Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS)

Cryopyrin-associated periodic syndrome (CAPS) is characterized by dysregulated inflammation with excessive interleukin (IL)-1 beta activation and secretion. Neonatal-onset multi-system inflammatory disease (NOMID) is the most severe form. We explored cytokine responses in 32 CAPS patients before and after IL-1 beta blocking therapy. We measured cytokines produced by activated peripheral blood monuclear cells (PBMCs) from treated and untreated CAPS patients after stimulation for 48 h with phytohaemagglutinin (PHA), PHA plus IL-12, lipopolysaccharide (LPS) or LPS plus interferon (IFN)-gamma. We measured IL-1 beta, IL-6, IL-10, tumour necrosis factor (TNF), IL-12p70 and IFN-gamma in the supernatants. PBMCs from three untreated CAPS patients were cultured in the presence of the IL-1 beta blocker Anakinra. Fifty healthy individuals served as controls. CAPS patients had high spontaneous production of IL-1 beta, IL-6, TNF and IFN-gamma by unstimulated cells. However, stimulation indexes (SIs, ratio of stimulated to unstimulated production) of these cytokines to PHA and LPS were low in NOMID patients compared to controls. Unstimulated IL-10 and IL-12p70 production was normal, but up-regulation after PHA and LPS was also low. LPS plus IFN-gamma inadequately up-regulated the production of IL-1 beta, IL-6, TNF and IL-10 in CAPS patients. In-vitro but not in-vivo treatment with Anakinra improved SIs by lowering spontaneous cytokine production. However, in-vitro treatment did not improve the low stimulated cytokine levels. Activating mutations in NLRP3 in CAPS are correlated with poor SIs to PHA, LPS and IFN-gamma. The impairment in stimulated cytokine responses in spite of IL-1 beta blocking therapy suggests a broader intrinsic defect in CAPS patients, which is not corrected by targeting IL-1 beta.