Immunoglobulin germline gene variation and its impact on human disease

Mikocziova, Ivana; Greiff, Victor; Sollid, Ludvig M.

doi:10.1038/s41435-021-00145-5

“…Variability in escape patterns suggests that a diversity of antibodies are targeting these epitopes. Intra-species germline diversity in immunoglobulin genes may help explain why individuals with similar exposures often mount distinct responses [ 79 , 80 ]. On the other hand, escape profiles were more consistent in the SH-H, where the responses of convalescent macaques and vaccinated humans appeared to converge.…”

Section: Discussionmentioning

confidence: 99%

Detailed analysis of antibody responses to SARS-CoV-2 vaccination and infection in macaques

Willcox

¹

,

Sung

²

,

Garrett

³

et al. 2022

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Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses resemble the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage-DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in convalescent humans, convalescent (re-infected) rhesus macaques, mRNA-vaccinated humans, and repRNA-vaccinated pigtail macaques. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix-heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques. Differences in macaque species and exposure type may also contribute to these findings.

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“…Thus, different expression levels of various genes could be promoted by variation within non-coding regions such as promoters, 5’UTRs and leader sequences, introns, or recombination signal sequences. Polymorphisms within these regions have been suggested to influence V(D)J gene expression levels within B-cell receptor repertoires ( Mikocziova et al, 2021 ). We also observed that variation in the MHC locus is associated with V-gene usage biases for productive TCRs, but not non-productive TCRs.…”

Section: Discussionmentioning

confidence: 99%

“…Our results clearly demonstrate how variation in V(D)J recombination-related genes can bias TCR repertoire combinatorial and junctional diversity. In the case of B cells, genetically determined V(D)J gene usage biases within B-cell receptor repertoires have been linked to functional consequences for the overall immune response to specific antigens and, thus, an increased susceptibility to certain diseases ( Mikocziova et al, 2021 ). As such, the genetic TCR repertoire biases identified here lay the groundwork for further exploration into the diversity of immune responses and disease susceptibilities between individuals.…”

Section: Discussionmentioning

confidence: 99%

Combining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities

Russell

¹

,

Souquette

²

,

Levine

³

et al. 2022

eLife

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Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and functional TCRs. The extent to which an individual’s genetic background is associated with their resulting TCR repertoire diversity has yet to be fully explored. Using a previously published repertoire sequencing dataset paired with high-resolution genome-wide genotyping from a large human cohort, we infer specific genetic loci associated with V(D)J recombination probabilities using genome-wide association inference. We show that V(D)J gene usage profiles are associated with variation in the TCRB locus and, specifically for the functional TCR repertoire, variation in the major histocompatibility complex locus. Further, we identify specific variations in the genes encoding the Artemis protein and the TdT protein to be associated with biasing junctional nucleotide deletion and N-insertion, respectively. These results refine our understanding of genetically-determined TCR repertoire biases by confirming and extending previous studies on the genetic determinants of V(D)J gene usage and providing the first examples of trans genetic variants which are associated with modifying junctional diversity. Together, these insights lay the groundwork for further explorations into how immune responses vary between individuals.

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“…Variability in escape patterns suggests that a diversity of antibodies are targeting these epitopes. Intra-species germline diversity in immunoglobulin genes may help explain why individuals with similar exposures often mount distinct responses [ 83 , 84 ]. On the other hand, escape profiles were more consistent in the SH-H, where the responses of convalescent macaques and vaccinated humans appeared to converge.…”

Section: Discussionmentioning

confidence: 99%

Macaque-human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection

Willcox

¹

,

Sung

²

,

Garrett

³

et al. 2021

Preprint

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Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses recapitulate, and thus appropriately model, the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage- DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in humans and macaques following either vaccination or infection. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix- heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques.Author summaryNon-human primates, including macaques, are considered the best animal model for studying infectious diseases that infect humans. Vaccine candidates for SARS-CoV-2 are first tested in macaques to assess immune responses prior to advancing to human trials, and macaques are also used to model the human immune response to SARS-CoV-2 infection. However, there may be differences in how macaque and human antibodies recognize the SARS-CoV-2 entry protein, Spike. Here we characterized the locations on Spike that are recognized by antibodies from vaccinated or infected macaques and humans. We also made mutations to the viral sequence and assessed how these affected antibody binding, enabling a comparison of antibody binding requirements between macaques and humans at a very precise level. We found that macaques and humans share some responses, but also recognize distinct regions of Spike. We also found that in general, antibodies from different individuals had unique responses to viral mutations, regardless of species. These results will yield a better understanding of how macaque data can be used to inform human immunity to SARS-CoV-2.

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Immunoglobulin germline gene variation and its impact on human disease

Cited by 63 publications

References 136 publications

Detailed analysis of antibody responses to SARS-CoV-2 vaccination and infection in macaques

Detailed analysis of antibody responses to SARS-CoV-2 vaccination and infection in macaques

Combining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities

Macaque-human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection

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