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

Faro, José; Haeften, B. von; Gardner, Rui; Faro, E.

doi:10.3389/fimmu.2019.02038

Cited by 10 publications

(10 citation statements)

References 64 publications

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“…The purpose was not to identify which parameters have the greatest impact on the models' quantitative output, for which we could have resorted to Latin hypercube sampling and quantitative sensitivity analysis as done by others (e.g. [25,26]). Our more immediate goal was to relax the parameter settings in order to detect potential mixed scenarios.…”

Section: The Decaying Envelope and Temporal Organisation Of The Ca-spmentioning

confidence: 99%

“…Our more immediate goal was to relax the parameter settings in order to detect potential mixed scenarios. Because our assessment of the model output is essentially a qualitative (binary) criterium of coherence with observations, the quantitative sensitivity analysis via partial rank correlation coefficients (as in [25]) or other methods (as in [26]) was not feasible. Based on these considerations, we devised a simple algorithm inspired on adaptive evolutionary dynamics to explore the parameter space.…”

Section: The Decaying Envelope and Temporal Organisation Of The Ca-spmentioning

confidence: 99%

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Modular analysis of the control of flagellar Ca2+-spike trains produced by CatSper and CaV channels in sea urchin sperm

et al. 2020

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Intracellular calcium ([Ca 2+ ] i) is a basic and ubiquitous cellular signal controlling a wide variety of biological processes. A remarkable example is the steering of sea urchin spermatozoa towards the conspecific egg by a spatially and temporally orchestrated series of [Ca 2+ ] i spikes. Although this process has been an experimental paradigm for reproduction and sperm chemotaxis studies, the composition and regulation of the signalling network underlying the cytosolic calcium fluctuations are hitherto not fully understood. Here, we used a differential equations model of the signalling network to assess which set of channels can explain the characteristic envelope and temporal organisation of the [Ca 2+ ] i-spike trains. The signalling network comprises an initial membrane hyperpolarisation produced by an Upstream module triggered by the egg-released chemoattractant peptide, via receptor activation, cGMP synthesis and decay. Followed by downstream modules leading to intraflagellar pH (pH i), voltage and [Ca 2+ ] i fluctuations. The Upstream module outputs were fitted to kinetic data on cGMP activity and early membrane potential changes measured in bulk cell populations. Two candidate modules featuring voltage-dependent Ca 2+-channels link these outputs to the downstream dynamics and can independently explain the typical decaying envelope and the progressive spacing of the spikes. In the first module, [Ca 2+ ] i-spike trains require the concerted action of a classical Ca V-like channel and a potassium channel, BK (Slo1), whereas the second module relies on pH i-dependent CatSper dynamics articulated with voltage-dependent neutral sodium-proton exchanger (NHE). We analysed the dynamics of these two modules alone and in mixed scenarios. We show that the [Ca 2+ ] i dynamics observed experimentally after sustained alkalinisation can be reproduced by a model featuring the Cat-Sper and NHE module but not by those including the pH-independent Ca V and BK module or proportionate mixed scenarios. We conclude in favour of the module containing CatSper and NHE and highlight experimentally testable predictions that would corroborate this conclusion.

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Section: The Decaying Envelope and Temporal Organisation Of The Ca-spmentioning

confidence: 99%

Section: The Decaying Envelope and Temporal Organisation Of The Ca-spmentioning

confidence: 99%

Modular analysis of the control of flagellar Ca2+-spike trains produced by CatSper and CaV channels in sea urchin sperm

et al. 2020

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“…In general, the system’s response to the force will be determined by the sensitivity of the parameters with respect to the applied force. The sensitivity

, of the variable X with respect to f [ 57 , 58 ] is defined as:

…”

Section: Is There a Role For Catch-bonds In Bcr–ligand Interactions?mentioning

confidence: 99%

Affinity Selection in Germinal Centers: Cautionary Tales and New Opportunities

Faro

Castro

2021

Cells

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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. Recently, we have developed a mathematical framework to rationalize those discrepancies, focusing on the proper fine-grained description of the underlying kinetic steps involved in the immune synapse. In this perspective article, we apply this approach to unveil potential blind spots in the case of B-cell receptors (BCR) and to rethink the interactions between B cells and follicular dendritic cells (FDC) during the germinal center (GC) reaction. Also, we elaborate on the concept of “catch bonds” and on the recent observations that B-cell synapses retract and pull antigen generating a “retracting force”, and propose some testable predictions that can lead to future research.

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“…In general, the system's response to the force will be determined by the sensitivity of the parameters with respect to the applied force. The sensitivity σ X ( f ), of the variable X with respect to f [57,58] is defined as:…”

Section: Conditions For the Existence Of Catch-slip Bonds In Bcr-ag Interactionsmentioning

confidence: 99%

Affinity selection in germinal centers: Cautionary tales and new opportunities

Faro

Castro

2021

Preprint

Self Cite

View full text Add to dashboard Cite

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 contradictory results to those obtained with techniques measuring 3-dimensional interactions. Recently, we have developed a mathematical framework to rationalize those discrepancies focusing on the proper fine-grained description of the underlying kinetic steps involved in the immune synapse. In this perspective article, we apply this approach to unveil potential blind spots in the case of B-cell receptors (BCR) and to rethink the interactions between B cells and follicular dendritic cells (FDC) during the germinal center (GC) reaction. Also, we elaborate on the concept of "catch bonds" and on the recent observations that B-cell synapses retract and pull antigen generating a "retracting force", and propose some testable predictions that can lead to future research.

show abstract

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

Cited by 10 publications

References 64 publications

Modular analysis of the control of flagellar Ca2+-spike trains produced by CatSper and CaV channels in sea urchin sperm

Modular analysis of the control of flagellar Ca2+-spike trains produced by CatSper and CaV channels in sea urchin sperm

Affinity Selection in Germinal Centers: Cautionary Tales and New Opportunities

Affinity selection in germinal centers: Cautionary tales and new opportunities

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