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Monte Carlo study of B-cell receptor clustering mediated by antigen crosslinking and directed transport

Cellular & Molecular Immunology 2011年第3期8卷 255-264页

作者： A Srinivas Reddy philippos k tsourkas Subhadip Raychaudhuri Department of Biomedical Engineering University of California DavisDavisUSA Biophysics Graduate Group University of California DavisDavisUSA Graduate Group in Applied Mathematics University of California DavisDavisUSA

It is known from experiments that in the presence of soluble antigen,B-cell receptors(BCRs)assemble into microclusters and then collect into a macrocluster known as a‘cap’.However,the mechanisms of BCR cluster formation during recognition of soluble antigens remain *** previous work,we demonstrated that effective intrinsic attractions among BCRs can lead to the formation of small microclusters of BCR *** effective intrinsic attractions could be caused by multivalent antigen binding,association with lipid rafts,or other biochemical *** the present study,we have developed and studied a Monte Carlo model of BCR clustering mediated by explicit binding and crosslinking of soluble bivalent *** crosslinking is shown to microcluster BCRs in an affinity-dependent manner and also in a biologically relevant timescale;however,antigen crosslinking alone does not appear to be sufficient for the formation of a single macrocluster of receptor *** show that directed transport of BCRs is needed to drive the formation of large *** constructed a simple model of directed transport,where BCR molecules diffuse towards the largest cluster or towards a random BCR microcluster,which results in a single macrocluster of receptor *** mechanisms for both types of directed transport are compared using network-based *** also develop and use appropriate network measures to analyze the effect of BCR and antigen concentration on BCR clustering,the stability of the formed clusters over time and the size of BCR–antigen crosslinked chains.

关键词： B-cell activation B-cell receptor cell signaling Monte Carlo simulation receptor clustering

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Discrimination of membrane antigen affinity by B cells requires dominance of kinetic proofreading over serial engagement

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Cellular & Molecular Immunology 2012年第1期9卷 62-74页

作者： philippos k tsourkas Wanli Liu Somkanya C Das Susan k Pierce Subhadip Raychaudhuri Department of Biomedical Engineering University of CaliforniaDavisCAUSA Laboratory of Immunogenetics National Institute of Allergy and Infectious DiseasesNational Institutes of HealthRockvilleMDUSA

B-cell receptor signaling in response to membrane-bound antigen increases with antigen affinity,a process known as affinity *** use computational modeling to show that B-cell affinity discrimination requires that kinetic proofreading predominate over serial *** find that if B-cell receptors become signaling-capable immediately upon antigen binding,which results in decreasing serial engagement as affinity increases,then increasing affinity can lead to weaker ***,antigen must stay bound to B-cell receptors for a threshold time of several seconds before becoming signaling-capable,a process similar to kinetic *** process overcomes the loss in serial engagement due to increasing antigen affinity,and replicates the monotonic increase in B-cell signaling with increasing affinity that has been observed in B-cell activation *** finding matches well with the experimentally observed time(,20 s)required for the B-cell receptor signaling domains to undergo antigen and lipid raft-mediated conformational changes that lead to Src-family kinase *** hypothesize that the physical basis for a threshold time of antigen binding might lie in the formation timescale of B-cell receptor *** time required for dimer formation decreases with increasing antigen affinity,thereby resulting in shorter threshold antigen binding times as affinity *** an affinity-dependent kinetic proofreading requirement results in affinity discrimination very similar to that observed in biological experiments.B-cell affinity discrimination is critical to the process of affinity maturation and the production of high-affinity antibodies,and thus our results have important implications in applications such as vaccine design.

关键词： computational modeling Monte Carlo lymphocyte signaling Lyn Syk

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