Modeling Cellular Dynamics: The Germinal Center.
Abstract: We have
developed an agent-based computer simulation framework (PathSim2) capable of modeling
overall human immune system dynamics, with a focus on local cellular interactions within
lymphatic tissue. Our simulation predicts that the generation and maintenance of both a
naive primary follicle and an activated secondary follicle containing a germinal center
(GC) can be explained by ... read morethe action of chemotaxis-driven competition for space within
the dense cellular environment of the lymph node. Specifically, the simulation predicts
that chemotaxis-driven competition is sufficient to generate, as emergent behavior,
biologically accurate GC behavior at both the macro (self organizing structure formation
and anatomy, including the creation of light, dark and mantle zones) and single cell
(movement dynamics, including the characteristic "persistent random walk" and
inter-zonal crossing behaviors) levels. For the first time we provide an explanation for
the underlying mechanism responsible for driving the previously unexplained and complex
"persistent random walk" motion of GC B-cells. The key insight of our study is that
chemotaxis can only generate these behaviors if movement is regulated by the
incompressibility of cells competing for space within the densely packed environment of
the GC. We validate the model by successfully predicting the experimentally observed
movement behavior from intra-vital studies reported by three separate groups. This is
the first complete analysis and comparison of these data and demonstrates that they are,
for the most part, fully consistent with each other. Lastly, we show that these data can
all be accommodated and explained by a new model of GC dynamics termed the "modified
cyclic re-entry" model. In addition to local cellular interactions, PathSim2 generates
physiological whole-body lymphocyte populations. Lymphocytes circulate between the blood
and lymphatic system pools where they compete for limited survival resources. This
encapsulated model is sufficient to recapitulate experimentally observed population
dynamics. Thus, PathSim2 serves as a complete framework from which to study infection
and its effect on the entire immune system. Our long-term goal is to use this simulation
framework to model the dynamics of Epstein-Barr virus infection and
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Immunology.
Advisor: David Thorley-Lawson.
Committee: Peter Brodeur, Stephen Bunnell, Alexander Poltorak, John Coffin, and Garnett Kelsoe.
Keywords: Immunology, and Systems science.read less