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To register, please email s.green
 immunology.org
Information
Registration from 08:30
Speakers
- 9:00-9:30 coffee
- 9:30-10:30
Vijay Subramanian (Hamilton Institute)
An Analysis of the Cyton Model Using Branching Processes
Rather, What Can One Do With the Analysis?
Abstract: Starting with a brief introduction to a cell-level stochastic model of
lymphocyte population dynamics called the Cyton Model, we will present
a refined analysis using Branching Processes.
The Cyton Model was introduced by Hawkins et al. (Proc. Natl. Acad. Sci. USA
104, 503instance the model assumed stochastically independent values for division and
survival times for each cell in a responding population, as well as an independence
across generation. The model was further refined using detailed cine-lapse
photography by Hawkins et al. (Proc. Natl. Acad. Sci. USA 106, 13457-13462,
2009), where it was demonstrated that the fates of cells in the same family tree
are not stochastically independent.
Using a generalization to the Bellman-Harris process, we show how one can
derive all the moments of the number of lymphocytes at any given time. Along
the way we will demonstrate how the correlations revealed by cine-lapse
photography can be incorporated. Armed with the moments, we then proceed,
in some detail, to showing their value in constraining the parameters of the model
when using techniques like bootstrap.
- 10:30-11:30
Michal Or-Guil (Berlin)
Aspects of modelling antibody affinity maturation in germinal centres
Central to the humoural immune response is the micro-evolutionary
process of B cell affinity maturation that leads to the generation of
high affinity antibodies. Affinity maturation takes place in dynamic
microstructures called germinal centres that form during T cell
dependent immune responses. There, B cells undergo rapid
proliferation, somatic hypermutation, and selection of cells bearing
high-affinity B cell receptors. Since long, mathematical models have
been used as a tool to interpret experimental observations, aiming at
unveiling mechanistic details of this evolutionary process. We give a
short introduction to the aspects of B cell biology and antibody
affinity maturation, to then review successes and limits of
mathematical modelling. We discuss some of the challenges posed on
modelling and on the generation of experimental data that need to be
overcome to unveil the protein evolution aspects of affinity
maturation.
- 11:30-12:00 coffee
- 12:00-1:00
David Kipling (Cardiff)
Modelling accelerated replicative senescence in a human premature ageing syndrome
Most normal human cells do not have an infinite ability to
proliferate, but rather undergo a limited number of cell divisions
before entering a viable but non-dividing state called replicative
senescence. Although well studied as an in vitro phenomenon, it has
only been recently that direct demonstrations of the occurrence of
senescent cells in human tissue, and their accumulation with age, has
been obtained. Replicative senescence is hypothesised to be one of
several basic ageing mechanisms that underpin age-related disease and
degeneration in later life. Understanding the causes and consequences
of cell senescence will thus help develop new therapies against these
conditions.
Much is now known about the signalling pathways that link cell division to replicative senescence. In particular, the gradual erosion of chromosomal telomeres in telomerase-negative normal human cells is a widely cell division that triggers cell cycle arrest through the recognition of uncapped telomeres as a signal to the DNA damage response pathway.
In human Werner syndrome (a rare genetic syndrome associated with null mutations in a recQ DNA helicase) the ageing of the individual occurs much faster, and this is paralleled by accelerated cellular senescence of cells from Werner patients in the laboratory. A plausible hypothesis is that the accelerated cell senescence is causal (directly or indirectly) in the premature ageing of these patients. A key question that we have been addressing is the cellular mechanism linking loss of the recQ helicase to premature senescence. Recently we have shown a major role for the p38MAPK stress signalling pathway in this accelerated senescence. Inhibition of this pathway using small molecule drugs is able to prevent the premature senescence of WS fibroblasts.
A central feature of this system is the interplay between several
signalling pathways (p53, p38, pRb etc) downstream of multiple cell
intrinsic and extrinsic signals. Some of these signals are
potentially continuous and quantitative in nature, others are of a
more stochastic nature. All must be integrated in order that the
decision to undergo cell division (or not) can be taken. A simple
simulation environment that blends both progressive and stochastic
signals, including a detailed modelling of the biology of telomere
erosion and inheritance dynamics, will be presented and used to
explore the mechanism whereby a stochastic telomere-independent signal
(from p38MAPK, related to replication stress) can synergise with
progressive telomere erosion so as to generate the differential
phenotype of WS cells observed in culture.
This simulation environment can be readily adapted to reflect other
biological scenarios, such as the developmental stage-dependent
variability in telomerase activity that is characteristic of
lymphocytes, and provides a mechanism to explore the complex interplay
of signalling and population-level selection in cultures of primary
human cells.
(David Kipling, Terry Davis and Mark Bagley
Schools of Medicine and Chemistry, Cardiff University)
1:00-2:00 lunch
- 2:00-3:00
Deborah Dunn-Walters (Kings College)
B cell repertoire analysis in health and disease
Much of the success of the adaptive immune system lies in the
diversity of the lymphocyte repertoire, enabling the recognition of a
huge range of different antigens. Diversity of the B cell
receptor/antibodies is initially achieved by rearrangement of germline
genes in bone marrow precursor cells. One antibody is made up of two
different rearranged genes - a heavy chain and a light chain. The
heavy chain gene comprises a V (variable), D (diversity) and J
(joining) region, together with a C (constant) region. The junction
of the V-D-J genes is extremely variable and can be used as a
fingerprint for a particular B cell and its progeny. This forms the
complementarity determining region (CDR)3 - which is particularly
important for antigen binding. B cell development in the periphery is
also a crucial process in the humoral adaptive immune response, where
the rearranged antibody gene repertoire is changed by hypermutation,
class switching and selective processes in response to stimulation.
We measure the diversity of a B cell repertoire in two ways: 1. By
analysis of the CDR3 lengths in a population and 2. By sequencing the
complete antibody genes using deep sequencing technology. Such large
scale methods require a substantial amount of downstream analysis. We
have used them to show a link between loss of B cell diversity in old
age and frailty, and we have shown that different B cell populations
have distinctive repertoire characteristics.
(Deborah Dunn-Walters and David Kipling)
- 3:00-4:00
Michael P H Stumpf (Imperial College)
Multi-scale modelling of the innate immune response in zebrafish
Zebrafish embryos are transparent and experimentally convenient model
organisms to study processes that span from molecular scales all thw
way to the whole organism. In particular we can combine real-time
in-vivo imaging techniques with molecular biology investigations in
order to study how cells of the immune system make decisions. This
talk will draw on recent developments in mathematical modelling of
spatio-temporal systems, spatial statistical physics and Bayesian
statistics. In order to capture the dynamics of immune signalling we
have developed an automated cell identification and tracking system
which allows us to determine the characteristics of more cell
trajectories than had previously been possible. We then characterize
the heterogeneous behaviour in the population of immune cells and show
that we can shift the population behaviour by selectively targeting
molecular signalling networks inside the immune system. It is possible
to calibrate the resulting multi-scale models against suitable data in
an approximate Bayesian computation (ABC) framework. The only
requirement of ABC methods is the availability of efficient simulation
methods; if this is the case we can apply the whole paraphernalia of
Bayesian model selection in the analysis of complex systems such as
the immune signalling. Finally, we will discuss simple models that
describe the decision making processes in immune cells.
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