scholarly journals The Physiological Landscape and Specificity of Antibody Repertoires

2021 ◽  
Author(s):  
Lucia Csepregi ◽  
Kenneth B. Hoehn ◽  
Daniel Neumeier ◽  
Joseph M. Taft ◽  
Simon Friedensohn ◽  
...  
Keyword(s):  
B Cell ◽  
Humoral Response ◽  
High Serum ◽  
Lymphoid Organs ◽  
Antibody Repertoire ◽  
Antigen Specificity ◽  
Cell Clones ◽  
Gene Usage ◽  
Antibody Repertoires ◽  
And Migration

Diverse antibody repertoires spanning multiple lymphoid organs (e.g., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response, remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice, and discovered that organ-specific antibody repertoire features (e.g., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen-specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.

scholarly journals B Cell Mobilization, Dissemination, Fine Tuning of Local Antigen Specificity and Isotype Selection in Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Line Ohm-Laursen ◽  
Hailong Meng ◽  
Kenneth B. Hoehn ◽  
Nima Nouri ◽  
Yue Jiang ◽  
...  
Keyword(s):  
B Cells ◽  
Respiratory Tract ◽  
B Cell ◽  
Lower Respiratory Tract ◽  
Plasma Cells ◽  
Fine Tuning ◽  
Atopic Asthma ◽  
Antibody Repertoire ◽  
Antigen Specificity ◽  
Antibody Repertoires

In order to better understand how the immune system interacts with environmental triggers to produce organ-specific disease, we here address the hypothesis that B and plasma cells are free to migrate through the mucosal surfaces of the upper and lower respiratory tracts, and that their total antibody repertoire is modified in a common respiratory tract disease, in this case atopic asthma. Using Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) we have catalogued the antibody repertoires of B cell clones retrieved near contemporaneously from multiple sites in the upper and lower respiratory tract mucosa of adult volunteers with atopic asthma and non-atopic controls and traced their migration. We show that the lower and upper respiratory tracts are immunologically connected, with trafficking of B cells directionally biased from the upper to the lower respiratory tract and points of selection when migrating from the nasal mucosa and into the bronchial mucosa. The repertoires are characterized by both IgD-only B cells and others undergoing class switch recombination, with restriction of the antibody repertoire distinct in asthmatics compared with controls. We conclude that B cells and plasma cells migrate freely throughout the respiratory tract and exhibit distinct antibody repertoires in health and disease.

scholarly journals Signatures of selection in the human antibody repertoire: Selective sweeps, competing subclones, and neutral drift

2019 ◽  
Vol 116 (4) ◽  
pp. 1261-1266 ◽  
Author(s):  
Felix Horns ◽  
Christopher Vollmers ◽  
Cornelia L. Dekker ◽  
Stephen R. Quake
Keyword(s):  
B Cell ◽  
Binding Affinity ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Selective Sweeps ◽  
Human Immune System ◽  
Evolutionary Processes ◽  
Neutral Drift ◽  
Cell Lineages ◽  
Antibody Repertoires

Antibodies are created and refined by somatic evolution in B cell populations, which endows the human immune system with the ability to recognize and eliminate diverse pathogens. However, the evolutionary processes that sculpt antibody repertoires remain poorly understood. Here, using an unbiased repertoire-scale approach, we show that the population genetic signatures of evolution are evident in human B cell lineages and reveal how antibodies evolve somatically. We measured the dynamics and genetic diversity of B cell responses in five adults longitudinally before and after influenza vaccination using high-throughput antibody repertoire sequencing. We identified vaccine-responsive B cell lineages that carry signatures of selective sweeps driven by positive selection, and discovered that they often display evidence for selective sweeps favoring multiple subclones. We also found persistent B cell lineages that exhibit stable population dynamics and carry signatures of neutral drift. By exploiting the relationship between B cell fitness and antibody binding affinity, we demonstrate the potential for using phylogenetic approaches to identify antibodies with high binding affinity. This quantitative characterization reveals that antibody repertoires are shaped by an unexpectedly broad spectrum of evolutionary processes and shows how signatures of evolutionary history can be harnessed for antibody discovery and engineering.

scholarly journals Landscapes and dynamic diversifications of B-cell receptor repertoires in COVID-19 patients

2020 ◽  
Author(s):  
Haitao Xiang ◽  
Yingze Zhao ◽  
Xinyang Li ◽  
Peipei Liu ◽  
Longlong Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Cell Receptor ◽  
Cell Immune Response ◽  
Next Generation Sequencing Technology ◽  
Network Analyses ◽  
Cell Clones ◽  
Gene Usage ◽  
Therapeutic Development

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19). Great international efforts have been put into the development of prophylactic vaccines and neutralizing antibodies. However, the knowledge about the B cell immune response induced by the SARS-CoV-2 virus is still limited. Here, we report a comprehensive characterization of the dynamics of immunoglobin heavy chain (IGH) repertoire in COVID-19 patients. By using next-generation sequencing technology, we examined the temporal changes in the landscape of the patient’s immunological status, and found dramatic changes in the IGH within the patients’ immune system after the onset of COVID-19 symptoms. Although different patients have distinct immune responses to SARS-CoV-2 infection, by employing clonotype overlap, lineage expansion and clonotype network analyses, we observed a higher clonotype overlap and substantial lineage expansion of B cell clones during 2-3 weeks of illness, which is of great importance to B-cell immune responses. Meanwhile, for preferences of V gene usage during SARS-CoV-2 infection, IGHV3-74 and IGHV4-34 and IGHV4-39 in COVID-19 patients were more abundant than that of healthy controls. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development as well as mechanistic research.

scholarly journals Antitopoisomerase I monoclonal autoantibodies from scleroderma patients and tight skin mouse interact with similar epitopes.

1992 ◽  
Vol 175 (4) ◽  
pp. 1103-1109 ◽  
Author(s):  
T Muryoi ◽  
K N Kasturi ◽  
M J Kafina ◽  
D S Cram ◽  
L C Harrison ◽  
...  
Keyword(s):  
Fusion Protein ◽  
B Cell ◽  
Fusion Proteins ◽  
Topoisomerase I ◽  
Protein C ◽  
Molecular Mimicry ◽  
Antigen Specificity ◽  
Tight Skin ◽  
Cell Clones ◽  
Human And Mouse

We have generated for the first time monoclonal antibodies (mAbs) specific for topoisomerase I (topo I) from scleroderma patients, and tight skin mice which develop a scleroderma-like syndrome. The epitope specificity of these antibodies has been determined using a series of fusion proteins containing contiguous portions of topo I polypeptide. Western blot analysis demonstrated that both human and mouse mAbs bound strongly to fusion protein C encompassing the NH2-terminal portion of the enzyme, and weakly to fusion proteins F and G containing regions close to the COOH-terminal end of the molecule. This crossreactivity is related to a tripeptide sequence homology in F, G, and C fusion proteins. It is interesting that a pentapeptide sequence homologous to that in fusion protein C was identified in the UL70 protein of cytomegalovirus, suggesting that activation of autoreactive B cell clones by molecular mimicry is possible. Both human and mouse mAbs exhibiting the same antigen specificity, also share an interspecies cross-reactive idiotope. These data suggest that B cell clones producing antitopo autoantibodies present in human and mouse repertoire are conserved during phylogeny, and are activated during the development of scleroderma disease.

scholarly journals Vaccination boosts naturally enhanced neutralizing breadth to SARS-CoV-2 one year after infection

2021 ◽  
Author(s):  
Zijun Wang ◽  
Frauke Muecksch ◽  
Dennis Schaefer-Babajew ◽  
Shlomo Finkin ◽  
Charlotte Viant ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Response ◽  
Memory B Cells ◽  
Receptor Binding Domain ◽  
Neutralizing Activity ◽  
Specific Memory ◽  
Cell Clones ◽  
One Year ◽  
Over Time

Over one year after its inception, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several excellent vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies. Here we report on a cohort of 63 COVID-19-convalescent individuals assessed at 1.3, 6.2 and 12 months after infection, 41% of whom also received mRNA vaccines. In the absence of vaccination antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable from 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in serum neutralizing activities against variants of concern that are comparable to or greater than neutralizing activity against the original Wuhan Hu-1 achieved by vaccination of naive individuals. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover, and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in variants of concern. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants. Should memory responses evolve in a similar manner in vaccinated individuals, additional appropriately timed boosting with available vaccines could cover most circulating variants of concern.

Characterizing the B-Cell and Humoral Response in Tertiary Lymphoid Organs in Kidney Allografts

2019 ◽  
Vol 17 (3) ◽  
pp. 330-338
Author(s):  
Anna K. Nowocin ◽  
◽  
Lucy Meader ◽  
Kathryn Brown ◽  
Raul Elgueta ◽  
...  
Keyword(s):  
B Cell ◽  
Humoral Response ◽  
Lymphoid Organs

scholarly journals Proteo-Genomic Analysis Identifies Two Major Sites of Vulnerability on Ebolavirus Glycoprotein for Neutralizing Antibodies in Convalescent Human Plasma

2021 ◽  
Vol 12 ◽  
Author(s):  
Pavlo Gilchuk ◽  
Adrian Guthals ◽  
Stefano R. Bonissone ◽  
Jared B. Shaw ◽  
Philipp A. Ilinykh ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Ebola Virus ◽  
Single Cells ◽  
Humoral Response ◽  
Memory B Cells ◽  
The Body ◽  
Antibody Repertoire ◽  
Antigenic Sites ◽  
Cell Antibody

Three clinically relevant ebolaviruses – Ebola (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) viruses, are responsible for severe disease and occasional deadly outbreaks in Africa. The largest Ebola virus disease (EVD) epidemic to date in 2013-2016 in West Africa highlighted the urgent need for countermeasures, leading to the development and FDA approval of the Ebola virus vaccine rVSV-ZEBOV (Ervebo®) in 2020 and two monoclonal antibody (mAb)-based therapeutics (Inmazeb® [atoltivimab, maftivimab, and odesivimab-ebgn] and Ebanga® (ansuvimab-zykl) in 2020. The humoral response plays an indispensable role in ebolavirus immunity, based on studies of mAbs isolated from the antibody genes in peripheral blood circulating ebolavirus-specific human memory B cells. However, antibodies in the body are not secreted by circulating memory B cells in the blood but rather principally by plasma cells in the bone marrow. Little is known about the protective polyclonal antibody responses in convalescent plasma. Here we exploited both single-cell antibody gene sequencing and proteomic sequencing approaches to assess the composition of the ebolavirus glycoprotein (GP)-reactive antibody repertoire in the plasma of an EVD survivor. We first identified 1,512 GP-specific mAb variable gene sequences from single cells in the memory B cell compartment. Using mass spectrometric analysis of the corresponding GP-specific plasma IgG, we found that only a portion of the large B cell antibody repertoire was represented in the plasma. Molecular and functional analysis of proteomics-identified mAbs revealed recognition of epitopes in three major antigenic sites - the GP head domain, the glycan cap, and the base region, with a high prevalence of neutralizing and protective mAb specificities that targeted the base and glycan cap regions on the GP. Polyclonal plasma antibodies from the survivor reacted broadly to EBOV, BDBV, and SUDV GP, while reactivity of the potently neutralizing mAbs we identified was limited mostly to the homologous EBOV GP. Together these results reveal a restricted diversity of neutralizing humoral response in which mAbs targeting two antigenic sites on GP – glycan cap and base – play a principal role in plasma-antibody-mediated protective immunity against EVD.

scholarly journals Limited VH gene usage in B-cell clones established with nurse-like cells from patients with rheumatoid arthritis

Rheumatology ◽  
2005 ◽  
Vol 45 (5) ◽  
pp. 549-557 ◽  
Author(s):  
S. Nakamura-Kikuoka ◽  
K. Takahi ◽  
H. Tsuboi ◽  
T. Toyosaki-Maeda ◽  
M. Maeda-Tanimura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cell ◽  
Cell Clones ◽  
Gene Usage ◽  
Vh Gene

scholarly journals The fundamental principles of antibody repertoire architecture revealed by large-scale network analysis

2017 ◽  
Author(s):  
Enkelejda Miho ◽  
Victor Greifft ◽  
Rok Roškar ◽  
Sai T. Reddy
Keyword(s):  
Network Analysis ◽  
B Cell ◽  
High Performance ◽  
Large Scale ◽  
High Throughput Sequencing ◽  
Antibody Repertoire ◽  
Sequencing Data ◽  
Cell Receptors ◽  
Computing Platform ◽  
Antibody Repertoires

ABSTRACTThe antibody repertoire is a vast and diverse collection of B-cell receptors and antibodies that confer protection against a plethora of pathogens. The architecture of the antibody repertoire, defined by the network similarity landscape of its sequences, is unknown. Here, we established a novel high-performance computing platform to construct large-scale networks from high-throughput sequencing data (>100’000 unique antibodies), in order to uncover the architecture of antibody repertoires. We identified three fundamental principles of antibody repertoire architecture across B-cell development: reproducibility, robustness and redundancy. Reproducibility of network structure explains clonal expansion and selection. Robustness ensures a functional immune response even under extensive loss of clones (50%). Redundancy in mutational pathways suggests that there is a pre-programmed evolvability in antibody repertoires. Our analysis provides guidelines for a quantitative network analysis of antibody repertoires, which can be applied to other facets of adaptive immunity (e.g., T cell receptors), and may direct the construction of synthetic repertoires for biomedical applications.

scholarly journals Large-scale Analysis of 2,152 dataset reveals key features of B cell biology and the antibody repertoire

2019 ◽  
Author(s):  
Xiujia Yang ◽  
Minhui Wang ◽  
Dianchun Shi ◽  
Yanfang Zhang ◽  
Huikun Zeng ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Cell Biology ◽  
Large Scale ◽  
Somatic Hypermutation ◽  
Population Level ◽  
Antibody Repertoire ◽  
V Genes ◽  
Gene Usage ◽  
Key Features

AbstractAntibody repertoire sequencing (Ig-seq) has been widely used in studying humoral responses, with promising results. However, the promise of Ig-seq has not yet been fully realized, and key features of the antibody repertoire remain elusive or controversial. To clarify these key features, we analyzed 2,152 high-quality heavy chain antibody repertoires, representing 582 donors and a total of 360 million clones. Our study revealed that individuals exhibit very similar gene usage patterns for germline V, D, and J genes and that 53 core V genes contribute to more than 99% of the heavy chain repertoire. We further found that genetic background is sufficient but not necessary to determine usage of V, D, and J genes. Although gene usage pattern is not affected by age, we observed a significant sex preference for 24 V genes, 9 D genes and 5 J genes, but found no positional bias for V-D and D-J recombination. In addition, we found that the number of observed clones that were shared between any two repertoires followed a linear model and noted that the mutability of hot/cold spots and single nucleotides within antibody genes suggested a strand-specific somatic hypermutation mechanism. This population-level analysis resolves some critical characteristics of the antibody repertoire and thus may serve as a reference for research aiming to unravel B cell-related biology or diseases. The metrics revealed here will be of significant value to the large cadre of scientists who study the antibody repertoire.

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