Shaping Polyclonal Responses via Antigen-Mediated Antibody Interference

Yan, Le; Wang, Shenshen

doi:10.1016/j.isci.2020.101568

Cited by 7 publications

(9 citation statements)

References 75 publications

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“…Power-law statistics of lineages and the occurrence of elite neutralisers are commonly ascribed to antigenmediated selection on immune repertoires, often through multiple exposures [43,35,44,45,36]. Here we have shown that similar features can already emerge in the primary immune response to an acute infection, prior to any antigen-mediated selection effects.…”

Section: Discussionmentioning

confidence: 59%

Non-equilibrium antigen recognition in acute infections

Tovar

Lässig

2023

Preprint

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The immune response to an acute primary infection is a coupled process of antigen proliferation, molecular recognition by naive B-cells, and their subsequent proliferation and antibody shedding. Here we show B-cells can efficiently recognise new antigens by a tuned kinetic proofreading mechanism, where the number of proofreading steps and the characteristic rate of each step are set by the complexity of the immune repertoire. This process produces potent, specific and fast recognition of antigens, maintaining a spectrum of genetically distinct B-cell lineages as input for affinity maturation. We show that the proliferation-recognition dynamics of a primary infection can be mapped onto a generalised Luria-Delbrück process, akin to the dynamics of the classic fluctuation experiment. We derive the resulting statistics of the activated immune repertoire: antigen binding affinity, expected size, and frequency of active B-cell clones are related by power laws. Their exponents depend on the antigen and B-cell proliferation rate, the number of proofreading steps, and the lineage density of the naive repertoire. Empirical data of mouse immune repertoires are found to be consistent with activation involving at least three proofreading steps. Our model predicts key clinical characteristics of acute infections. The primary immune response to a given antigen is strongly heterogeneous across individuals; few elite responders are distinguished by early activation of high-affinity clones. Conversely, ageing of the immune system, by reducing the density of naive clones, degrades potency and speed of pathogen recognition.

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Section: Discussionmentioning

confidence: 59%

Non-equilibrium antigen recognition in acute infections

Tovar

Lässig

2023

Preprint

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“…4.1.5 we model this competition using an occlusion parameter o, with o = 0 for the fully noninteracting case, presented above, and o = 1 for the fully interacting (competing) case. We note that a similar approach to model clonal competition was used by Yan and Wang (45), who introduced interaction parameters to represent Ag binding interference from Abs produced by earlier generations of B-cells.…”

Section: Resultsmentioning

confidence: 99%

“…We note that the occlusion tensor is similar in spirit to the interaction matrix used by Yan and Wang (45). However, as these authors had a different purpose, specifically, to model synergistic vs. antagonistic effects of Abs derived from previous B cell lineages on B cells in the current generation, they allowed negative interference values, which are not physically justifiable in our model, as they would imply creation of Ag.…”

Section: Integration Of Model Equationsmentioning

confidence: 99%

A Coarse-Grained Model of Affinity Maturation Indicates the Importance of B-Cell Receptor Avidity in Epitope Subdominance

Ovchinnikov

Karplus

2022

Front. Immunol.

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The elicitation of broadly neutralizing antibodies (bnAbs) is a major goal in the design of vaccines against rapidly-mutating viruses. In the case of influenza, many bnAbs that target conserved epitopes on the stem of the hemagglutinin protein (HA) have been discovered. However, these antibodies are rare, are not boosted well upon reinfection, and often have low neutralization potency, compared to strain-specific antibodies directed to the HA head. Different hypotheses have been proposed to explain this phenomenon. We use a coarse-grained computational model of the germinal center reaction to investigate how B-cell receptor binding valency affects the growth and affinity maturation of competing B-cells. We find that receptors that are unable to bind antigen bivalently, and also those that do not bind antigen cooperatively, have significantly slower rates of growth, memory B-cell production, and, under certain conditions, rates of affinity maturation. The corresponding B-cells are predicted to be outcompeted by B-cells that bind bivalently and cooperatively. We use the model to explore strategies for a universal influenza vaccine, e.g., how to boost the concentrations of the slower growing cross-reactive antibodies directed to the stem. The results suggest that, upon natural reinfections subsequent to vaccination, the protectiveness of such vaccines would erode, possibly requiring regular boosts. Collectively, our results strongly support the importance of bivalent antibody binding in immunodominance, and suggest guidelines for developing a universal influenza vaccine.

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“…For instance, in the case of complex antigens composed of multiple epitopes, synergistic interactions among coevolving B cell lineages -e.g. through binding to allosterically coupled epitopes -can promote persistence of low-affinity clones [52]. Response to non-native antigen forms may also contribute [9].…”

Section: Discussionmentioning

confidence: 99%

Molecular tug of war reveals adaptive potential of an immune cell repertoire

Jiang¹,

Wang²

2022

Preprint

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The adaptive immune system constantly remodels its lymphocyte repertoire for better protection against future pathogens. Its ability to improve antigen recognition on the fly relies on somatic mutation and selective expansion of B lymphocytes expressing high-affinity antigen receptors. However, this Darwinian process inside an individual appears ineffective, hitting a modest ceiling of antigen-binding affinity. Experiment began to reveal that evolving B cells physically extract antigens from presenting cells and that the extraction level dictates clonal expansion; this challenges the prevailing assumption that the equilibrium constant of receptor-antigen binding determines selective advantage. We present a theoretical framework to explore whether, and how, such tug-of-war antigen extraction impacts the quality and diversity of an evolved B cell repertoire. We find that the apparent ineffectiveness of clonal selection can be a direct consequence of the non-equilibrium nature of antigen recognition. Our theory predicts that the physical strength of antigen tethering under tugging forces sets the affinity ceiling. Meanwhile, the model showed that, intriguingly, cells can use force variability to diversify binding phenotype without compromising fitness, thus remaining plastic under resource constraint. These results suggest that active probing of receptor quality via a molecular tug of war during antigen recognition limit the potency of response to the current antigen, but confer adaptive benefit for protection against future variants. Importantly, a saddle point in the fitness landscape of B cell-phenotype evolution emerges from the tug-of-war setting, which rationalizes multiple key phenomenology and puts forward a role of active physical dynamics in immune adaptation.

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Shaping Polyclonal Responses via Antigen-Mediated Antibody Interference

Cited by 7 publications

References 75 publications

Non-equilibrium antigen recognition in acute infections

Non-equilibrium antigen recognition in acute infections

A Coarse-Grained Model of Affinity Maturation Indicates the Importance of B-Cell Receptor Avidity in Epitope Subdominance

Molecular tug of war reveals adaptive potential of an immune cell repertoire

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