A multiscale approach toward understanding the role of antigen presentation in immunity

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A multiscale approach toward understanding the
role of antigen presentation in immunity

• Tom Riggs1, MD, PhD
• Jennifer Linderman2,3,4, PhD
• Denise Kirschner1,2,3, PhD
• 1Microbiology and Immunology, 2Biomedical
  Engineering,
• 3Center for Computational Medicine and Biology,
• 4Chemical Engineering

Antigen presenting cell interacting with a T cell
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• Immune response is a complex system of complex
  systems with events occurring over multiple
  length and time scales
• Antigen presentation is the process by which
  immune cells are informed of the presence of a
  pathogen so that they can initiate a response.
• Need something to respond to, so focus on a
  model pathogen- M. tuberculosis
• Goal build a multi-scale, integrative model
  that bridges these length and time scales -
  systems biology

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Antigen Presentation primer
Antigen presenting cell or APC
T cell
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Antigen Presentation in Immunity
Antigen presenting cells (APC) take up antigen
and present it in the context of MHC II
APC interact with T helper cells in the lymph node
Activation of T helper cells leads to a full
immune response
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Our Approach

• Build models at individual scales
• -choose appropriate method (e.g. statistical,
  simulation)
• -validate at that scale
• Link individual models
• -initially assume information flows only in one
  direction
• -ultimately include information flow in both
  directions
• Infect system with M. tuberculosis (wont discuss
  today)
• Sensitivity and uncertainty analysis
• - developed and performed for each scale and
  across scales

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Molecular Level

• Can peptide-MHC binding affinity prediction be
  improved by consideration of peptide length?
  affinities? Statistical algorithm

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Peptide-MHC II Binding Predictions
Mean AROC scores between predicted and measured
values.
Chang, Ghosh, Kirschner, and Linderman, Peptide
length-based prediction of Peptide-MHC class II
binding, Bioinformatics 22 2761-7, 2006.
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Cellular Level

• Can the number of peptide-MHC complexes be
  predicted?
• Nonlinear ODE
• Parameter from first level (affinity) used in
  second model

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Processing of Antigen by the APC
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Single APC Model
Results can be used to understand why Mtb uses
multiple mechanisms to inhibit antigen
presentation and how to design experiments to
detect these mechanisms.
Chang, Linderman and Kirschner, A role for
multiple mechanisms in the inhibition of MHC
class II-mediated antigen presentation by M.
tuberculosis, PNAS 102 4530-5, 2005.
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Lymph nodes are key sites of immune activity
How does output of LN depend on cell movement,
contacting, and levels of antigenpresented?
Microscopy and in silico model
Tissue Level
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Antigen presentation in the LNs-
Dendritic cells (green) and T cells (red)
interacting within a section of the LN measuring
75x100 ?m, as revealed by two-photon microscopy
imaging. (Mark Miller, Wash. U.)
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Agent based model (see poster)

• Agents
• Rules governing agent interactions
• Time scales
• Environment

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A first step toward building a systems model
Multiple compartments

• Marino, S and Kirschner, D. The Role of Dendritic
  cells in the Human Immune Response to
  Mycobacterium tuberculosis in the lung and lymph
  node. Journal of Theoretical Biology, 227(4) pp
  463-486, 2004 and
• S. Marino, Santosh Pawr, Todd A. Reinhart, JoAnne
  L. Flynn and Kirschner, D. Dendritic Cell
  Trafficking and Antigen Presentation in the Human
  Immune Response to Mycobacterium tuberculosis
  Journal of Immunology, Jul 1173(1)494-506,
  2004.

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How can we begin to synthesize the models into a
single multi-scale representation?
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Multi-scale Model of Antigen Presentation in
Immunity
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Acknowledgements
Jennifer Linderman
Nicolas Perry
Denise Kirschner
Tom Riggs
Adrienne Walts
Stewart Chang
Mark Miller
Joanne Flynn
Debashis Ghosh
Funding sources NIH and NSF and The University
of Michigan