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Simulation of the dynamics of primary immunodeficiencies in B cells

Teku, Gabriel Ndipagbornchi LU and Vihinen, Mauno LU (2018) In Frontiers in Immunology 9(AUG).
Abstract

Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1... (More)

Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-of-function CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-of-function CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.

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publication status
published
subject
keywords
B-cell network model, B-cell network simulation, Biological, Models, Primary immunodeficiency, Semi-quantitative network simulation, Systems analysis
in
Frontiers in Immunology
volume
9
issue
AUG
article number
1785
publisher
Frontiers Media S. A.
external identifiers
  • pmid:30116248
  • scopus:85051118917
ISSN
1664-3224
DOI
10.3389/fimmu.2018.01785
language
English
LU publication?
yes
id
7cf5d20e-a4ce-43a7-aa12-5b3a22d3982e
date added to LUP
2018-08-22 11:14:23
date last changed
2021-03-03 05:46:12
@article{7cf5d20e-a4ce-43a7-aa12-5b3a22d3982e,
  abstract     = {<p>Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-of-function CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-of-function CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.</p>},
  author       = {Teku, Gabriel Ndipagbornchi and Vihinen, Mauno},
  issn         = {1664-3224},
  language     = {eng},
  month        = {08},
  number       = {AUG},
  publisher    = {Frontiers Media S. A.},
  series       = {Frontiers in Immunology},
  title        = {Simulation of the dynamics of primary immunodeficiencies in B cells},
  url          = {http://dx.doi.org/10.3389/fimmu.2018.01785},
  doi          = {10.3389/fimmu.2018.01785},
  volume       = {9},
  year         = {2018},
}