Maturation of the human B-cell receptor repertoire with age

Ghraichy, Marie; Galson, Jacob D.; Kovaltsuk, Aleksandr; Niederhaeusern, Valentin von; Schmid, Jana Pachlopnik; Recher, Mike; Jauch, Annaïse; Miho, Enkelejda; Kelly, Dominic F.; Deane, Charlotte; Trueck, Johannes

doi:10.1101/609651

Cited by 4 publications

(4 citation statements)

References 60 publications

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“…IGHA and IGHG BCR sequencing yielded on average 135,437 unique sequences, and 23,742 clonotypes per sample (Supplementary Table 1). To characterise the B cell response in COVID-19, we compared this BCR repertoire data to BCR repertoire data from healthy controls obtained in a separate study 15 . Comparing IGHV gene segment usage revealed a significantly different IGHV gene usage in COVID-19 patients compared to the healthy controls, most notably with increases in the usage of IGHV2-5 (2.6x IGHA, 1.0x IGHG increase), IGHV2-70 (4.6x IGHA, 4.1x IGHG increase), IGHV3-30 (2.0x IGHA, 1.4x IGHG increase), IGHV5-51 (3.5x IGHA, 2.0x IGHG increase), and IGHV4-34 (1.4x IGHA, 2.4x IGHG increase) in the COVID-19 patients (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…A large number (777) of highly convergent clonotypes unique to COVID-19 were identified. Our approach of subtracting the convergent clonotypes also observed in healthy controls 15, allowed us to identify convergence specific to the disease cohort. The unbiased nature of the BCR repertoire analysis approach means that, whilst these convergent clonotypes are likely to include many antibodies to the spike protein and other parts of the virus they may also include other protective antibodies, including those to host proteins.…”

Section: Discussionmentioning

confidence: 99%

“…The healthy control BCR sequence dataset used here has been described previously 15 . Only samples from participants aged 10 years or older, and from peripheral blood were used, resulting in a mean age of 28 (range: 11-51).…”

Section: Methodsmentioning

confidence: 99%

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Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Galson¹,

Schaetzle²,

Bashford-Rogers

et al. 2020

Preprint

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Deep sequencing of B cell receptor (BCR) heavy chains from a cohort of 19 COVID-19 patients from the UK reveals a stereotypical naive immune response to SARS-CoV-2 which is consistent across patients and may be a positive indicator of disease outcome. Clonal expansion of the B cell memory response is also observed and may be the result of memory bystander effects. There was a strong convergent sequence signature across patients, and we identified 777 clonotypes convergent between at least four of the COVID-19 patients, but not present in healthy controls. A subset of the convergent clonotypes were homologous to known SARS and SARS-CoV-2 spike protein neutralising antibodies. Convergence was also demonstrated across wide geographies by comparison of data sets between patients from UK, USA and China, further validating the disease association and consistency of the stereotypical immune response even at the sequence level. These convergent clonotypes provide a resource to identify potential therapeutic and prophylactic antibodies and demonstrate the potential of BCR profiling as a tool to help understand and predict positive patient responses.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Galson¹,

Schaetzle²,

Bashford-Rogers

et al. 2020

Preprint

Self Cite

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“…Clustering based on their proposed H3 templates resulted in the separation of antibodies from different stages of the immune response, indicating that there are structural changes that occur as the response progresses. The effect of aging on the repertoire has also been studied in this way, revealing that older individuals have a higher number of antibodies that are structurally distinct from the germline (113).…”

Section: Biological Insights From Antibody Repertoire Datamentioning

confidence: 99%

How repertoire data are changing antibody science

Marks

Deane

2020

Journal of Biological Chemistry

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Antibodies are vital proteins of the immune system that recognize potentially harmful molecules and initiate their removal. Mammals can efficiently create vast numbers of antibodies with different sequences capable of binding to any antigen with high affinity and specificity. Because they can be developed to bind to many disease agents, antibodies can be used as therapeutics. In an organism, after antigen exposure, antibodies specific to that antigen are enriched through clonal selection, expansion, and somatic hypermutation. The antibodies present in an organism therefore report on its immune status, describe its innate ability to deal with harmful substances, and reveal how it has previously responded. Next-generation sequencing technologies are being increasingly used to query the antibody, or B-cell receptor (BCR), sequence repertoire, and the amount of BCR data in public repositories is growing. The Observed Antibody Space database, for example, currently contains over a billion sequences from 68 different studies. Repertoires are available that represent both the naive state (i.e. antigen-inexperienced) and that after immunization. This wealth of data has created opportunities to learn more about our immune system. In this review, we discuss the many ways in which BCR repertoire data have been or could be exploited. We highlight its utility for providing insights into how the naive immune repertoire is generated and how it responds to antigens. We also consider how structural information can be used to enhance these data and may lead to more accurate depictions of the sequence space and to applications in the discovery of new therapeutics.

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A cell-based in vitro assay for testing of immunological integrity of Tetanus toxoid vaccine antigen

et al. 2021

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Vaccines containing inactivated toxins confer protection by eliciting a neutralizing antibody response against bacterial toxins such as tetanus and diphtheria. At present, release of tetanus toxoid (TT) and diphtheria toxoid (DT)-containing vaccines relies on in vivo experiments showing the protective vaccine response. The aim of this study was to develop a reliable in vitro assay for TT vaccine antigen characterization with the potential of replacing in vivo potency experiments. To this end, we exploited that TT elicits a recall response in vaccinated donors: human peripheral blood mononuclear cells (PBMC) were stimulated with alum-adsorbed TT bulk antigen and low concentrations of TLR9 ligand; induction of TT-specific IgG was quantified via ELISpot after 5 days. Proof-of-concept was obtained using paired samples from donors before and after vaccination; anti-TT IgG was only detected in PBMC collected after booster vaccination; specificity was demonstrated with DT stimulation as control. Notably, when using PBMC from buffy coats, the specific response to TT was reproducible in 30% of cells; responsiveness correlated with higher numbers of switched memory B cells. Consecutive results showed that TT-specific IgG was also detectable when PBMC were stimulated with DTaP final vaccine product. Thus, the assay provides a viable means to test B-cell differentiation and induction of TT-specific IgG secretion using bulk antigen and final vaccine. However, prequalification of PBMC is required for reliable performance. Along with physicochemical and immunochemical methods, the functional assay could represent a complementary tool to replace in vivo potency assays in batch release of TT-containing vaccines.

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Maturation of the human B-cell receptor repertoire with age

Cited by 4 publications

References 60 publications

Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

How repertoire data are changing antibody science

A cell-based in vitro assay for testing of immunological integrity of Tetanus toxoid vaccine antigen

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