authors analyse, using high-throughput sequencing of both exon and intron regions, the mutation and lineage development of an HIV-neutralizing antibody to find an unexpected early emergence of broadly neutralizing species.
- Erik L. Johnson
- , Nicole A. Doria-Rose
- & George Georgiou
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Article
| Open Access
A licensing step links AID to transcription elongation for mutagenesis in B cells
Activation-induced deaminase (AID) is important for inducing desirable mutations at the B cell receptor genes for effective antibody responses. Here the authors show that three key arginine residues of AID link AID-chromatin association with transcription elongation to license AID for specific mutagenesis in B cells.
- Stephen P. Methot
- , Ludivine C. Litzler
- & Javier M. Di Noia
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Article
| Open Access
Accurate immune repertoire sequencing reveals malaria infection driven antibody lineage diversification in young children
Somatic hypermutation of antibodies can occur in infants but are difficult to track. Here the authors present a new method called MIDCIRS for deep quantitative repertoire sequencing with few cells, and show infants as young as 3 months can expand antibody lineage complexity in response to malaria infection.
- Ben S. Wendel
- , Chenfeng He
- & Ning Jiang
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Article
| Open Access
Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection
Long-lived IgG plasma cells develop in germinal centres and then home to the bone marrow and persist for a lifetime. Here the authors identify long-lived IgM plasma cells in the murine spleen, which carry IgH mutations but can develop independently of germinal centres, and confer protective antiviral immunity.
- Caitlin Bohannon
- , Ryan Powers
- & Joshy Jacob
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Efficient AID targeting of switch regions is not sufficient for optimal class switch recombination
Activation-induced cytidine deaminase can induce both somatic hypermutation (SHM) and class switch recombination in immunoglobulin loci. Here the authors show that spliced and repetitive switch regions are exquisite SHM targets, but are not sufficient by themselves for class switch recombination.
- Amélie Bonaud
- , Fabien Lechouane
- & Christophe Sirac
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Article
| Open Access
Analysis of immunoglobulin transcripts and hypermutation following SHIVAD8 infection and protein-plus-adjuvant immunization
HIV vaccine development will be facilitated by having animal models that are predictive for translation to humans. Here, the authors use two nonhuman primate models to compare the effects of natural infection and different adjuvants on antigen persistence, diversity and humoral immunity.
- Joseph R. Francica
- , Zizhang Sheng
- & Robert A. Seder
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A source of the single-stranded DNA substrate for activation-induced deaminase during somatic hypermutation
The process of somatic hypermutation, used by B cells to increase antibody diversity, is catalysed by the activation-induced deaminase (AID), which needs to access single-stranded DNA to mediate its function. Here, the authors propose a mechanism for the generation of single-stranded DNA substrate required for AID activity.
- Xiaohua Wang
- , Manxia Fan
- & Matthew D. Scharff
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Article
| Open Access
Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells
Coeliac disease is characterized by an inappropriate immune response to dietary gluten proteins, involving the production of antibodies reactive to gluten. Here, the authors study the intestinal antibody response against gluten and show that gluten-specific antibodies have a low degree of somatic hypermutations.
- Øyvind Steinsbø
- , Carole J. Henry Dunand
- & Ludvig M. Sollid
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Article
| Open Access
GANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy
The affinity of antibodies for their targets is enhanced by somatic hypermutation, in which the cytidine deaminase AID is recruited to immunoglobulin variable region genes in B cells. Here the authors show that the nuclear protein GANP has an important role in this process by modifying chromatin structure and enhancing AID recruitment.
- Shailendra Kumar Singh
- , Kazuhiko Maeda
- & Nobuo Sakaguchi
An ancestral SARS-CoV-2 vaccine induces anti-Omicron variants antibodies by hypermutation