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BIOMD0000000625 - Leber2016 - Expanded model of Tfh-Tfr differentiation - Helicobacter pylori infection

 

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Reference Publication
Publication ID: 26947272
Leber A, Abedi V, Hontecillas R, Viladomiu M, Hoops S, Ciupe S, Caughman J, Andrew T, Bassaganya-Riera J.
Bistability analyses of CD4+ T follicular helper and regulatory cells during Helicobacter pylori infection.
J. Theor. Biol. 2016 Jun; 398: 74-84
Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.  [more]
Model
Original Model: Leber2016_TfhTfrExpanded
Submitter: Andrew Leber
Submission ID: MODEL1603010000
Submission Date: 01 Mar 2016 16:21:29 UTC
Last Modification Date: 16 Jun 2017 19:20:21 UTC
Creation Date: 25 May 2015 11:11:04 UTC
Encoders:  Andrew Leber
   Varun Kothamachu
set #1
bqbiol:hasProperty Human Disease Ontology duodenal ulcer
Human Disease Ontology peptic ulcer disease
bqbiol:hasTaxon Taxonomy Mus musculus
Taxonomy Helicobacter pylori
bqbiol:occursIn Brenda Tissue Ontology gastrointestinal mucosa
bqbiol:isVersionOf Gene Ontology interspecies interaction between organisms
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
Notes
Leber2016 - Expanded model of Tfh-Tfr differentiation - Helicobacter pylori infection

The parameters used in the model were obtained from experiments conducted by the authors, previous publications [ 1, 2, 3] and parameter optimisation carried out in the paper using particle swarm and genetic algorithms. 

This model is described in the article:

Leber A, Abedi V, Hontecillas R, Viladomiu M, Hoops S, Ciupe S, Caughman J, Andrew T, Bassaganya-Riera J.
J. Theor. Biol. 2016 Jun; 398: 74-84

Abstract:

T follicular helper (Tfh) cells are a highly plastic subset of CD4+ T cells specialized in providing B cell help and promoting inflammatory and effector responses during infectious and immune-mediate diseases. Helicobacter pylori is the dominant member of the gastric microbiota and exerts both beneficial and harmful effects on the host. Chronic inflammation in the context of H. pylori has been linked to an upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes, controlled in part by the cytokine, interleukin-21. This study investigates the differentiation and regulation of Tfh cells, major producers of IL-21, in the immune response to H. pylori challenge. To better understand the conditions influencing the promotion and inhibition of a chronically elevated Tfh population, we used top-down and bottom-up approaches to develop computational models of Tfh and T follicular regulatory (Tfr) cell differentiation. Stability analysis was used to characterize the presence of two bi-stable steady states in the calibrated Tfh/Tfr models. Stochastic simulation was used to illustrate the ability of the parameter set to dictate two distinct behavioral patterns. Furthermore, sensitivity analysis helped identify the importance of various parameters on the establishment of Tfh and Tfr cell populations. The core network model was expanded into a more comprehensive and predictive model by including cytokine production and signaling pathways. From the expanded network, the interaction between TGFB-Induced Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was displayed to exert control over the determination of the Tfh response. Model simulations predict that Tgif1 and RXR respectively induce and curtail Tfh responses. This computational hypothesis was validated experimentally by assaying Tgif1, RXR and Tfh in stomachs of mice infected with H. pylori.

The impulse of RXR as shown in the paper (figure 7C) can be implemented by creating an event in the curated SBML file.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 26947272 Submission Date: 01 Mar 2016 16:21:29 UTC Last Modification Date: 16 Jun 2017 19:20:21 UTC Creation Date: 25 May 2015 11:11:04 UTC
Mathematical expressions
Reactions
NaiveCD4 Source NaiveCD4 Death nTreg Source nTreg Death
Tfh Differentiation Tfr Differentiation Tfh Death Tfr Death
Bcl6 Activation Blimp1 Activation FoxP3 Activation STAT3 Activation
STAT5 Activation CXCR5 Production ICOS Production IL2 Production
IL4 Production IL6 Production IL10 Production Bcl6 Degradation
Blimp1 Degradation FoxP3 Degradation STAT3 Degradation STAT5 Degradation
CXCR5 Degradation ICOS Degradation IL2 Degradation IL4 Degradation
IL6 Degradation IL10 Degradation IL21 Degradation IL21 Production
TGFb Production TGFb Degradation RXR Activation Tgif1 Production
RXR Degradation Tgif1 Degradation    
Physical entities
Compartments Species
compartment NaiveCD4 nTreg Tfh
Tfr Bcl6 Blimp1
FoxP3 STAT3 STAT5
IL2 IL4 IL6
IL10 IL21 CXCR5
ICOS TGFb Tgif1
RXR    
Reactions (38)
 
 NaiveCD4 Source  → [NaiveCD4];  
 
 NaiveCD4 Death [NaiveCD4] → ;  
 
 nTreg Source  → [nTreg];  
 
 nTreg Death [nTreg] → ;  
 
 Tfh Differentiation [NaiveCD4] → [Tfh];   {Bcl6} , {IL10}
 
 Tfr Differentiation [nTreg] → [Tfr];   {Bcl6} , {CXCR5}
 
 Tfh Death [Tfh] → ;  
 
 Tfr Death [Tfr] → ;  
 
 Bcl6 Activation  → [Bcl6];   {ICOS} , {STAT3} , {Blimp1} , {STAT5} , {RXR}
 
 Blimp1 Activation  → [Blimp1];   {Tfr} , {Bcl6}
 
 FoxP3 Activation  → [FoxP3];   {nTreg}
 
 STAT3 Activation  → [STAT3];   {IL6} , {IL21}
 
 STAT5 Activation  → [STAT5];   {IL2}
 
 CXCR5 Production  → [CXCR5];   {Tfh} , {Tfr} , {Blimp1}
 
 ICOS Production  → [ICOS];   {Tfh}
 
 IL2 Production  → [IL2];  
 
 IL4 Production  → [IL4];   {Tfh}
 
 IL6 Production  → [IL6];   {IL4}
 
 IL10 Production  → [IL10];   {Tfr}
 
 Bcl6 Degradation [Bcl6] → ;  
 
 Blimp1 Degradation [Blimp1] → ;  
 
 FoxP3 Degradation [FoxP3] → ;  
 
 STAT3 Degradation [STAT3] → ;  
 
 STAT5 Degradation [STAT5] → ;  
 
 CXCR5 Degradation [CXCR5] → ;  
 
 ICOS Degradation [ICOS] → ;  
 
 IL2 Degradation [IL2] → ;  
 
 IL4 Degradation [IL4] → ;  
 
 IL6 Degradation [IL6] → ;  
 
 IL10 Degradation [IL10] → ;  
 
 IL21 Degradation [IL21] → ;  
 
 IL21 Production  → [IL21];   {Tfh}
 
 TGFb Production  → [TGFb];   {IL10}
 
 TGFb Degradation [TGFb] → ;  
 
 RXR Activation  → [RXR];   {TGFb} , {Tgif1}
 
 Tgif1 Production  → [Tgif1];   {Tfh}
 
 RXR Degradation [RXR] → ;  
 
 Tgif1 Degradation [Tgif1] → ;  
 
Functions (14)
 
 Molecule Production (1A/0I)_2 lambda(IL2, sigma, sigma*IL2)
 
 Constant flux (irreversible) lambda(v, v)
 
 Molecule Production (1A/0I)_1 lambda(nTreg, sigma, sigma*nTreg)
 
 Molecule Production (2A/3I) v2_1 lambda(Blimp1, ICOS, RXR, STAT3, STAT5, alpha1, alpha2, alpha3, sigma1, sigma2, (sigma1*ICOS+sigma2*STAT3)/((alpha1+Blimp1)*(alpha2+STAT5)*(alpha3+RXR)))
 
 Molecule Production (0A/1I)_1 lambda(IL4, alpha1, sigma1, sigma1/(alpha1+IL4))
 
 Molecule Production (1A/0I)_5 lambda(IL10, sigma, sigma*IL10)
 
 Cell Differentiation (2A)_1 lambda(Bcl6, CXCR5, gamma1, gamma2, nTreg, gamma1*nTreg*Bcl6+gamma2*nTreg*CXCR5)
 
 Molecule Production (2A/0I)_1 lambda(IL21, IL6, sigma1, sigma2, sigma1*IL6+sigma2*IL21)
 
 Molecule Production (2A/1I)_1 lambda(Blimp1, Tfh, Tfr, alpha, sigma1, sigma2, (sigma1*Tfh+sigma2*Tfr)/(alpha+Blimp1))
 
 Molecule Production (1A/0I)_4 lambda(Tfr, sigma, sigma*Tfr)
 
 Molecule Production (1A/1I)_2 lambda(TGFb, Tgif1, alpha, sigma, sigma*TGFb/(alpha+Tgif1))
 
 Molecule Production (1A/1I)_1 lambda(Bcl6, Tfr, alpha, sigma, sigma*Tfr/(alpha+Bcl6))
 
 Molecule Production (1A/0I)_3 lambda(Tfh, sigma, sigma*Tfh)
 
 Cell Differentiation (1A/1I)_1 lambda(Bcl6, IL10, NaiveCD4, alpha, gamma, gamma*NaiveCD4*Bcl6/(alpha+IL10))
 
 compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 NaiveCD4
Compartment: compartment
Initial concentration: 200.0
 
 nTreg
Compartment: compartment
Initial concentration: 100.0
 
 Tfh
Compartment: compartment
Initial concentration: 1.0
 
 Tfr
Compartment: compartment
Initial concentration: 1.0
 
 Bcl6
Compartment: compartment
Initial concentration: 1.0
 
 Blimp1
Compartment: compartment
Initial concentration: 1.0
 
 FoxP3
Compartment: compartment
Initial concentration: 1.0
 
 STAT3
Compartment: compartment
Initial concentration: 1.0
 
 STAT5
Compartment: compartment
Initial concentration: 0.0
Constant
 
 IL2
Compartment: compartment
Initial concentration: 1.0E-4
Constant
 
 IL4
Compartment: compartment
Initial concentration: 1.0
 
 IL6
Compartment: compartment
Initial concentration: 1.0
 
 IL10
Compartment: compartment
Initial concentration: 1.0
 
 IL21
Compartment: compartment
Initial concentration: 1.0
 
 CXCR5
Compartment: compartment
Initial concentration: 1.0
 
 ICOS
Compartment: compartment
Initial concentration: 1.0
 
 TGFb
Compartment: compartment
Initial concentration: 1.0
 
 Tgif1
Compartment: compartment
Initial concentration: 1.0
 
 RXR
Compartment: compartment
Initial concentration: 1.0
 
NaiveCD4 Source (1)
 
 v
Value: 100.0
Constant
 
NaiveCD4 Death (1)
 
 k1
Value: 0.035655
Constant
 
nTreg Source (1)
 
 v
Value: 10.0
Constant
 
nTreg Death (1)
 
 k1
Value: 0.03
Constant
 
Tfh Differentiation (2)
 
 alpha
Value: 0.1
Constant
 
 gamma
Value: 0.364318
Constant
 
Tfr Differentiation (2)
 
 gamma1
Value: 0.0555708
Constant
 
 gamma2
Value: 0.111444
Constant
 
Tfh Death (1)
 
 k1
Value: 0.03
Constant
 
Tfr Death (1)
 
 k1
Value: 0.03
Constant
 
Bcl6 Activation (5)
 
 alpha1
Value: 0.20001
Constant
 
 alpha2
Value: 1.36752
Constant
 
 alpha3
Value: 0.1253
Constant
 
 sigma1
Value: 3.24417
Constant
 
 sigma2
Value: 3.2195
Constant
 
Blimp1 Activation (2)
 
 alpha
Value: 2.386
Constant
 
 sigma
Value: 3.59995
Constant
 
FoxP3 Activation (1)
 
 sigma
Value: 0.1
Constant
 
STAT3 Activation (2)
 
 sigma1
Value: 0.1253
Constant
 
 sigma2
Value: 0.1
Constant
 
STAT5 Activation (1)
 
 sigma
Value: 10.0
Constant
 
CXCR5 Production (3)
 
 alpha
Value: 0.0539319
Constant
 
 sigma1
Value: 3.0403
Constant
 
 sigma2
Value: 2.92243
Constant
 
ICOS Production (1)
 
 sigma
Value: 0.01787
Constant
 
IL2 Production (1)
 
 v
Value: 0.1
Constant
 
IL4 Production (1)
 
 sigma
Value: 0.014555
Constant
 
IL6 Production (2)
 
 alpha1
Value: 0.43475
Constant
 
 sigma1
Value: 0.9901
Constant
 
IL10 Production (1)
 
 sigma
Value: 0.0677
Constant
 
Bcl6 Degradation (1)
 
 k1
Value: 0.16373
Constant
 
Blimp1 Degradation (1)
 
 k1
Value: 0.1106
Constant
 
FoxP3 Degradation (1)
 
 k1
Value: 0.1
Constant
 
STAT3 Degradation (1)
 
 k1
Value: 0.1
Constant
 
STAT5 Degradation (1)
 
 k1
Value: 0.1
Constant
 
CXCR5 Degradation (1)
 
 k1
Value: 0.1
Constant
 
ICOS Degradation (1)
 
 k1
Value: 0.1
Constant
 
IL2 Degradation (1)
 
 k1
Value: 0.1
Constant
 
IL4 Degradation (1)
 
 k1
Value: 0.1
Constant
 
IL6 Degradation (1)
 
 k1
Value: 0.69675
Constant
 
IL10 Degradation (1)
 
 k1
Value: 0.1
Constant
 
IL21 Degradation (1)
 
 k1
Value: 0.1
Constant
 
IL21 Production (1)
 
 sigma
Value: 0.06005
Constant
 
TGFb Production (1)
 
 sigma
Value: 0.1
Constant
 
TGFb Degradation (1)
 
 k1
Value: 0.1
Constant
 
RXR Activation (2)
 
 alpha
Value: 3.04985
Constant
 
 sigma
Value: 0.05
Constant
 
Tgif1 Production (1)
 
 sigma
Value: 0.1
Constant
 
RXR Degradation (1)
 
 k1
Value: 0.08465
Constant
 
Tgif1 Degradation (1)
 
 k1
Value: 0.1
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000625

Curator's comment: (updated: 27 Mar 2017 11:40:00 BST)

The model reproduces figure 7b in the paper qualitatively. In comparison to the figure in the paper, the time taken by the system to reach steady state is twice as long.

The model was simulated on Cell Designer 4.4 and the plot was generated using Matlab.

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