Boolean network and simulation

We used Probabilistic Boolean Modelling (PBM) to simulate the effects of IFNG on sensory perception of itching post-treatment with dupilumab, i.e., inhibition of IL4R. For this purpose, we first converted the individual KC map in the AD map into a Boolean network (BN) in an automated fashion using CaSQ tool (PMID: 32403123). Then we considered the following pathways in the converted BN for our simulations: i) IL4R -> TSLP -> sensory perception of itching, (ii) IL4R -> KLK5 -> sensory perception of itching, (iii) IL4R -> KLK7 -> sensory perception of itching, (iv) IFNG -> TSLP -> sensory perception of itching, (v) IFNG -| KLK5 -> sensory perception of itching and (vi) IFNG -| KLK7 -> sensory perception of itching. The PBM approach uses a series of random walks to determine the probability of components within the model (PMID:35782730). This approach integrates qualities of both discrete and continuous Markov processes within a Monte Carlo framework (PMID: 37325771). To establish a foundational baseline for our simulations, we parameterized initial state probabilities of ON/OFF. This step is critical as it sets the starting point for the model, reflecting the pre-simulation status of molecular interactions. The equation for updating the state probabilities is given by: where Pt+1(s) is the probability of state s at the next time point and P(s′∣s) is the transition probability from a previous state s′ to the current state s.

Graphical analysis

Sensory Perception of Itch under Different Conditions: Orange Line (IFNG OFF, IL-4 OFF - Dupilumab): Indicates a significant reduction in itch over time. Blue Line (IFNG ON, IL-4 OFF - Dupilumab): Shows a less pronounced reduction in itch compared to the IFNG OFF scenario.

When IFNG is expressed (IFNG ON) in the presence of dupilumab (IL4 OFF), we observe an increase in TSLP levels, a decrease in KLK5 and KLK7 levels and a reduction of around 50% in the activity level of sensory perception of itch.

When IFNG is not expressed (IFNG OFF) in the presence of dupilumab (IL4 OFF), we observe a decrease in TSLP levels, an increase in KLK5 and KLK7 levels and a reduction of around 70% in the activity level of sensory perception of itch.