An analysis of B cell selection mechanisms in germinal centers

In order to target threatening pathogens, the adaptive immune system performs a continuous reorganization of its lymphocyte repertoire. Following an immune challenge, the B cell repertoire can evolve cells of increased specificity for the encountered strain. This process of affinity maturation generates a memory pool whose diversity and size remain difficult to predict. We assume that the immune system follows a strategy that maximizes the long-term immune coverage and minimi...

We present a model that considers the maturation of the antibody population following primary antigen presentation as a global optimization problem. The trade-off that emerges from our model describes the balance between the safety of mutations that lead to local improvements in affinity and the necessity of the system to undergo global reconfigurations in the antibody's shape in order to achieve its goals, in this example of fast-paced evolution. The parameter p which quanti...

B cells signaling in response to antigen is proportional to antigen affinity, a process known as affinity discrimination. Recent research suggests that B cells can acquire antigen in membrane-bound form on the surface of antigen-presenting cells (APCs), with signaling being initiated within a few seconds of B cell/APC contact. During the earliest stages of B cell/APC contact, B cell receptors (BCRs) on protrusions of the B cell surface bind to antigen on the APC surface and f...

The clustering of B cell receptor (BCR) molecules and the formation of the protein segregation structure known as the immunological synapse appears to precede antigen (Ag) uptake by B cells. The mature B cell synapse is characterized by a central cluster of BCR/Ag molecular complexes surrounded by a ring of LFA-1/ICAM-1 complexes. Recent experimental evidence shows receptor clustering in B cells can occur via mechanical or signaling-driven processes. An alternative mechanism ...

We analyze the interactions between division, mutation and selection in a simplified evolutionary model, assuming that the population observed can be classified into fitness levels. The construction of our mathematical framework is motivated by the modeling of antibody affinity maturation of B-cells in Germinal Centers during an immune response. This is a key process in adaptive immunity leading to the production of high affinity antibodies against a presented antigen. Our ai...

B cells encounter antigen over a wide affinity range. The strength of B cell signaling in response to antigen increases with affinity, a process known as "affinity discrimination". In this work, we use a computational simulation of B cell surface dynamics and signaling to show that affinity discrimination can arise from the formation of BCR oligomers. It is known that BCRs form oligomers upon encountering antigen, and that the size and rate of formation of these oligomers inc...

The antibody repertoire of each individual is continuously updated by the evolutionary process of B cell receptor mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B cell sequence data, and then apply them to a very deep short-read data set of B cell receptors. We find that the substitution process i...

We are interested in modeling theoretical immunology within a statistical mechanics flavor: focusing on the antigen-independent maturation process of B-cells, in this paper we try to revise the problem of self vs non-self discrimination by mature B lymphocytes. We consider only B lymphocytes: despite this is of course an oversimplification, however such a toy model may help to highlight features of their interactions otherwise shadowed by main driven mechanisms due to i.e. he...

Cells are known to exert forces to sense their physical surroundings for guidance of motion and fate decisions. Here, we propose that cells might do mechanical work to drive their own evolution, taking inspiration from the adaptive immune system. Growing evidence indicates that immune B cells - capable of rapid Darwinian evolution - use cytoskeletal forces to actively extract antigen from other cells' surface. To elucidate the evolutionary significance of force usage, we deve...

We present and study an agent-based model of T-Cell cross-regulation in the adaptive immune system, which we apply to binary classification. Our method expands an existing analytical model of T-cell cross-regulation (Carneiro et al. in Immunol Rev 216(1):48-68, 2007) that was used to study the self-organizing dynamics of a single population of T-Cells in interaction with an idealized antigen presenting cell capable of presenting a single antigen. With agent-based modeling we ...