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.

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 Identification of Tumor-Reactive B Cells and Systemic IgG in Breast Cancer Based on Clonal Frequency in the Sentinel Lymph Node

2017 ◽  
Author(s):  
Jonathan R. McDaniel ◽  
Stephanie C. Pero ◽  
William N. Voss ◽  
Girja S. Shukla ◽  
Yujing Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
B Cells ◽  
Sentinel Lymph Node ◽  
B Cell ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
High Throughput ◽  
Affinity Maturation ◽  
Breast Cancer Patients

ABSTRACTA better understanding of antitumor immune responses is key to advancing the field of cancer immunotherapy. Endogenous immunity in cancer patients, such as circulating anticancer antibodies or tumor-reactive B cells, has been historically yet incompletely described. Here, we demonstrate that tumor-draining (sentinel) lymph node (SN) is a rich source for tumor-reactive B cells that give rise to systemic IgG anticancer antibodies circulating in the bloodstream of breast cancer patients. Using a synergistic combination of high-throughput B-cell sequencing and quantitative immunoproteomics, we describe the prospective identification of tumor-reactive SN B cells (based on clonal frequency) and also demonstrate an unequivocal link between affinity-matured expanded B-cell clones in the SN and antitumor IgG in the blood. This technology could facilitate the discovery of antitumor antibody therapeutics and conceivably identify novel tumor antigens. Lastly, these findings highlight the unique and specialized niche the SN can fill in the advancement of cancer immunotherapy.SIGNIFICANCEUsing high-throughput molecular cloning and antibody proteomics to study coordinated antitumor immunity in breast cancer patients, we simultaneously demonstrate that the sentinel lymph node is a localized source of expanded antitumor B cells undergoing affinity maturation and that their secreted antibodies are abundant as systemic IgG circulating in blood.

scholarly journals Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1448 ◽  
Author(s):  
Aurélien Pélissier ◽  
Youcef Akrout ◽  
Katharina Jahn  ◽  
Jack Kuipers  ◽  
Ulf Klein  ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Phylogenetic Trees ◽  
Clonal Diversity ◽  
Quantitative Model ◽  
Affinity Maturation ◽  
B Cell Receptors ◽  
Cellular Interactions ◽  
B Cell Differentiation ◽  
Cell Receptors

Germinal centers (GCs) are specialized compartments within the secondary lymphoid organs where B cells proliferate, differentiate, and mutate their antibody genes in response to the presence of foreign antigens. Through the GC lifespan, interclonal competition between B cells leads to increased affinity of the B cell receptors for antigens accompanied by a loss of clonal diversity, although the mechanisms underlying clonal dynamics are not completely understood. We present here a multi-scale quantitative model of the GC reaction that integrates an intracellular component, accounting for the genetic events that shape B cell differentiation, and an extracellular stochastic component, which accounts for the random cellular interactions within the GC. In addition, B cell receptors are represented as sequences of nucleotides that mature and diversify through somatic hypermutations. We exploit extensive experimental characterizations of the GC dynamics to parameterize our model, and visualize affinity maturation by means of evolutionary phylogenetic trees. Our explicit modeling of B cell maturation enables us to characterise the evolutionary processes and competition at the heart of the GC dynamics, and explains the emergence of clonal dominance as a result of initially small stochastic advantages in the affinity to antigen. Interestingly, a subset of the GC undergoes massive expansion of higher-affinity B cell variants (clonal bursts), leading to a loss of clonal diversity at a significantly faster rate than in GCs that do not exhibit clonal dominance. Our work contributes towards an in silico vaccine design, and has implications for the better understanding of the mechanisms underlying autoimmune disease and GC-derived lymphomas.

scholarly journals Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation

2017 ◽  
Vol 215 (1) ◽  
pp. 77-90 ◽  
Author(s):  
Jared Silver ◽  
Teng Zuo ◽  
Neha Chaudhary ◽  
Rupa Kumari ◽  
Pei Tong ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
De Novo ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
B Cell Receptors ◽  
Antibody Affinity ◽  
V Region ◽  
Combinatorial Assembly

Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, whether stochastic activation of noncognate B cells can generate new affinity to antigen in GCs is unclear. Using a mouse model whose knock-in BCR does not functionally engage with immunizing antigen, we found that chronic immunization induced antigen-specific serological responses with diverse SHM-mediated antibody affinity maturation pathways and divergent epitope targeting. Thus, intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement.

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.

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