The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20080178
The Journal of Experimental Medicine, Vol. 205, No. 8, 1869-1877
The Rockefeller University Press, 0022-1007 $30.00
© Björkqvist et al.
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ARTICLE

 A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease

Maria Björkqvist1, Edward J. Wild2, Jenny Thiele3, Aurelio Silvestroni4, Ralph Andre2, Nayana Lahiri2, Elsa Raibon4, Richard V. Lee4, Caroline L. Benn5, Denis Soulet1, Anna Magnusson1, Ben Woodman5, Christian Landles5, Mahmoud A. Pouladi3, Michael R. Hayden3, Azadeh Khalili-Shirazi2, Mark W. Lowdell6, Patrik Brundin1, Gillian P. Bates5, Blair R. Leavitt3, Thomas Möller4, and Sarah J. Tabrizi2

1 Neuronal Survival Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, S-221 00 Lund, Sweden
2 Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, England, UK
3 Department of Medical Genetics and Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
4 Department of Neurology, School of Medicine, University of Washington, Seattle, WA 98195
5 Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, England, UK
6 Department of Haematology, Royal Free & University College Hospital, Hampstead Campus, London WC1E 6BT, England, UK

CORRESPONDENCE Sarah J. Tabrizi: sarah.tabrizi{at}prion.ucl.ac.uk

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.

Abbreviations used: AUC, area under the curve; B2M, β-2-microglobulin; CNS, central nervous system; CSF, cerebrospinal fluid; HD, Huntington's disease; QPCR, quantitative PCR; ROC, receiver operating characteristic; TFC, total functional capacity; UHDRS, unified HD rating scale; YAC, yeast artificial chromosome.

M. Björkqvist and E.J. Wild contributed equally to this paper.

© 2008 Björkqvist et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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