Akdeniz ailevi ateşi ve kriyopyrin ilişkili periyodik semptomların bütünleşik modellemesi

Familial Mediterranean Fever (FMF) and Cryopyrin Associated Periodic Syndromes (CAPS) are two related autoinflammatory diseases, characterized by recurrent episodes of fever and inflammation. FMF is caused by inherited loss-of-function mutations in pyrin, and CAPS by gain-of-function mutations in cryopyrin, two proteins that play key roles in the control and regulation of inflamma-tion along with an enzyme, Caspase 1, and a cytokine, IL-1β. Normally, triggered by an infection or a sterile insult, cryopyrin forms an inflammasome that converts precursor proCaspase 1 into active Caspase 1. Once activated, Caspase 1 proteolytically cleaves IL-1β into an active peptide with a proinflammatory effect. Pyrin, on the other hand, acts as an anti-inflammatory mediator that con-trols and prevents cryopyrin inflammasome formation by binding both to Caspase 1 and its inactive form proCaspase 1. Mutated pyrin can no longer act as an effective suppressor of inflammasome formation. Mutations in cryopyrin, on the other hand, result in elevated inflammasome formation even in the absence of a trigger. Overproduction of IL-1β by Caspase 1 as a result is the main cause of fever and inflammatory episodes in FMF and CAPS. In this thesis, we present a unifying dynamical model for FMF and CAPS in the form of coupled nonlinear ordinary differential equations. The model is composed of two subsystems. The first sub-system captures the interactions and dynamics of pyrin, cryopyrin, proCaspase 1, Caspase 1, and inflammasome formation, including the effect of triggers. The second subsytem, which contains a coupled positive-negative feedback motif, captures the dynamics of IL-1β, its receptor and receptor antagonist, including Caspase 1-independent cleavage of IL-1β. The two subsystems are coupled via the key player Caspase 1. We perform a comprehensive bifurcation analysis of the model and show that it exhibits three modes, capturing the Healthy, FMF and CAPS cases. The mutations in pyrin and cryopyrin are reflected in the values of three parameters in the model. We then present extensive simulation results for the model, which match clinical observations. In the presence of a trigger, there is a normal increase in inflammation initiators in the Healthy mode. In FMF, the response to trigger introduction is more intense and a severe inflammatory cascade is activated. In CAPS, on the other hand, even in the absence of a trigger, periodically recurring, severe inflammatory episodes are observed. The proposed model also explains why a proCaspase 1 inhibitor can be effective in treating FMF, but not CAPS, for which drugs that directly inhibit IL-1β are used.