A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.
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.
Björkqvist
Maria
M
Neuronal Survival Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, S-221 00 Lund, Sweden.
Wild
Edward J
EJ
Thiele
Jenny
J
Silvestroni
Aurelio
A
Andre
Ralph
R
Lahiri
Nayana
N
Raibon
Elsa
E
Lee
Richard V
RV
Benn
Caroline L
CL
Soulet
Denis
D
Magnusson
Anna
A
Woodman
Ben
B
Landles
Christian
C
Pouladi
Mahmoud A
MA
Hayden
Michael R
MR
Khalili-Shirazi
Azadeh
A
Lowdell
Mark W
MW
Brundin
Patrik
P
Bates
Gillian P
GP
Leavitt
Blair R
BR
Möller
Thomas
T
Tabrizi
Sarah J
SJ
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
D016207:Cytokines; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins