Gap junction-mediated antigen transport in immune responses

Handel, Andreas; Yates, Andrew J.; Pilyugin, Sergei S.; Antia, Rustom

doi:10.1016/j.it.2007.08.006

Cited by 23 publications

(20 citation statements)

References 49 publications

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“…The function of these gap junctions has been attributed to synchronizing both electrotonic and metabolic functions in different tissues. They are found in all organs and in most cells of solid tissues, including the lympho-reticular systems at certain times in their development and function (43). In general, GJIC appears to be critical for the control of cell pro-liferation (38), development and differentiation (44), apoptosis (45).…”

Section: Multiple Hypothesis Of Carcinogenesismentioning

confidence: 99%

Evolution of Energy Metabolism, Stem Cells and Cancer Stem Cells: How the Warburg and Barker Hypotheses Might Be Linked

Trosko

Kang²

2012

Int J Stem Cells

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The evolutionary transition from single cells to the metazoan forced the appearance of adult stem cells and a hypoxic niche, when oxygenation of the environment forced the appearance of oxidative phosphorylation from that of glycolysis. The prevailing paradigm in the cancer field is that cancers start from the "immortalization" or "re-programming" of a normal, differentiated cell with many mitochondria, that metabolize via oxidative phosphorylation. This paradigm has been challenged with one that assumes that the target cell for carcinogenesis is the normal, immortal adult stem cell, with few mitochondria. This adult organ-specific stem cell is blocked from "mortalizing" or from "programming" to be terminally differentiated. Two hypotheses have been offered to explain cancers, namely, the "stem cell theory" and the "de-differentiation" or "re-programming" theory. This Commentary postulates that the paleochemistry of the oceans, which, initially, provided conditions for life's energy to arise via glycolysis, changed to oxidative phosphorylation for life's processes. In doing so, stem cells evolved, within hypoxic niches, to protect the species germinal and somatic genomes. This Commentary provides support for the "stem cell theory", in that cancer cells, which, unlike differentiated cells, have few mitochondria and metabolize via glycolysis. The major argument against the "de-differentiation theory" is that, if re-programming of a differentiated cell to an "induced pluri-potent stem cell" happened in an adult, teratomas, rather than carcinomas, should be the result.

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Section: Multiple Hypothesis Of Carcinogenesismentioning

confidence: 99%

Evolution of Energy Metabolism, Stem Cells and Cancer Stem Cells: How the Warburg and Barker Hypotheses Might Be Linked

Trosko

Kang²

2012

Int J Stem Cells

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“…How exactly this would affect our system is not immediately obvious. The fitness measurement as defined here, namely area under the virus load curve, does not depend on details such as proximity between uninfected and infected cells [93,96], kinetic features such as speed of infection spread [94] or potentially oscillatory behaviour for persistent infections [92]. We expect that while a rsif.royalsocietypublishing.org J. R. Soc.…”

Section: Discussionmentioning

confidence: 99%

How sticky should a virus be? The impact of virus binding and release on transmission fitness using influenza as an example

Handel

Akin

Pilyugin

et al. 2014

J. R. Soc. Interface.

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Budding viruses face a trade-off: virions need to efficiently attach to and enter uninfected cells while newly generated virions need to efficiently detach from infected cells. The right balance between attachment and detachment-the right amount of stickiness-is needed for maximum fitness. Here, we design and analyse a mathematical model to study in detail the impact of attachment and detachment rates on virus fitness. We apply our model to influenza, where stickiness is determined by a balance of the haemagglutinin (HA) and neuraminidase (NA) proteins. We investigate how drugs, the adaptive immune response and vaccines impact influenza stickiness and fitness. Our model suggests that the location in the 'stickiness landscape' of the virus determines how well interventions such as drugs or vaccines are expected to work. We discuss why hypothetical NA enhancer drugs might occasionally perform better than the currently available NA inhibitors in reducing virus fitness. We show that an increased antibody or T-cell-mediated immune response leads to maximum fitness at higher stickiness. We further show that antibody-based vaccines targeting mainly HA or NA, which leads to a shift in stickiness, might reduce virus fitness above what can be achieved by the direct immunological action of the vaccine. Overall, our findings provide potentially useful conceptual insights for future vaccine and drug development and can be applied to other budding viruses beyond influenza.

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“…Since the diffusion time scales with the square of the distance, the increase in diffusion time can be large (Handel et al 2007a). The FB idea is a fundamentally spatial mechanism; therefore, a spatial model is required to properly study it.…”

Section: Gmat Is Beneficial In a Spatially Structured Systemmentioning

confidence: 99%

“…Since DC need to present viral antigen to activate T cells, but are not always infected by the virus, they need to acquire antigen by different mechanisms, a process termed cross-presentation (Cresswell et al 2005;Trombetta & Mellman 2005). Several pathways for cross-presentation are known (Heath et al 2004;Yewdell & Haeryfar 2005); GMAT might be another such pathway ( Neijssen et al 2005;Handel et al 2007a).…”

Section: Introductionmentioning

confidence: 99%

“…We suggested previously that the effect of such a FB mechanism would be most marked for densely packed target cells and slowly diffusing virions (Handel et al 2007a). Here, we use two models, one based on ordinary differential equations (ODE) and the other based on a spatially explicit, agent-based model (ABM), to further explore the potential impact of GMAT during immune responses.…”

Section: Introductionmentioning

confidence: 99%

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Sharing the burden: antigen transport and firebreaks in immune responses

Handel

Yates

Pilyugin

et al. 2008

J. R. Soc. Interface.

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Communication between cells is crucial for immune responses. An important means of communication during viral infections is the presentation of viral antigen on the surface of an infected cell. Recently, it has been shown that antigen can be shared between infected and uninfected cells through gap junctions, connexin-based channels, that allow the transport of small molecules. The uninfected cell receiving antigen can present it on its surface. Cells presenting viral antigen are detected and killed by cytotoxic T lymphocytes. The killing of uninfected cells can lead to increased immunopathology. However, the immune response might also profit from killing those uninfected bystander cells. One benefit might be the removal of future 'virus factories'. Another benefit might be through the creation of 'firebreaks', areas void of target cells, which increase the diffusion time of free virions, making their clearance more likely. Here, we use theoretical models and simulations to explore how the mechanism of gap junction-mediated antigen transport (GMAT) affects the dynamics of the virus and immune response. We show that under the assumption of a well-mixed system, GMAT leads to increased immunopathology, which always outweighs the benefit of reduced virus production due to the removal of future virus factories. By contrast, a spatially explicit model leads to quite different results. Here we find that the firebreak mechanism reduces both viral load and immunopathology. Our study thus shows the potential benefits of GMAT and illustrates how spatial effects may be crucial for the quantitative understanding of infection dynamics and immune responses.

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Gap junction-mediated antigen transport in immune responses

Cited by 23 publications

References 49 publications

Evolution of Energy Metabolism, Stem Cells and Cancer Stem Cells: How the Warburg and Barker Hypotheses Might Be Linked

Evolution of Energy Metabolism, Stem Cells and Cancer Stem Cells: How the Warburg and Barker Hypotheses Might Be Linked

How sticky should a virus be? The impact of virus binding and release on transmission fitness using influenza as an example

Sharing the burden: antigen transport and firebreaks in immune responses

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