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

Authors

  • M. H. Haverkamp,

    Corresponding author
    1. Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
    2. Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
    • Correspondence: M. H. Haverkamp, Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.

      E-mail: M.H.Haverkamp@lumc.nl

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  • E. van de Vosse,

    1. Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
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  • R. Goldbach-Mansky,

    1. Translational Autoinflammatory Disease Section, National Institutes of Health, Bethesda, MD, USA
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  • S. M. Holland

    1. Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Summary

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.

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