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

Clin Exp Immunol. 2014 Sep;177(3):720-31. doi: 10.1111/cei.12361.


Cryopyrin-associated periodic syndrome (CAPS) is characterized by dysregulated inflammation with excessive interleukin (IL)-1β 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-1β 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)-γ. We measured IL-1β, IL-6, IL-10, tumour necrosis factor (TNF), IL-12p70 and IFN-γ in the supernatants. PBMCs from three untreated CAPS patients were cultured in the presence of the IL-1β blocker Anakinra. Fifty healthy individuals served as controls. CAPS patients had high spontaneous production of IL-1β, IL-6, TNF and IFN-γ 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-γ inadequately up-regulated the production of IL-1β, 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-γ. The impairment in stimulated cytokine responses in spite of IL-1β blocking therapy suggests a broader intrinsic defect in CAPS patients, which is not corrected by targeting IL-1β.

Keywords: Anakinra; CAPS; NOMID; cytokine.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Carrier Proteins / genetics
  • Child
  • Child, Preschool
  • Cryopyrin-Associated Periodic Syndromes / drug therapy
  • Cryopyrin-Associated Periodic Syndromes / genetics
  • Cryopyrin-Associated Periodic Syndromes / metabolism*
  • Cytokines / metabolism*
  • Humans
  • Infant
  • Interleukin-1beta / antagonists & inhibitors
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Middle Aged
  • Mutation / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Young Adult


  • Carrier Proteins
  • Cytokines
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human