Multi-step antibody class switching in a primary human response is restricted after IGHG2 and dependent on B cell maturation stage Article Swipe
Guillem Montamat
,
Joseph Ng
,
Alex Stewart
,
Emma Sinclair
,
Paul W. Blair
,
Diana Kateregga
,
Amir Gander
,
David Kipling
,
Dongjun Guo
,
Lutecia Servius
,
Christopher Piper
,
Zara Baig
,
Franca Fraternali
,
Claudia Mauri
,
Deborah K. Dunn‐Walters
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.07.652638
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.07.652638
Class switch recombination (CSR) allows the formation of functionally specialized antibodies. Understanding of CSR dynamics is key for better design and prediction of vaccines to protect mucosal surfaces. To investigate CSR in a primary human immune response under a controlled setting, we sampled healthy volunteers without COVID-19 history every other day during the first three weeks after SARS-CoV-2 vaccination, with additional time points up to six months. Leveraging bulk and single-cell B cell receptor repertoires, single-cell transcriptomics, and immunophenotyping, we uncover paradigm-shifting insights into CSR. Newly activated B cells produce sterile transcripts of all antibody isotype constant regions ( IGHC ) simultaneously up to IGHG2 , challenging the view that sterile transcription occurs for only a single IGHC gene at a time. CSR follows a multistep progression along the IGHC locus; in this challenge vaccine-induced B cells switch from IGHM to IGHG3 and IGHG1 , followed by a subsequent switching to IGHA1 and IGHG2 after secondary immunization. IGHA2 clones require pre-switching to IGHA1 clones. Notably, switching tendency, measured by IGHC sterile transcription, is memory B cell subtype dependent, particularly beyond IGHG2 . Contrary to other vaccines, antigen-specific B cells are enriched in DN2, Cmem2 and DN4 subtypes after immunization. We also observe a temporal decoupling of CSR and somatic hypermutation (SHM), with the latter detectable only after six months post-immunization. Our data describes the dynamics between CSR, SHM, sterile transcription and B cell memory development during a human primary response, challenges textbook models of CSR and offers new insights to aid control of CSR direction. Graphical Abstract One Sentence Summary Class switch recombination occurs independently of somatic hypermutation and in a multistep fashion up to IGHG2 during a primary response in humans.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.05.07.652638
- https://www.biorxiv.org/content/biorxiv/early/2025/05/08/2025.05.07.652638.full.pdf
- OA Status
- green
- References
- 88
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4410211863
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4410211863Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.05.07.652638Digital Object Identifier
- Title
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Multi-step antibody class switching in a primary human response is restricted after IGHG2 and dependent on B cell maturation stageWork title
- Type
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preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2025Year of publication
- Publication date
-
2025-05-08Full publication date if available
- Authors
-
Guillem Montamat, Joseph Ng, Alex Stewart, Emma Sinclair, Paul W. Blair, Diana Kateregga, Amir Gander, David Kipling, Dongjun Guo, Lutecia Servius, Christopher Piper, Zara Baig, Franca Fraternali, Claudia Mauri, Deborah K. Dunn‐WaltersList of authors in order
- Landing page
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https://doi.org/10.1101/2025.05.07.652638Publisher landing page
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https://www.biorxiv.org/content/biorxiv/early/2025/05/08/2025.05.07.652638.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
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https://www.biorxiv.org/content/biorxiv/early/2025/05/08/2025.05.07.652638.full.pdfDirect OA link when available
- Concepts
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Stage (stratigraphy), Class (philosophy), Antibody response, Antibody, Primary (astronomy), Immunoglobulin class switching, Biology, Cell biology, Immunology, Mathematics, B cell, Computer science, Physics, Artificial intelligence, Paleontology, AstronomyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
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88Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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