Recirculation of germinal center B cells: a multilevel selection strategy for antibody maturation

  title={Recirculation of germinal center B cells: a multilevel selection strategy for antibody maturation},
  author={Michal Or-Guil and Nicole Wittenbrink and Armin A. Weiser and Johannes Schuchhardt},
  journal={Immunological Reviews},
Summary:  Optimization of antibody affinity is a hallmark of the humoral immune response. It takes place in hundreds of transient microstructures called germinal centers (GCs). Their function and time‐dependent behavior are subjects of active investigation. According to a generally accepted notion, their individual kinetics follows the average kinetics of all GCs present in the observed lymphatic tissue. In this review, we challenge this view and point out, with the help of mathematical… 

Broad Volume Distributions Indicate Nonsynchronized Growth and Suggest Sudden Collapses of Germinal Center B Cell Populations

This model succeeds in reproducing the empirical average kinetics of GC volumes as well as the underlying broad size distributions, indicating that individual GCs certainly do not obey the average time course of the GC volumes and that their growth is nonsynchronized.

How oligoclonal are germinal centers? A new method for estimating clonal diversity from immunohistological sections

BackgroundThe germinal center (GC) reaction leads to antibody affinity maturation and generation of memory B cells, but its underlying mechanisms are poorly understood. To assemble this puzzle,

Reassessing Germinal Centre Reaction Concepts

An extended mathematical model is proposed that includes an estimation of errors created by data sampling, two new parameters that take into account possible mistakes in classification of single population GC sections, and the likely variability in the number of seeding B cells.

PopulationsSudden Collapses of Germinal Center B Cell Nonsynchronized Growth and Suggest Broad Volume Distributions Indicate

A computer-aided three-dimensional reconstructions of splenic GCs to measure size distributions at consecutive time points following immunization with a conjugate of 2-phenyl-oxazolone and chicken serum albumin reveals a broad volume distribution of GCs, indicating that individual GCs certainly do not obey the average time course of the GC volumes and that their growth is nonsynchronized.

A Major Hindrance in Antibody Affinity Maturation Investigation: We Never Succeeded in Falsifying the Hypothesis of Single-Step Selection

The single-step selection concept is proposed to be a null-hypothesis which should be attempted to be falsified, and the focus on a process of random non-directed acquisition of mutations, which minimizes the need for unverified assumptions.

Computational Model Reveals Limited Correlation between Germinal Center B-Cell Subclone Abundancy and Affinity: Implications for Repertoire Sequencing

A computational model that simulates affinity maturation in a single GC while tracking individual subclones in terms of abundancy and affinity is developed and suggests that selecting highly abundant subClones from repertoire sequencing experiments would not always lead to the high(est) affinity B cells.

Optimality of Mutation and Selection in Germinal Centers

A coarse-grained model is presented to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement.



Dynamics of one-pass germinal center models: Implications for affinity maturation

This work addresses the question of whether a mechanism in which mutants are generated and then selected in one pass, with no post-selection amplification, can account for the observed efficiency of affinity maturation, and analyses a set of one-pass models of the germinal center reaction, with decaying antigen, and mutation occurring at transcription or at replication.

The Development of B Cells and the B‐Cell Repertoire in the Microenvironment of the Germinal Center

  • C. Berek
  • Biology, Medicine
    Immunological reviews
  • 1992
The interaction of T,| cells with antigen-activated B cells and antigen-presenting cells initiates a cascade of as yet poorly understood reactions which leads to the maturation of the immune response and the development of memory cells.

A mathematical model for germinal centre kinetics and affinity maturation.

It is shown that antigen masking by antibodies which are produced by emerging plasma cells can drive affinity maturation and provide a feedback mechanism by which the reaction is stable against variations in the initial antigen amount over several orders of magnitude.

Imaging of Germinal Center Selection Events During Affinity Maturation

Using two-photon microscopy of mouse lymph nodes, it is revealed that GC B cells are highly motile and extend long cell processes, and a model in which competition for T cell help plays a more dominant role in the selection of GC B Cells is proposed.

A mathematical model on germinal center kinetics and termination.

It is found that GC T cells play a major role in GC formation, but that the maintenance of established GC reactions requires very few T cells only and that the termination of a GC reaction is largely caused by lack of Ag on the follicular dendritic cells and is hardly influenced by Th cells.

An analysis of B cell selection mechanisms in germinal centers.

It is shown that for physiologically reasonable parameter values affinity maturation can be driven by competition for neither binding sites nor antigen--even in the presence of competing secreted antibodies.

Somatic hypermutation in B cells: an optimal control treatment.

The results show that the optimum mutation schedule is one with brief bursts of high mutation rates interspersed between periods of mutation-free growth, and this model provides a framework within which the anatomy and kinetics of the germinal center reaction can be understood.

Identification of Murine Germinal Center B Cell Subsets Defined by the Expression of Surface Isotypes and Differentiation Antigens1

The murine GC compartment was resolved into subsets based on the differential expression of activation markers, surface Ig isotypes, and differentiation Ags, and Expression of the activation marker BLA-1 was dynamic over time, with all GC B cells being positive early after immunization, followed by progressive loss as the GC reaction matured into the second and third week.

Germinal centre B cells: antigen specificity and changes in heavy chain class expression

It is demonstrated that germinal centres are a major site of proliferation and differentiation of antigen-specific B cells in vivo, and suggested that the Germinal centre microenvironment may have an important role in heavy chain class switching during B-cell responses.