scholarly journals IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yuval Avnir ◽  
Corey T. Watson ◽  
Jacob Glanville ◽  
Eric C. Peterson ◽  
Aimee S. Tallarico ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Cell Function ◽  
Somatic Hypermutation ◽  
Population Level ◽  
Humoral Immune ◽  
Humoral Immune System ◽  
The Individual ◽  
Universal Influenza Vaccine

Abstract IGHV polymorphism provides a rich source of humoral immune system diversity. One important example is the IGHV1-69 germline gene where the biased use of alleles that encode the critical CDR-H2 Phe54 (F-alleles) to make broadly neutralizing antibodies (HV1-69-sBnAb) to the influenza A hemagglutinin stem domain has been clearly established. However, whether IGHV1-69 polymorphism can also modulate B cell function and Ab repertoire expression through promoter and copy number (CN) variations has not been reported, nor has whether IGHV1-69 allelic distribution is impacted by ethnicity. Here we studied a cohort of NIH H5N1 vaccinees and demonstrate for the first time the influence of IGHV1-69 polymorphism on V-segment usage, somatic hypermutation and B cell expansion that elucidates the dominance of F-alleles in HV1-69-sBnAbs. We provide evidence that Phe54/Leu54 (F/L) polymorphism correlates with shifted repertoire usage of other IGHV germline genes. In addition, we analyzed ethnically diverse individuals within the 1000 genomes project and discovered marked variations in F- and L- genotypes and CN among the various ethnic groups that may impact HV1-69-sBnAb responses. These results have immediate implications for understanding HV1-69-sBnAb responses at the individual and population level and for the design and implementation of “universal” influenza vaccine.

scholarly journals Different B cell subpopulations show distinct patterns in their IgH repertoire metrics

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Marie Ghraichy ◽  
Valentin von Niederhäusern ◽  
Aleksandr Kovaltsuk ◽  
Jacob D Galson ◽  
Charlotte M Deane ◽  
...  
Keyword(s):  
B Cell ◽  
In Silico ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Bioinformatic Analysis ◽  
Cell Repertoire ◽  
Humoral Immune ◽  
B Cell Repertoire ◽  
Cell Subpopulations ◽  
The Individual

Several human B-cell subpopulations are recognized in the peripheral blood, which play distinct roles in the humoral immune response. These cells undergo developmental and maturational changes involving VDJ recombination, somatic hypermutation and class switch recombination, altogether shaping their immunoglobulin heavy chain (IgH) repertoire. Here, we sequenced the IgH repertoire of naïve, marginal zone, switched and plasma cells from 10 healthy adults along with matched unsorted and in silico separated CD19+ bulk B cells. Using advanced bioinformatic analysis and machine learning, we show that sorted B cell subpopulations are characterised by distinct repertoire characteristics on both the individual sequence and the repertoire level. Sorted subpopulations shared similar repertoire characteristics with their corresponding in silico separated subsets. Furthermore, certain IgH repertoire characteristics correlated with the position of the constant region on the IgH locus. Overall, this study provides unprecedented insight over mechanisms of B cell repertoire control in peripherally circulating B cell subpopulations.

scholarly journals Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247963 ◽  
Author(s):  
Alexander A. Cohen ◽  
Zhi Yang ◽  
Priyanthi N. P. Gnanapragasam ◽  
Susan Ou ◽  
Kim-Marie A. Dam ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Electron Tomography ◽  
Covalent Attachment ◽  
Humoral Immune ◽  
Group 2 ◽  
Multiple Strains ◽  
Universal Influenza Vaccine

Current influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.

scholarly journals Different B cell subpopulations show distinct patterns in their IgH repertoire metrics

2021 ◽  
Author(s):  
Marie Ghraichy ◽  
Valentin von Niederhäusern ◽  
Aleksandr Kovaltsuk ◽  
Jacob Daniel Galson ◽  
Charlotte M Deane ◽  
...  
Keyword(s):  
B Cell ◽  
In Silico ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Bioinformatic Analysis ◽  
Cell Repertoire ◽  
Humoral Immune ◽  
B Cell Repertoire ◽  
Cell Subpopulations ◽  
The Individual

Background: Several human B-cell subpopulations are recognized in the peripheral blood, which play distinct roles in the humoral immune response. These cells undergo developmental and maturational changes involving VDJ recombination, somatic hypermutation and class switch recombination, altogether shaping their immunoglobulin heavy chain (IgH) repertoire. Methods: Here, we sequenced the IgH repertoire of naïve, marginal zone, switched and plasma cells from 10 healthy adults along with matched unsorted and in silico separated CD19+ bulk B cells. We used advanced bioinformatic analysis and machine learning to thoroughly examine and compare these repertoires. Results: We show that sorted B cell subpopulations are characterised by distinct repertoire characteristics on both the individual sequence and the repertoire level. Sorted subpopulations shared similar repertoire characteristics with their corresponding in silico separated subsets. Furthermore, certain IgH repertoire characteristics correlated with the position of the constant region on the IgH locus. Conclusion: Overall, this study provides unprecedented insight over mechanisms of B cell repertoire control in peripherally circulating B cell subpopulations.

scholarly journals Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

2020 ◽  
Author(s):  
Alexander A. Cohen ◽  
Zhi Yang ◽  
Priyanthi NP Gnanapragasam ◽  
Susan Ou ◽  
Kim-Marie A. Dam ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Electron Tomography ◽  
Covalent Attachment ◽  
Humoral Immune ◽  
Group 2 ◽  
Multiple Strains ◽  
Universal Influenza Vaccine

AbstractCurrent influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.

scholarly journals Dissecting Human Antibody Responses: Useful, Basic, and Surprising Findings

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-49-SCI-49
Author(s):  
Antonio Lanzavecchia
Keyword(s):  
B Cell ◽  
Dna Sequences ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Somatic Mutations ◽  
Vaccine Design ◽  
Human Memory ◽  
Affinity Maturation ◽  
Effective Vaccine ◽  
Human Antibody

Abstract We use cell culture-based high-throughput methods to interrogate human memory B cell and plasma cell repertoires and to isolate antibodies selected on the basis of their neutralizing potency and breadth. Relevant examples are antibodies that neutralize all influenza A viruses or even four paramyxoviruses. By targeting conserved structures, these broadly neutralizing antibodies are less prone to select escape mutants and are promising candidates for prophylaxis and therapy of infections, as well as tools for vaccine design. The value of a target-agnostic approach to vaccine design is illustrated by our discovery of extremely potent antibodies that neutralize human cytomegalovirus, which led to the identification of their viral ligand, a pentameric complex that was then produced and tested as an effective vaccine. By reconstructing the genealogy trees of specific B cell clones, we investigate the role of somatic mutations in affinity maturation and in generation of antibody variants with broader or different specificity. Somatic mutations can also generate autoantibodies, as found in patients with pemphigus and autoimmune pulmonary alveolar proteinosis. Recently, while searching for antibodies that broadly react with malaria variant antigens, we discovered a new mechanism of antibody diversification, which relies on templated insertions of genomic DNA sequences into immunoglobulin genes, followed by somatic mutations. Disclosures Lanzavecchia: Humabs SA: Equity Ownership, Research Funding.

scholarly journals Survival dynamical systems: individual-level survival analysis from population-level epidemic models

2019 ◽  
Vol 10 (1) ◽  
pp. 20190048 ◽  
Author(s):  
Wasiur R. KhudaBukhsh ◽  
Boseung Choi ◽  
Eben Kenah ◽  
Grzegorz A. Rempała
Keyword(s):  
Influenza A ◽  
Large Population ◽  
Synthetic Data ◽  
Population Level ◽  
Epidemic Models ◽  
Hazard Functions ◽  
Individual Level ◽  
Washington State University ◽  
Influenza A H1n1 ◽  
The Individual

In this paper, we show that solutions to ordinary differential equations describing the large-population limits of Markovian stochastic epidemic models can be interpreted as survival or cumulative hazard functions when analysing data on individuals sampled from the population. We refer to the individual-level survival and hazard functions derived from population-level equations as a survival dynamical system (SDS). To illustrate how population-level dynamics imply probability laws for individual-level infection and recovery times that can be used for statistical inference, we show numerical examples based on synthetic data. In these examples, we show that an SDS analysis compares favourably with a complete-data maximum-likelihood analysis. Finally, we use the SDS approach to analyse data from a 2009 influenza A(H1N1) outbreak at Washington State University.

scholarly journals LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1448-1455 ◽  
Author(s):  
Julia Rastelli ◽  
Cornelia Hömig-Hölzel ◽  
Jane Seagal ◽  
Werner Müller ◽  
Andrea C. Hermann ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Somatic Hypermutation ◽  
Class Switch Recombination ◽  
Cd40 Ligand ◽  
Barr Virus ◽  
Class Switch ◽  
Epstein Barr

AbstractThe Epstein-Barr virus (EBV) protein LMP1 is considered to be a functional homologue of the CD40 receptor. However, in contrast to the latter, LMP1 is a constitutively active signaling molecule. To compare B cell–specific LMP1 and CD40 signaling in an unambiguous manner, we generated transgenic mice conditionally expressing a CD40/LMP1 fusion protein, which retained the LMP1 cytoplasmic tail but has lost the constitutive activity of LMP1 and needs to be activated by the CD40 ligand. We show that LMP1 signaling can completely substitute CD40 signaling in B cells, leading to normal B-cell development, activation, and immune responses including class-switch recombination, germinal center formation, and somatic hypermutation. In addition, the LMP1-signaling domain has a unique property in that it can induce class-switch recombination to IgG1 independent of cytokines. Thus, our data indicate that LMP1 has evolved to imitate T-helper cell function allowing activation, proliferation, and differentiation of EBV-infected B cells independent of T cells.

scholarly journals High-affinity, neutralizing antibodies to SARS-CoV-2 can be made in the absence of T follicular helper cells

2021 ◽  
Author(s):  
Jennifer S. Chen ◽  
Ryan D. Chow ◽  
Eric Song ◽  
Tianyang Mao ◽  
Benjamin Israelow ◽  
...  
Keyword(s):  
B Cell ◽  
Antibody Production ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Neutralizing Antibody ◽  
New Paradigm ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Canonical Pathways

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 as well as influenza A virus. Tfh-independent responses were mediated by a population we call lymph node (LN)-Th1 cells, which remain in the LN and interact with B cells outside of GCs to promote high-affinity but broad-spectrum antibodies. Strikingly, antibodies generated in the presence and absence of Tfh cells displayed similar neutralization potency against homologous SARS-CoV-2 as well as the B.1.351 variant of concern. These data support a new paradigm for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GCs and even compensate for GCs damaged by viral inflammation.

scholarly journals Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan Antonio Aguilar-Pimentel ◽  
Yi-Li Cho ◽  
Raffaele Gerlini ◽  
Julia Calzada-Wack ◽  
Maria Wimmer ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Allergic Inflammation ◽  
Male Mice ◽  
Humoral Immune ◽  
B Cell Function ◽  
Endogenous Estrogen ◽  
Ige Synthesis ◽  
Immunoglobulin Levels

Abstract Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.

scholarly journals Suboptimal Humoral Immune Response against Influenza A(H7N9) Virus Is Related to Its Internal Genes

2015 ◽  
Vol 22 (12) ◽  
pp. 1235-1243 ◽  
Author(s):  
Andrew C. Y. Lee ◽  
Houshun Zhu ◽  
Anna J. X. Zhang ◽  
Can Li ◽  
Pui Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Humoral Immune Response ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Case Fatality ◽  
H7n9 Virus ◽  
Humoral Immune ◽  
Homologous Virus ◽  
Antibody Titers

ABSTRACTInfluenza A(H7N9) virus pneumonia is associated with a high case fatality rate in humans. Multiple viral factors have been postulated to account for the high virulence of the virus. It has been reported that patients with influenza A(H7N9) virus infection have relatively low titers of neutralizing antibodies compared to those with seasonal influenza virus infections. In this study, we compared serum hemagglutination inhibition (HI) and microneutralization (MN) antibody titers of mice challenged with wild-type A(H7N9) viruses [H7N9(Anhui) and H7N9(Zhejiang)], an A(H1N1)pdm09 virus [pH1N1(2009)], and a recombinant A(H7N9) virus with PR8/H1N1 internal genes (rg-PR8-H7-N9). All mice infected by H7N9(Anhui) and H7N9(Zhejiang) developed serum HI antibodies at 14 days postinfection (dpi) but no detectable MN antibodies, even at 28 dpi. A low level of neutralizing activity was detected in H7N9(Anhui)- and H7N9(Zhejiang)-infected mice using fluorescent focus MN assay, but convalescent-phase serum samples obtained from H7N9(Anhui)-infected mice did not reduce the mortality of naive mice after homologous virus challenge. Reinfection with homologous A(H7N9) virus induced higher HI and MN titers than first infection. In contrast, pH1N1(2009) virus infection induced robust HI and MN antibody responses, even during the first infection. Moreover, rg-PR8-H7-N9 induced significantly higher HI and MN antibody titers than H7N9(Zhejiang). In conclusion, the internal genes of A(H7N9) virus can affect the humoral immune response against homologous viral surface proteins, which may also contribute to the virulence of A(H7N9) virus.

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