Simulation of the dynamics of primary immunodeficiencies in CD4+ T-cells.

Primary immunodeficiencies (PIDs) form a large and heterogeneous group of mainly rare disorders that affect the immune system. T-cell deficiencies account for about one-tenth of PIDs, most of them being monogenic. Apart from genetic and clinical information, lots of other data are available for PID proteins and genes, including functions and interactions. Thus, it is possible to perform systems biology studies on the effects of PIDs on T-cell physiology and response. To achieve this, we reconstructed a T-cell network model based on literature mining and TPPIN, a previously published core T-cell network, and performed semi-quantitative dynamic network simulations on both normal and T-cell PID failure modes. The results for several loss-of-function PID simulations correspond to results of previously reported molecular studies. The simulations for TCR PTPRC, LCK, ZAP70 and ITK indicate profound changes to numerous proteins in the network. Significant effects were observed also in the BCL10, CARD11, MALT1, NEMO, IKKB and MAP3K14 simulations. No major effects were observed for PIDs that are caused by constitutively active proteins. The T-cell model facilitates the understanding of the underlying dynamics of PID disease processes. The approach confirms previous knowledge about T-cell signaling network and indicates several new important proteins that may be of interest when developing novel diagnosis and therapies to treat immunological defects.