Computational modelling of immune interaction and epidermal homeostasis in Psoriasis

Abstract

Psoriasis is an incurable chronic inflammatory skin disease characterised by immune cytokinestimulated epidermal hyperproliferation. This results in the skin becoming red with scaly plaques that can appear anywhere on the body, decreasing the quality of life for patients. Previous modelling studies of psoriatic skin have been limited to 2D models and lacked cellcell interactions. I have developed a 3D agent-based model of epidermal cell dynamics to gain insights into how immune cytokine stimuli induces hyperproliferation in psoriasis to better understand disease formation and structural changes. The model takes into account the main cell types - stem, transit-amplifying (TA), differentiated and T cells with the growth and division of stem and TA cells governed by extracellular calcium, endogenous growth factors and immune cytokines in line with known experimental data. Each cell has a set of attributes (growth rate, division probability, position, etc) whose values are governed by processes such as monod-based cellular growth model, probability-based division based on calcium and cytokine concentration and various forces to form the epidermal layers. Different scenarios can be simulated including delineating how psoriasis developed in response to immune stimuli concentration and duration and changing the rate of division of proliferative cells to capture how it changes from normal to diseased state. The model has 2 steady states, healthy (non-lesional) and psoriatic (lesional) skin. Transition from healthy to psoriatic state is triggered by a temporary cytokine stimulus which causes hyperproliferation to occur, a hallmark of psoriasis. This results in the deepening of rete ridges and thickening of the epidermal structure. The model has been validated against population ratios of stem, TA, differentiated, and T cells, cell cycle and turnover times in vivo. The model simulates the structural properties of epidermis, including layer stratification, formation of wave-like rete ridges, change in epidermal height and length of rete ridges from normal to psoriatic. The model has helped gain some insights on the complex spatio-temporal changes when transitioning between the 2 steady states and how a shot of temporary cytokine stimulus can induce different severity of psoriasis and how proliferation is altered between healthy and psoriatic skin in line with known literature. This provides the basis to study different cytokine simulation variations of psoriasis development and tracking of cell proliferation in the lab. In addition, it provides a base to model the effects of psoriasis treatments such as UVB or biologics and predict potential treatment outcomes for patients.