An analysis of B cell selection mechanisms in germinal centers

Many events in the vertebrate immune system are influenced by some element of chance. The objective of the present work is to describe affinity maturation of B lymphocytes (in which random events are perhaps the most characteristic), and to study a possible network model of immune memory. In our model stochastic processes govern all events. A major novelty of this approach is that it permits studying random variations in the immune process. Four basic components are simulated...

B cells receptor (BCR) signaling in response to membrane-bound antigen increases with antigen affinity, a process known as affinity discrimination. We use computational modeling to show that B cell affinity discrimination requires that kinetic proofreading predominate over serial engagement. We find that if BCR molecules become signaling-capable immediately upon binding antigen, the loss in serial engagement as affinity increases results in weaker signaling with increasing af...

The specific morphology of germinal centers is analyzed in the context of the optimization of the humoral immune response. The relevance of dark and light zones for the affinity maturation process is investigated in the framework of a theoretical model for the germinal center reaction. Especially, it is shown that an intermediate appearance of dark zones in germinal center reactions is advantageous for the process of antibody optimization. Methodological aspects are discussed...

Affinity Maturation (AM) is the process through which the immune system is able to develop potent antibodies against new pathogens it encounters, and is at the base of the efficacy of vaccines. At its core AM is analogous to a Darwinian evolutionary process, where B-cells mutate and are selected on the base of their affinity for an Antigen (Ag), and Ag availability tunes the selective pressure. In cases when this selective pressure is high the number of B-cells might quickly ...

We study the maturation of the antibody population following primary antigen presentation as a global optimization problem. Emphasis is placed on the trade-off between the safety of mutations that lead to local improvements to the antibody's affinity and the necessity of eventual mutations that result in global reconfigurations in the antibody's shape. The model described herein gives evidence of the underlying optimization process from which the rapidity and consistency of t...

The affinity of antibodies (Abs) produced in vivo for their target antigens (Ags) is typically well below the maximum affinity possible. Nearly 25 years ago, Foote and Eisen explained how an 'affinity ceiling' could arise from constraints associated with the acquisition of soluble antigen by B cells. However, recent studies have shown that B cells in germinal centers (where Ab affinity maturation occurs) acquire Ag not in soluble form but presented as receptor-bound immune co...

The adaptive immune system relies on the diversity of receptors expressed on the surface of B and T-cells to protect the organism from a vast amount of pathogenic threats. The proliferation and degradation dynamics of different cell types (B cells, T cells, naive, memory) is governed by a variety of antigenic and environmental signals, yet the observed clone sizes follow a universal power law distribution. Guided by this reproducibility we propose effective models of somatic ...

The clonal expansion of T cells during an infection is tightly regulated to ensure an appropriate immune response against invading pathogens. Although experiments have mapped the trajectory from expansion to contraction, the interplay between mechanisms that control this response are not fully understood. Based on experimental data, we propose a model in which the dynamics of CD4+ T cell expansion is controlled through the interactions between T cells and antigen-presenting c...

Lymphocyte selection is a fundamental operation of adaptive immunity. In order to produce B-lymphocytes with a desired antigenic profile, a process of mutation-selection occurs in the germinal center, which is part of the lymph nodes. We introduce in this article a simplified mathematical model of this process, taking into account the main mechanisms of division, mutation and selection. This model is written as a non-linear, non-local, inhomogeneous second order partial diffe...

The evolution of the adaptive immune system is characterized by changes in the relative abundances of the B- and T-cell clones that make up its repertoires. To fully capture this evolution, we need to describe the complex dynamics of the response to pathogenic and self-antigenic stimulations, as well as the statistics of novel lymphocyte receptors introduced throughout life. Recent experiments, ranging from high-throughput immune repertoire sequencing to quantification of the...