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 Entry of Francisella tularensis into Murine B Cells: The Role of B Cell Receptors and Complement Receptors

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0132571 ◽  
Author(s):  
Lenka Plzakova ◽  
Zuzana Krocova ◽  
Klara Kubelkova ◽  
Ales Macela
Keyword(s):  
B Cells ◽  
B Cell ◽  
Francisella Tularensis ◽  
B Cell Receptors ◽  
Complement Receptors ◽  
Cell Receptors

scholarly journals Autoreactive B Cell Receptors Mimic Autonomous Pre-B Cell Receptor Signaling and Induce Proliferation of Early B Cells

Immunity ◽  
2008 ◽  
Vol 29 (6) ◽  
pp. 912-921 ◽  
Author(s):  
Fabian Köhler ◽  
Eva Hug ◽  
Cathrin Eschbach ◽  
Sonja Meixlsperger ◽  
Elias Hobeika ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
B Cell Receptors ◽  
Receptor Signaling ◽  
Cell Receptors ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

scholarly journals Diverse Recombinant HIV-1 Envs Fail To Activate B Cells Expressing the Germline B Cell Receptors of the Broadly Neutralizing Anti-HIV-1 Antibodies PG9 and 447-52D

2013 ◽  
Vol 88 (5) ◽  
pp. 2645-2657 ◽  
Author(s):  
A. T. McGuire ◽  
J. A. Glenn ◽  
A. Lippy ◽  
L. Stamatatos ◽  
R. W. Doms
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Cell Receptors ◽  
Cell Receptors ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism

2010 ◽  
Vol 207 (2) ◽  
pp. 365-378 ◽  
Author(s):  
Dimitra Zotos ◽  
Jonathan M. Coquet ◽  
Yang Zhang ◽  
Amanda Light ◽  
Kathy D'Costa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Target Cells ◽  
B Cell Differentiation ◽  
Follicular Helper

Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.

Repertoire selection by pre-B-cell receptors and B-cell receptors, and genetic control of B-cell development from immature to mature B cells

2000 ◽  
Vol 175 (1) ◽  
pp. 33-46 ◽  
Author(s):  
Fritz Melchers ◽  
Edwin ten Boekel ◽  
Thomas Seidl ◽  
Xian Chu Kong ◽  
Tamotsu Yamagami ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Genetic Control ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Receptors ◽  
Cell Receptors ◽  
Repertoire Selection

scholarly journals Signal transduction through μκ B‐cell receptors expressed on pre‐B cells is different from that through B‐cell receptors on mature B cells

Immunology ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 593-599 ◽  
Author(s):  
T. NAKAMURA ◽  
M. KOYAMA ◽  
A. YONEYAMA ◽  
M. HIGASHIHARA ◽  
T. KAWAKAMI ◽  
...  
Keyword(s):  
Signal Transduction ◽  
B Cells ◽  
B Cell ◽  
B Cell Receptors ◽  
Cell Receptors

scholarly journals Altered Germinal-Center Metabolism in B Cells in Autoimmunity

Metabolites ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 40
Author(s):  
Ashton K. Shiraz ◽  
Eric J. Panther ◽  
Christopher M. Reilly
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Germinal Center ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Cell Metabolism ◽  
Affinity Maturation ◽  
B Cell Differentiation ◽  
Contributing Factors

B lymphocytes play an important role in the pathophysiology of many autoimmune disorders by producing autoantibodies, secreting cytokines, and presenting antigens. B cells undergo extreme physiological changes as they develop and differentiate. Aberrant function in tolerogenic checkpoints and the metabolic state of B cells might be the contributing factors to the dysfunctionality of autoimmune B cells. Understanding B-cell metabolism in autoimmunity is important as it can give rise to new treatments. Recent investigations have revealed that alterations in metabolism occur in the activation of B cells. Several reports have suggested that germinal center (GC) B cells of individuals with systemic lupus erythematosus (SLE) have altered metabolic function. GCs are unique microenvironments in which the delicate and complex process of B-cell affinity maturation occurs through somatic hypermutation (SHM) and class switching recombination (CSR) and where Bcl6 tightly regulates B-cell differentiation into memory B-cells or plasma cells. GC B cells rely heavily on glucose, fatty acids, and oxidative phosphorylation (OXPHOS) for their energy requirements. However, the complicated association between GC B cells and their metabolism is still not clearly understood. Here, we review several studies of B-cell metabolism, highlighting the significant transformations that occur in GC progression, and suggest possible approaches that may be investigated to more precisely target aberrant B-cell metabolism in SLE.

scholarly journals Molecular design, optimization and genomic integration of chimeric B cell receptors in murine B cells

2019 ◽  
Author(s):  
Theresa Pesch ◽  
Lucia Bonati ◽  
William Kelton ◽  
Cristina Parola ◽  
Roy A Ehling ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Design Optimization ◽  
Intracellular Signaling ◽  
Molecular Design ◽  
Recombinant Antibody ◽  
B Cell Receptors ◽  
Antigen Receptors ◽  
Cell Receptors ◽  
Genomic Integration

AbstractImmune cell therapies based on the integration of synthetic antigen receptors provide a powerful strategy for the treatment of diverse diseases, most notably retargeting T cells engineered to express chimeric antigen receptors (CAR) for cancer therapy. In addition to T lymphocytes, B lymphocytes may also represent valuable immune cells that can be engineered for therapeutic purposes such as protein replacement therapy or recombinant antibody production. In this article, we report a promising concept for the molecular design, optimization and genomic integration of a novel class of synthetic antigen receptors, chimeric B cell receptors (CBCR). We initially optimized CBCR expression and detection by modifying the extracellular surface tag, the transmembrane regions and intracellular signaling domains. For this purpose, we stably integrated a series of CBCR variants into immortalized B cell hybridomas using CRISPR-Cas9. Subsequently, we developed a reliable and consistent pipeline to precisely introduce cassettes of several kilobases size into the genome of primary murine B cells, again via CRISPR-Cas9 induced HDR. Finally, we were able to show the robust surface expression and antigen recognition of a synthetic CBCR in primary B cells. We anticipate that CBCRs and our approach for engineering primary B cells will be a valuable tool for the advancement of future B cell-based immune therapies.

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