title: Role of interleukin-1β in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy.
abstract: OBJECTIVE
  A new class of autoinflammatory syndromes called NLRP12-associated disorders (NLRP12AD) has been associated with mutations in NLRP12. Conflicting data on the putative role of NLRP12 in interleukin-1β (IL-1β) signaling have been found in in vitro analyses. This prospective study was undertaken to assess the secretion of IL-1β and 3 IL-1β-induced cytokines (IL-1 receptor antagonist [IL-1Ra], IL-6, and tumor necrosis factor α [TNFα]) in patients' peripheral blood mononuclear cells (PBMCs) cultured ex vivo and to evaluate the patients' response to IL-1Ra (anakinra), a major drug used in the treatment of autoinflammatory disorders.
  
  
  METHODS
  Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment.
  
  
  RESULTS
  Spontaneous secretion of IL-1β by patients' PBMCs was found to be dramatically increased (80-175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near-normalization of IL-1β secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNFα secretion, persistent elevated levels of IL-1Ra and IL-6, and a reactivation of IL-1β secretion. Anakinra was discontinued after 14 months of therapy.
  
  
  CONCLUSIONS
  Our findings provide in vivo evidence of the crucial role of IL-1β in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti-IL-1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, UMR S933, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jéru
authors.forename: Véronique
authors.initials: V
authors.lastname: Hentgen
authors.forename: Sylvain
authors.initials: S
authors.lastname: Normand
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cochet
authors.forename: Adriana
authors.initials: A
authors.lastname: Delwail
authors.forename: Gilles
authors.initials: G
authors.lastname: Grateau
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lecron
mesh_terms: D004797:Enzyme-Linked Immunosorbent Assay; D056660:Hereditary Autoinflammatory Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D011446:Prospective Studies; D015398:Signal Transduction
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C476731:NLRP12 protein, human