B cell receptors and free antibodies have different antigen-binding kinetics.

Since the pioneering works of Berg and Purcell, discriminating between diffusion followed by binding has played a central role in understanding cell signaling. B cell receptors (BCR) and antibodies (Ab) challenge that simplified view as binding to the antigen follows after a chain of diffusion and rotations, including whole molecule rotation and independent tilts and twists of their Fab arms due to their Y-shaped structure and flexibility. In this paper, we combine analytical calculations with Brownian simulations to derive the first-passage times due to these three rotations positioning the Fab paratopes at a proper distance and orientation required for antigen binding.

Dynamically consistent objective and subjective rationality.

A group of experts, for instance climate scientists, is to advise a decision maker about the choice between two policies and . Consider the following decision rule. If all experts agree that the expected utility of is higher than the expected utility of , the unanimity rule applies, and is chosen.

A Method to Analyze Models of the Dynamics of Germinal Centers.

Germinal centers (GC) are dynamic, short-lived anatomical structures generated within lymphoid follicles during immune responses to protein-containing antigens. There, follicular dendritic cells, antigen-specific B cells, and follicular T helper cells engage with each other in an antigen dependent way, setting into play a mini-evolutionary ecosystem that ultimately lead to antibody affinity maturation, with the resulting GC reaction following a rise-and-fall dynamics. The complexity of the cell-to-cell interaction processes makes very difficult to mechanistically understand the GC dynamics.

Affinity Selection in Germinal Centers: Cautionary Tales and New Opportunities.

Our current quantitative knowledge of the kinetics of antibody-mediated immunity is partly based on idealized experiments throughout the last decades. However, new experimental techniques often render contradictory quantitative outcomes that shake previously uncontroversial assumptions. This has been the case in the field of T-cell receptors, where recent techniques for measuring the 2-dimensional rate constants of T-cell receptor-ligand interactions exposed results contradictory to those obtained with techniques measuring 3-dimensional interactions.

Ovarian aging increases small extracellular vesicle CD81 release in human follicular fluid and influences miRNA profiles.

Ovarian aging affects female reproductive potential and is characterized by alterations in proteins, mRNAs and non-coding RNAs inside the ovarian follicle. Ovarian somatic cells and the oocyte communicate with each other secreting different molecules into the follicular fluid, by extracellular vesicles. The cargo of follicular fluid vesicles may influence female reproductive ability; accordingly, analysis of extracellular vesicle content could provide information about the quality of the female germ cell.

A Sensitivity Analysis Comparison of Three Models for the Dynamics of Germinal Centers.

Germinal centers (GCs) are transient anatomical microenvironments where antibody affinity maturation and memory B cells generation takes place. In the past, models of Germinal Center (GC) dynamics have focused on understanding antibody affinity maturation rather than on the main mechanism(s) driving their rise-and-fall dynamics. Here, based on a population dynamics model core, we compare three mechanisms potentially responsible for this GC biphasic behavior dependent on follicular dendritic cell (FDC) maturation, follicular T helper (Tfh) cell maturation, and antigen depletion.

A unifying mathematical framework for experimental TCR-pMHC kinetic constants.

Receptor binding and triggering are central in Immunology as T cells activated through their T cell receptors (TCR) by protein antigens orchestrate immune responses. In order to understand receptor-ligand interactions, many groups working with different experimental techniques and assays have generated a vast body of knowledge during the last decades. However, in recent years a type of assays, referred to as two-dimensional or membrane-to-membrane, has questioned our current understanding of the role of different kinetic constants (for instance, on- versus off-rate constants) on TCR-ligand interaction and subsequent T cell activation.

T follicular helper and T follicular regulatory cells have different TCR specificity.

Immunization leads to the formation of germinal centres (GCs) that contain both T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Whether T-cell receptor (TCR) specificity defines the differential functions of Tfh and Tfr cells is unclear. Here we show that antigen-specific T cells after immunization are preferentially recruited to the GC to become Tfh cells, but not Tfr cells.

An automated algorithm for extracting functional immunologic V-genes from genomes in jawed vertebrates.

Variable (V) domains of immunoglobulins (Ig) and T cell receptors (TCR) are generated from genomic V gene segments (V-genes). At present, such V-genes have been annotated only within the genome of a few species. We have developed a bioinformatics tool that accelerates the task of identifying functional V-genes from genome datasets.

Software tool for 3D extraction of germinal centers.

Background: Germinal Centers (GC) are short-lived micro-anatomical structures, within lymphoid organs, where affinity maturation is initiated. Theoretical modeling of the dynamics of the GC reaction including follicular CD4+ T helper and the recently described follicular regulatory CD4+ T cell populations, predicts that the intensity and life span of such reactions is driven by both types of T cells, yet controlled primarily by follicular regulatory CD4+ T cells. In order to calibrate GC models, it is necessary to properly analyze the kinetics of GC sizes.

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

Background: The 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, several key pieces of information are needed, one in particular being the number of participating B cell clones. Since this clonal diversity cannot be observed directly, earlier studies resorted to interpreting two types of available experimental data: Immunohistology of GCs containing two phenotypically distinct B-cell populations, and antibody gene sequences of small B-cell samples from GCs.

Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells.

Follicular helper T (T(FH)) cells participate in humoral responses providing selection signals to germinal center B cells. Recently, expression of CXCR5, PD-1, and the transcription factor Bcl-6 has allowed the identification of T(FH) cells. We found that a proportion of follicular T cells, with phenotypic characteristics of T(FH) cells and expressing Foxp3, are recruited during the course of a germinal center (GC) reaction.

Assessing methods for blood cell cytotoxic responses to inorganic nanoparticles and nanoparticle aggregates.

Inorganic nanoparticles (NPs) show great potential for medicinal therapy. However, biocompatibility studies are essential to determine if they are safe. Here, five different NPs are compared for their cytotoxicity, internalization, aggregation in medium, and reactive oxygen species (ROS) production, using tumoral and normal human blood cells.

Immune responses to polysaccharides: lessons from humans and mice.

This review focuses on the immune response to non-conjugated and conjugated polysaccharide vaccines derived from encapsulated pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. Special attention is paid to a number of side effects observed following the use of some of these vaccines. For example, we discuss the long-lasting specific refractoriness induced by unconjugated polysaccharides, and the absence of an effective immune response in adults vaccinated with some conjugated vaccines.

When three is not a crowd: a Crossregulation model of the dynamics and repertoire selection of regulatory CD4+ T cells.

Regulatory CD4(+) T cells, enriched in the CD25 pool of healthy individuals, mediate natural tolerance and prevent autoimmune diseases. Despite their fundamental and potential clinical significance, regulatory T (T(R)) cells have not yet been incorporated in a coherent theory of the immune system. This article reviews experimental evidence and theoretical arguments supporting a model of T(R) cell dynamics, uncovering some of its most relevant biological implications.

Modelling two possible mechanisms for the regulation of the germinal center dynamics.

Research on the germinal center has tried to unravel the mechanisms that control its dynamics. In this study we focus on the termination of the germinal center reaction, which is still an open problem. We propose two hypothetical biological mechanisms that may be responsible for the control of germinal center dynamics and analyze them through mathematical models.

Re-evaluating the recycling hypothesis in the germinal centre.

Mathematical models have been used to study different aspects of the germinal centre reaction, in particular, affinity maturation of antibodies and the hypothesis of recycling. So far, interpretation of several theoretical and experimental results has pointed to the existence of recycling. However, theoretical models have seldom been compared with experimental data from specific immune responses and the potential relevance of recycling in the germinal centre is still an open problem.

A general mathematical framework to model generation structure in a population of asynchronously dividing cells.

In otherwise homogeneous cell populations, individual cells undergo asynchronous cell cycles. In recent years, interest in this fundamental observation has been boosted by the wide usage of CFSE, a fluorescent dye that allows the precise estimation by flow cytometry of the number of divisions performed by different cells in a population, and thus the generation structure. In this work, we propose two general mathematical frameworks to model the time evolution of generation structure in a cell population.

The impact of thymic antigen diversity on the size of the selected T cell repertoire.

The TCR repertoire of a normal animal is shaped in the thymus by ligand-specific positive- and negative-selection events. These processes are believed to be determined at the single-cell level primarily by the affinity of the TCR-ligand interactions. The relationships among all the variables involved are still unknown due to the complexity of the interactions and the lack of quantitative analysis of those parameters.

Inverse correlation between the incidences of autoimmune disease and infection predicted by a model of T cell mediated tolerance.

The contribution of pathogenic infections to the etiology of autoimmune diseases remains one of the outstanding problems in immunology. According to the classical concept of antigen mimicry, a direct correlation between the incidence of autoimmunity and infections would be expected. This view is supported by a few examples of autoimmune disorders, which are documented as being caused by infection with particular pathogens.