title: A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.
abstract: Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
authors.affiliation: Neuronal Survival Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, S-221 00 Lund, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Björkqvist
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Wild
authors.forename: Jenny
authors.initials: J
authors.lastname: Thiele
authors.forename: Aurelio
authors.initials: A
authors.lastname: Silvestroni
authors.forename: Ralph
authors.initials: R
authors.lastname: Andre
authors.forename: Nayana
authors.initials: N
authors.lastname: Lahiri
authors.forename: Elsa
authors.initials: E
authors.lastname: Raibon
authors.forename: Richard V
authors.initials: RV
authors.lastname: Lee
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Benn
authors.forename: Denis
authors.initials: D
authors.lastname: Soulet
authors.forename: Anna
authors.initials: A
authors.lastname: Magnusson
authors.forename: Ben
authors.initials: B
authors.lastname: Woodman
authors.forename: Christian
authors.initials: C
authors.lastname: Landles
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Azadeh
authors.initials: A
authors.lastname: Khalili-Shirazi
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lowdell
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Thomas
authors.initials: T
authors.lastname: Möller
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D018448:Models, Immunological; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: D016207:Cytokines; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins