title: TLR2/TLR4-dependent exaggerated cytokine production in hyperimmunoglobulinaemia D and periodic fever syndrome.
abstract: OBJECTIVE
  The autoinflammatory hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is characterized by recurrent episodes of fever and inflammation. As part of the mevalonate kinase deficiency spectrum, it is caused by MVK mutations, resulting in decreased mevalonate kinase activity in the isoprenoid pathway. Although IL-1β is considered a major cytokine in its pathogenesis, IL-1 blockade is not successful in a proportion of patients. We aimed to further characterize the pro-inflammatory cytokine profile of HIDS.
  
  
  METHODS
  Peripheral blood mononuclear cells from HIDS patients and healthy donors were incubated with several stimuli. Cytokine concentrations were detected by ELISA. To analyse mRNA and protein expression, we performed quantitative RT-PCR and western blot, respectively.
  
  
  RESULTS
  We observed significant differences in cytokine production when cells were incubated with ligands for Toll-like receptor 2 (TLR2), TLR4 and nucleotide-binding oligomerization domain-containing 2 (NOD2). The increased ratio between active and inactive caspase-1 protein in HIDS patients could explain why these cells are more easily triggered to secrete IL-1β. This is apparently not regulated at the transcriptional level, since expression levels of caspase-1 and IL-1β mRNA were similar in patients and controls. Both anakinra and tocilizumab treatment resulted in decreased inflammation, both ex vivo as well as in vivo.
  
  
  CONCLUSIONS
  The increased cytokine secretion in HIDS is specific for TLR2, TLR4 and NOD2 ligation. Although IL-1β is important in the HIDS pathology, our data suggest it is a multicytokine disease. A more rigorous clinical trial is required to determine whether IL-6 receptor blockade may be considered in patients not responding to anakinra treatment.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands. Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Stoffels
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands. Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Johanna
authors.initials: J
authors.lastname: Jongekrijg
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands. Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: Remijn
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands. Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Nina
authors.initials: N
authors.lastname: Kok
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands. Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands. Department of Internal Medicine, Radboud University Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands. anna.simon@radboudumc.nl.
authors.forename: Anna
authors.initials: A
authors.lastname: Simon
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000494:pharmacology; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D054078:Mevalonate Kinase Deficiency / Q000378:metabolism*; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: anakinra; autoinflammatory syndrome; hyper-IgD syndrome; mevalonate kinase deficiency; periodic fever; tocilizumab