title: Unified Modeling of Familial Mediterranean Fever and Cryopyrin Associated Periodic Syndromes.
abstract: Familial mediterranean fever (FMF) and Cryopyrin associated periodic syndromes (CAPS) are two prototypical hereditary autoinflammatory diseases, characterized by recurrent episodes of fever and inflammation as a result of mutations in MEFV and NLRP3 genes encoding Pyrin and Cryopyrin proteins, respectively. Pyrin and Cryopyrin play key roles in the multiprotein inflammasome complex assembly, which regulates activity of an enzyme, Caspase 1, and its target cytokine, IL-1β. Overproduction of IL-1β by Caspase 1 is the main cause of episodic fever and inflammatory findings in FMF and CAPS. 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, which capture the interactions and dynamics of the key molecular players and the insults on the immune system. One of the subsystems, which contains a coupled positive-negative feedback motif, captures the dynamics of inflammation formation and regulation. 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 present extensive simulation results for the model that match clinical observations.
authors.affiliation: Computational and Quantitative Biology Lab, Koc University, 34450 Istanbul, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Bozkurt
authors.affiliation: Computational and Quantitative Biology Lab, Koc University, 34450 Istanbul, Turkey.
authors.forename: Alper
authors.initials: A
authors.lastname: Demir
authors.affiliation: Computational and Quantitative Biology Lab, Koc University, 34450 Istanbul, Turkey.
authors.forename: Burak
authors.initials: B
authors.lastname: Erman
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Gül
mesh_terms: D000465:Algorithms; D002352:Carrier Proteins / Q000235:genetics; D003198:Computer Simulation; D056587:Cryopyrin-Associated Periodic Syndromes / Q000175:diagnosis* / Q000503:physiopathology*; D003598:Cytoskeletal Proteins / Q000235:genetics; D010505:Familial Mediterranean Fever / Q000175:diagnosis* / Q000503:physiopathology*; D006801:Humans; D058847:Inflammasomes; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000071198:Pyrin; D017472:Receptors, Interleukin-1 / Q000502:physiology; D053574:Receptors, Interleukin-1 Type II / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000071198:Pyrin; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II; C508585:IL1B protein, human; C508592:IL1R2 protein, human; C507763:IL1RN protein, human; C508600:IL6 protein, human; C000604192:MEFV protein, human; C453881:NLRP3 protein, human; C546891:SIGIRR protein, human