Supporting Figures

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Supporting Figure 8
Supporting Figure 9

Fig. 8. Administration of the IL-1 receptor antagonist, anakinra, in FMF. A 20-year-old man with FMF, homozygous for the M694V mutation, was referred to the Clinical Center of the National Institutes of Health with evidence of renal, gastrointestinal, and cardiac amyloidosis. He was unable to tolerate cochicine because of gastrointestinal toxiticity and had been treated with corticosteroids. In early June he developed renal failure requiring hemodialysis. Anakinra was begun at 100 mg/day s.c. and was increased to 200 mg/day, with continuation of corticosteroids. Serial determinations of the serum amyloid A (SAA) and C-reactive protein (CRP) are plotted. Acute-phase reactants were well controlled except during an episode of infection for which the anakinra was discontinued. Acute-phase reactants promptly decreased with resumption of treatment.

Fig. 9. Proposed role of pyrin in regulating caspase-1-mediated IL-1b processing. (A) Interaction of the C-terminal B30.2 domain of pyrin with caspase-1, as described in this article. Active p20 and p10 subunits of caspase-1 are produced in the inflammasome by induced proximity-mediated autocatalysis. The B30.2 domain of pyrin interacts with the p20 and p10 subunits of full-length caspase-1, possibly impairing its assembly into the inflammasome complex (Top). WT B30.2 domains also bind the individual p20 and p10 subunits, preventing their assembly into active p20/p10 heterodimers (Middle). FMF-associated pyrin B30.2 mutants bind p20 and p10 less avidly, thereby permitting heterodimer assembly, IL-1b activation, and induction of inflammation (Bottom). (B) Previous data from our laboratory indicate that WT pyrin also binds ASC through N-terminal PYRIN domain interactions, thereby reducing the availability of ASC for inflammasome assembly.