title: An autoinflammatory neurological disease due to interleukin 6 hypersecretion.
abstract: Autoinflammatory diseases are rare illnesses characterized by apparently unprovoked inflammation without high-titer auto-antibodies or antigen-specific T cells. They may cause neurological manifestations, such as meningitis and hearing loss, but they are also characterized by non-neurological manifestations. In this work we studied a 30-year-old man who had a chronic disease characterized by meningitis, progressive hearing loss, persistently raised inflammatory markers and diffuse leukoencephalopathy on brain MRI. He also suffered from chronic recurrent osteomyelitis of the mandible. The hypothesis of an autoinflammatory disease prompted us to test for the presence of mutations in interleukin-1-pathway genes and to investigate the function of this pathway in the mononuclear cells obtained from the patient. Search for mutations in genes associated with interleukin-1-pathway demonstrated a novel NLRP3 (CIAS1) mutation (p.I288M) and a previously described MEFV mutation (p.R761H), but their combination was found to be non-pathogenic. On the other hand, we uncovered a selective interleukin-6 hypersecretion within the central nervous system as the likely pathogenic mechanism. This is also supported by the response to the anti-interleukin-6-receptor monoclonal antibody tocilizumab, but not to the recombinant interleukin-1-receptor antagonist anakinra. Exome sequencing failed to identify mutations in other genes known to be involved in autoinflammatory diseases. We propose that the disease described in this patient might be a prototype of a novel category of autoinflammatory diseases characterized by prominent neurological involvement.
authors: UO Neurologia VIII, Department of Clinical Neurosciences, IRCCS Foundation, "C, Besta" Neurological Institute, Milan 20133, Italy. ettore.salsano@istituto-besta.it
authors: Ettore
authors: E
authors: Salsano
authors: Ambra
authors: A
authors: Rizzo
authors: Gloria
authors: G
authors: Bedini
authors: Loris
authors: L
authors: Bernard
authors: Valentina
authors: V
authors: Dall'olio
authors: Sara
authors: S
authors: Volorio
authors: Monica
authors: M
authors: Lazzaroni
authors: Isabella
authors: I
authors: Ceccherini
authors: Dejan
authors: D
authors: Lazarevic
authors: Davide
authors: D
authors: Cittaro
authors: Elia
authors: E
authors: Stupka
authors: Rosina
authors: R
authors: Paterra
authors: Laura
authors: L
authors: Farina
authors: Mario
authors: M
authors: Savoiardo
authors: Davide
authors: D
authors: Pareyson
authors: Francesca L
authors: FL
authors: Sciacca
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002908:Chronic Disease; D056660:Hereditary Autoinflammatory Diseases / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008581:Meningitis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D009422:Nervous System Diseases / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6