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.

Figure 1

Structure of Pyrin [14].

Figure 2

Cryopyrin inflammasome formation steps. (1) With DAMP or PAMP, inflammasome formation process is triggered. (2) A conformational change occurs in Cryopyrin protein due to the trigger. (3) Interaction between PYDs of ASC and Cryopyrin protein becomes possible after the conformational change. (4) CARD of ASC and procaspase 1 interact. (5) Cardinal brings another procaspase 1 to the system. (6) Induced proximity mediated autocatalysis results in the activation of Caspase 1. (7) Caspase 1 bioactivates IL-1β by cleavage.

Figure 3

Anti-inflammatory role of Pyrin.

Figure 4

Maturation and secretion of IL-1β requires two signals. Binding of ligand (PAMP or IL-1β) to TLR (1) activates NF-κB pathway (2). NF-κB signaling results in proIL-1β transcription and secretion (3 and 4). Binding of ATP to the P2X7 receptor is considered as the activation signal (5) which causes K⁺ efflux (6) and subsequently a decrease in intracellular K⁺ concentration (7). Together with PAMP or DAMP, fall in K⁺ acts as the initiator of the inflammasome formation (7). ProIL-1β is cleaved by the product of the inflammasome, Caspase 1 (8a). However, Caspase 1 is not the only protease that can cleave proIL-1β (8b). Mature IL-1β is secreted and inflammation process is then started (9). Dashed path shows the positive feedback relationship between the free IL-1β (I) and bound IL-1β (R).

Figure 5

Summary of the pathogenesis of FMF. With trigger, inflammasome formation process is triggered in Pyrin mutants (1 and 2a). Cryopyrin protein and procaspase 1 complex into an inflammasome due to nonfunctioning Pyrin (2b and 2c). Procaspase 1 turns into Caspase 1 by the inflammasome action (3). IL-1β is maturated by Caspase 1 (4). IL-1β binds to the receptor (5a). IL-1β signaling cascade followed by inflammation is activated by the binding of IL-1β (5b). Signaling by the Receptor-IL-1β complex leads to further transcription of proIL-1β, resulting in an increase in IL-1β levels. Here, we had only considered the Caspase 1 independent processing of IL-1β (5c). Signaling by the Receptor-IL-1β complex also stimulates the antagonist production (5d). Binding of antagonist to the receptor does not result in active IL-1β signaling (5e).

Figure 6

Summary of the pathogenesis of CAPS. Even without the trigger, inflammasome formation process takes place in Cryopyrin mutants (1a and 1b). Procaspase 1 turns into Caspase 1 by the inflammasome action (2). IL-1β is maturated by Caspase 1 (3). IL-1β binds to the receptor (4a). IL-1β signaling cascade followed by inflammation is activated by the binding of IL-1β (4b). Signaling by the Receptor-IL-1β complex leads to further transcription of proIL-1β and thus increase in Caspase 1 independent IL-1β levels (4c). Signaling by the Receptor-IL-1β complex also stimulates the antagonist production (4d). Binding of antagonist to the receptor does not result in active IL-1β signaling (4e).

Figure 7

The model as a composition of two subsystems. The direction of each green (red) arrow represents a stimulation (inhibition) effect.

Figure 8

Bifurcation analyses. Stable (unstable) solutions are shown as a solid black (red dashed) line. Periodic stable (unstable) solutions are represented by green solid (blue dashed) lines.

Figure 9

Classification of the three modes according to the bifurcation analysis.

Figure 10

Extended bifurcation analysis.

Figure 11

R levels in Healthy, FMF, and CAPS cases.

Figure 12

I levels in Healthy, FMF, and CAPS cases.

Figure 13

A levels in Healthy, FMF, and CAPS cases.

Figure 14

PC levels in Healthy, FMF, and CAPS cases.

Figure 15

C levels in Healthy, FMF, and CAPS cases.

Figure 16

Period of the attacks in CAPS as a function of Caspase 1 level.

Figure 17

R levels in CAPS with and without trigger.