scholarly journals Human B cell lineages engaged by germinal centers following influenza vaccination are measurably evolving

2021 ◽  
Author(s):  
Kenneth B. Hoehn ◽  
Jackson S. Turner ◽  
Frederick I. Miller ◽  
Ruoyi Jiang ◽  
Oliver G. Pybus ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccination ◽  
B Cell ◽  
Seasonal Influenza ◽  
Somatic Hypermutation ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Cell Lineages ◽  
Cell Responses ◽  
Human B Cell

Poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses. Consistent with this notion, no significant increase in somatic hypermutation (SHM) among circulating influenza-binding lineages was detected following seasonal vaccination in humans in a prior study. A more recent study showed that at least a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages can occur. Crucially, however, it has not been demonstrated whether these GC-engaged lineages actually accumulate additional SHM. Here, we address this point using a phylogenetic test of measurable evolution. We first validate this test through simulations and demonstrate measurable B cell evolution in known examples of affinity maturation such as the response to HIV infection. We then show that lineages in the blood are rarely measurably evolving following influenza vaccination, but that GC-engaged lineages - likely derived from memory B cells - are frequently measurably evolving. These findings confirm that seasonal influenza virus vaccination can stimulate additional SHM among responding B cell lineages.

scholarly journals Human B cell lineages associated with germinal centers following influenza vaccination are measurably evolving

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Kenneth B Hoehn ◽  
Jackson S Turner ◽  
Frederick I Miller ◽  
Ruoyi Jiang ◽  
Oliver G Pybus ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Influenza Vaccination ◽  
B Cell ◽  
Seasonal Influenza ◽  
Germinal Centers ◽  
Cell Lineages ◽  
Cell Evolution ◽  
The Poor ◽  
Poor Efficacy

The poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses. We previously showed that a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages against vaccine antigens can occur. However, it remains to be determined whether seasonal influenza vaccination stimulates additional evolution of vaccine-specific lineages, and previous work has found no significant increase in somatic hypermutation (SHM) among influenza-binding lineages sampled from the blood following seasonal vaccination in humans. Here, we investigate this issue using a phylogenetic test of measurable immunoglobulin sequence evolution. We first validate this test through simulations and survey measurable evolution across multiple conditions. We find significant heterogeneity in measurable B cell evolution across conditions, with enrichment in primary response conditions such as HIV infection and early childhood development. We then show that measurable evolution following influenza vaccination is highly compartmentalized: while lineages in the blood are rarely measurably evolving following influenza vaccination, lineages containing GC B cells are frequently measurably evolving. Many of these lineages appear to derive from memory B cells. We conclude from these findings that seasonal influenza virus vaccination can stimulate additional evolution of responding B cell lineages, and imply that the poor efficacy of seasonal influenza vaccination is not due to a complete inhibition of vaccine-specific B cell evolution.

scholarly journals Human B cell clonal expansion and convergent antibody responses to SARS-CoV-2

2020 ◽  
Author(s):  
Sandra C. A. Nielsen ◽  
Fan Yang ◽  
Katherine J. L. Jackson ◽  
Ramona A. Hoh ◽  
Katharina Röltgen ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Cell Responses ◽  
Ighv Gene ◽  
Gene Usage ◽  
Antibody Titers ◽  
Extensive Class ◽  
Iga Subclasses ◽  
Human B Cell

SUMMARYDuring virus infection B cells are critical for the production of antibodies and protective immunity. Here we show that the human B cell compartment in patients with diagnostically confirmed SARS-CoV-2 and clinical COVID-19 is rapidly altered with the early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify extensive convergence of antibody sequences across SARS-CoV-2 patients, highlighting stereotyped naïve responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and other zoonotic spillover coronaviruses.

The immunoglobulin heavy-chain locus hs3b and hs4 3′ enhancers are dispensable for VDJ assembly and somatic hypermutation

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1421-1427 ◽  
Author(s):  
Caroline Le Morvan ◽  
Eric Pinaud ◽  
Catherine Decourt ◽  
Armelle Cuvillier ◽  
Michel Cogné
Keyword(s):  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Somatic Hypermutation ◽  
Class Switch Recombination ◽  
Immunoglobulin Heavy Chain ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Class Switch ◽  
Endogenous Locus

Abstract The more distal enhancers of the immunoglobulin heavy-chain 3′ regulatory region, hs3b and hs4, were recently demonstrated as master control elements of germline transcription and class switch recombination to most immunoglobulin constant genes. In addition, they were shown to enhance the accumulation of somatic mutations on linked transgenes. Since somatic hypermutation and class switch recombination are tightly linked processes, their common dependency on the endogenous locus 3′ enhancers could be an attractive hypothesis. VDJ structure and somatic hypermutation were analyzed in B cells from mice carrying either a heterozygous or a homozygous deletion of these enhancers. We find that hs3b and hs4 are dispensable both for VDJ assembly and for the occurrence of mutations at a physiologic frequency in the endogenous locus. In addition, we show that cells functionally expressing the immunoglobulin M (IgM) class B-cell receptor encoded by an hs3b/hs4-deficient locus were fully able to enter germinal centers, undergo affinity maturation, and yield specific antibody responses in homozygous mutant mice, where IgG1 antibodies compensated for the defect in other IgG isotypes. By contrast, analysis of Peyer patches from heterozygous animals showed that peanut agglutinin (PNAhigh) B cells functionally expressing the hs3b/hs4-deficient allele were dramatically outclassed by B cells expressing the wild-type locus and normally switching to IgA. This study thus also highlights the role of germinal centers in the competition between B cells for affinity maturation and suggests that membrane IgA may promote recruitment in an activated B-cell compartment, or proliferation of activated B cells, more efficiently than IgM in Peyer patches.

scholarly journals Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine

2020 ◽  
Vol 117 (12) ◽  
pp. 6675-6685 ◽  
Author(s):  
Anna Z. Wec ◽  
Denise Haslwanter ◽  
Yasmina N. Abdiche ◽  
Laila Shehata ◽  
Nuria Pedreño-Lopez ◽  
...  
Keyword(s):  
B Cell ◽  
Yellow Fever ◽  
Cell Response ◽  
Affinity Maturation ◽  
Immunoglobulin M ◽  
Viral Envelope ◽  
Cell Responses ◽  
B Cell Responses ◽  
Human B Cell ◽  
B Cell Response

A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM+CD27+) and switched immunoglobulin (swIg+) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg+and atypical IgM+and IgD+MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.

scholarly journals Prolonged evolution of the human B cell response to SARS-CoV-2 infection

2021 ◽  
Vol 6 (56) ◽  
pp. eabg6916
Author(s):  
Mrunal Sakharkar ◽  
C. Garrett Rappazzo ◽  
Wendy F. Wieland-Alter ◽  
Ching-Lin Hsieh ◽  
Daniel Wrapp ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Response ◽  
De Novo ◽  
Somatic Hypermutation ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Specific Igg ◽  
Over Time ◽  
Human B Cell ◽  
B Cell Response

A comprehensive understanding of the kinetics and evolution of the human B cell response to SARS-CoV-2 infection will facilitate the development of next-generation vaccines and therapies. Here, we longitudinally profiled this response in mild and severe COVID-19 patients over a period of five months. Serum neutralizing antibody (nAb) responses waned rapidly but spike (S)-specific IgG+ memory B cells (MBCs) remained stable or increased over time. Analysis of 1,213 monoclonal antibodies (mAbs) isolated from S-specific MBCs revealed a primarily de novo response that displayed increased somatic hypermutation, binding affinity, and neutralization potency over time, providing evidence for prolonged antibody affinity maturation. B cell immunodominance hierarchies were similar across donor repertoires and remained relatively stable as the immune response progressed. Cross-reactive B cell populations, likely re-called from prior endemic beta-coronavirus exposures, comprised a small but stable fraction of the repertoires and did not contribute to the neutralizing response. The neutralizing antibody response was dominated by public clonotypes that displayed significantly reduced activity against SARS-CoV-2 variants emerging in Brazil and South Africa that harbor mutations at positions 501, 484 and 417 in the S protein. Overall, the results provide insight into the dynamics, durability, and functional properties of the human B cell response to SARS-CoV-2 infection and have implications for the design of immunogens that preferentially stimulate protective B cell responses.

scholarly journals Influenza Virus Vaccination Induces Interleukin-12/23 Receptor β1 (IL-12/23Rβ1)-Independent Production of Gamma Interferon (IFN-γ) and Humoral Immunity in Patients with Genetic Deficiencies in IL-12/23Rβ1 or IFN-γ Receptor I

2008 ◽  
Vol 15 (8) ◽  
pp. 1171-1175 ◽  
Author(s):  
Tjitske de Boer ◽  
Jaap T. van Dissel ◽  
Taco W. J. Kuijpers ◽  
Guus F. Rimmelzwaan ◽  
Frank P. Kroon ◽  
...  
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Seasonal Influenza ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Virus Vaccination ◽  
Cell Responses ◽  
Antibody Titers ◽  
Ifn Γ ◽  
Striking Contrast

ABSTRACT To investigate whether protective immune responses can be induced in the absence of normal interleukin-12/23/gamma interferon (IL-12/23/IFN-γ) axis signaling, we vaccinated with the seasonal influenza virus subunit vaccine two patients with complete IL-12/23 receptor β1 (IL-12/23Rβ1) deficiencies, two patients with partial IFN-γ receptor I (pIFN-γRI) deficiencies, and five healthy controls. Blood samples were analyzed before, 7 days after, and 28 days after vaccination. In most cases, antibody titers reached protective levels. Moreover, although T-cell responses in patients were lower than those observed in controls, significant influenza virus-specific T-cell proliferation, IFN-γ production, and numbers of IFN-γ-producing cells were found in all patients 7 days after the vaccination. Interestingly, influenza virus-specific IFN-γ responses were IL-12/23 independent, in striking contrast to mycobacterium-induced IFN-γ production. In conclusion, influenza virus vaccination induces IL-12/23-independent IFN-γ production by T cells and can result in sufficient humoral protection in both IL-12/23Rβ1- and pIFN-γRI-deficient individuals.

scholarly journals Learning the heterogeneous hypermutation landscape of immunoglobulins from high-throughput repertoire data

2020 ◽  
Author(s):  
Natanael Spisak ◽  
Aleksandra M. Walczak ◽  
Thierry Mora
Keyword(s):  
B Cell ◽  
High Throughput ◽  
Affinity Maturation ◽  
B Cell Receptors ◽  
Absolute Position ◽  
Sequence Context ◽  
Cell Lineages ◽  
Selective Forces ◽  
Antigenic Targets ◽  
Complementarity Determining Region

Somatic hypermutations of immunoglobulin (Ig) genes occurring during affinity maturation drive B-cell receptors’ ability to evolve strong binding to their antigenic targets. The landscape of these mutations is highly heterogeneous, with certain regions of the Ig gene being preferentially targeted. However, a rigorous quantification of this bias has been difficult because of phylogenetic correlations between sequences and the interference of selective forces. Here, we present an approach that corrects for these issues, and use it to learn a model of hypermutation preferences from a recently published large IgH repertoire dataset. The obtained model predicts mutation profiles accurately and in a reproducible way, including in the previously uncharacterized Complementarity Determining Region 3, revealing that both the sequence context of the mutation and its absolute position along the gene are important. In addition, we show that hypermutations occurring concomittantly along B-cell lineages tend to co-localize, suggesting a possible mechanism for accelerating affinity maturation.

scholarly journals Learning the heterogeneous hypermutation landscape of immunoglobulins from high-throughput repertoire data

2020 ◽  
Vol 48 (19) ◽  
pp. 10702-10712
Author(s):  
Natanael Spisak ◽  
Aleksandra M Walczak ◽  
Thierry Mora
Keyword(s):  
B Cell ◽  
High Throughput ◽  
Affinity Maturation ◽  
B Cell Receptors ◽  
Absolute Position ◽  
Sequence Context ◽  
Cell Lineages ◽  
Selective Forces ◽  
Antigenic Targets ◽  
Complementarity Determining Region

Abstract Somatic hypermutations of immunoglobulin (Ig) genes occurring during affinity maturation drive B-cell receptors’ ability to evolve strong binding to their antigenic targets. The landscape of these mutations is highly heterogeneous, with certain regions of the Ig gene being preferentially targeted. However, a rigorous quantification of this bias has been difficult because of phylogenetic correlations between sequences and the interference of selective forces. Here, we present an approach that corrects for these issues, and use it to learn a model of hypermutation preferences from a recently published large IgH repertoire dataset. The obtained model predicts mutation profiles accurately and in a reproducible way, including in the previously uncharacterized Complementarity Determining Region 3, revealing that both the sequence context of the mutation and its absolute position along the gene are important. In addition, we show that hypermutations occurring concomittantly along B-cell lineages tend to co-localize, suggesting a possible mechanism for accelerating affinity maturation.

In Vitro Effects of Cyclosporin A on Human B-Cell Responses

1983 ◽  
Vol 17 (3) ◽  
pp. 241-249 ◽  
Author(s):  
R. BERGER ◽  
J. G. MEINGASSNER ◽  
W. KNAPP
Keyword(s):  
Cyclosporin A ◽  
B Cell ◽  
Cell Responses ◽  
B Cell Responses ◽  
In Vitro Effects ◽  
Human B Cell

scholarly journals Mechanisms behind Functional Avidity Maturation in T Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Marina Rode von Essen ◽  
Martin Kongsbak ◽  
Carsten Geisler
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Affinity Maturation ◽  
Functional Avidity ◽  
Cell Clones ◽  
Genes Encoding ◽  
Avidity Maturation

During an immune response antigen-primed B-cells increase their antigen responsiveness by affinity maturation mediated by somatic hypermutation of the genes encoding the antigen-specific B-cell receptor (BCR) and by selection of higher-affinity B cell clones. Unlike the BCR, the T-cell receptor (TCR) cannot undergo affinity maturation. Nevertheless, antigen-primed T cells significantly increase their antigen responsiveness compared to antigen-inexperienced (naïve) T cells in a process called functional avidity maturation. This paper covers studies that describe differences in T-cell antigen responsiveness during T-cell differentiation along with examples of the mechanisms behind functional avidity maturation in T cells.

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