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)‐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.

[1]  M. Gahr,et al.  “Mutation negative” familial cold autoinflammatory syndrome (FCAS) in an 8-year-old boy: clinical course and functional studies , 2012, Rheumatology International.

[2]  S. Paul,et al.  Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. , 2012, Arthritis and rheumatism.

[3]  A. Martini,et al.  Deficient production of IL-1 receptor antagonist and IL-6 coupled to oxidative stress in cryopyrin-associated periodic syndrome monocytes , 2012, Annals of the rheumatic diseases.

[4]  G. Dannecker,et al.  NLRP3 E311K mutation in a large family with Muckle-Wells syndrome - description of a heterogeneous phenotype and response to treatment , 2011, Arthritis research & therapy.

[5]  O. Ohara,et al.  High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. , 2011, Arthritis and rheumatism.

[6]  A. Martini,et al.  Role of IL-1 Beta in the Development of Human TH17 Cells: Lesson from NLPR3 Mutated Patients , 2011, PloS one.

[7]  R. Goldbach-Mansky.  Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA , 2011, Current rheumatology reports.

[8]  C. Dinarello,et al.  Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. , 2011, Blood.

[9]  M. McDermott,et al.  Inflammasomes and autoimmunity. , 2011, Trends in molecular medicine.

[10]  J. Casanova,et al.  Partial recessive IFN-γR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds. , 2011, Human molecular genetics.

[11]  N. Jayaprakash,et al.  The serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous administration to non-human primates , 2010, Journal of Neuroimmunology.

[12]  R. Goldbach-Mansky,et al.  Monogenic IL-1 mediated autoinflammatory and immunodeficiency syndromes: finding the right balance in response to danger signals. , 2010, Clinical immunology.

[13]  U. Broeckel,et al.  An autoinflammatory disease due to homozygous deletion of the IL1RN locus. , 2009, The New England journal of medicine.

[14]  L. Joosten,et al.  Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. , 2009, Blood.

[15]  H. Takada,et al.  Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. , 2008, Blood.

[16]  S. Sicherer,et al.  Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1β Inhibition , 2007, Pediatrics.

[17]  A. Martini,et al.  Pattern of interleukin-1beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. , 2007, Arthritis and rheumatism.

[18]  J. V. van Dongen,et al.  Two Patients with Complete Defects in Interferon Gamma Receptor-Dependent Signaling , 2007, Journal of Clinical Immunology.

[19]  S. Adachi,et al.  Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells. , 2007, Blood.

[20]  E. Remmers,et al.  The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. , 2007, Arthritis and rheumatism.

[21]  S. Holland,et al.  Human host genetic factors in nontuberculous mycobacterial infection: lessons from single gene disorders affecting innate and adaptive immunity and lessons from molecular defects in interferon-gamma-dependent signaling. , 2006, Microbes and infection.

[22]  T. Matsubayashi,et al.  Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene. , 2006, Acta paediatrica.

[23]  T. Nakahata,et al.  Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome. , 2005, Arthritis and rheumatism.

[24]  M. Newport,et al.  Clinical features of dominant and recessive interferon γ receptor 1 deficiencies , 2004, The Lancet.

[25]  J. Yagüe,et al.  Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene. , 2004, Arthritis and rheumatism.

[26]  R. Janssen,et al.  Enhanced interleukin-1β and interleukin-18 release in a patient with chronic infantile neurologic, cutaneous, articular syndrome , 2004 .

[27]  S. Dorman,et al.  A Novel Mutation in IFN-γ Receptor 2 with Dominant Negative Activity: Biological Consequences of Homozygous and Heterozygous States1 , 2004, The Journal of Immunology.

[28]  F. Martinon,et al.  NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. , 2004, Immunity.

[29]  S. Amladi,et al.  Online Mendelian Inheritance in Man 'OMIM'. , 2003, Indian journal of dermatology, venereology and leprology.

[30]  E. Remmers,et al.  De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. , 2002, Arthritis and rheumatism.

[31]  A. Thatayatikom,et al.  Mutation of a New Gene Encoding a Putative Pyrin-Like Protein Causes Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome , 2002, Pediatrics.

[32]  D. Valle,et al.  Online Mendelian Inheritance In Man (OMIM) , 2000, Human mutation.

[33]  S. Dorman,et al.  Abnormal Regulation of Interferon-γ, Interleukin-12, and Tumor Necrosis Factor-α in Human Interferon-γ Receptor 1 Deficiency , 1998 .

[34]  S. Dorman,et al.  Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. , 1998, The Journal of clinical investigation.

[35]  M. Newport,et al.  A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. , 1996, The New England journal of medicine.

[36]  田中 尚子.  High incidence of NLRP3 somatic mosaicism in chronic infantile neurological cutaneous and articular syndrome patients : the results of an international multicenter collaborative study , 2012 .