alexander2

r10

r10: A suppression by Tregs of other specificity

A > ∅

r11

r11: A suppression by R

A > ∅

r1a

r1a: self-antigen uptake

G > ∅

r1b

r1b: pAPC maturation

A_im > A

r2

r2: self-antigen release triggered by E

∅ > G

r3

r3: R activation by A

∅ > R

r4

r4: R activation by A and E

∅ > R

r5

r5: E generation by A

∅ > E

r6

r6: A death

A > ∅

r7

r7: R death

R > ∅

r8

r8: E death

E > ∅

r9

r9: G clearance

G > ∅

Global parameters

Assignment rules

R0 = f * (v_max / k) * lambdaE * gamma / (mG * mA * muE)

mG = muG + v_max / k

mA = b1 + muA

Function definitions

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


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Self-tolerance and autoimmunity in a regulatory T cell model.

  • HK Alexander
  • Lindi M Wahl
Bull. Math. Biol. 2011; 73 (1): 33
Abstract
The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R(0) for each system. When R(0)<1, only the trivial equilibrium exists and is stable; when R(0)>1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system's qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub-clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach).
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000290) Biomodels notes: Reproduction of the results in the first row of Fig. 2 of the original publication. The time course was integrated using Copasi 4.6. JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.