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

Author:

Björkqvist Maria1,Wild Edward J.2,Thiele Jenny3,Silvestroni Aurelio4,Andre Ralph2,Lahiri Nayana2,Raibon Elsa4,Lee Richard V.4,Benn Caroline L.5,Soulet Denis1,Magnusson Anna1,Woodman Ben5,Landles Christian5,Pouladi Mahmoud A.3,Hayden Michael R.3,Khalili-Shirazi Azadeh2,Lowdell Mark W.6,Brundin Patrik1,Bates Gillian P.5,Leavitt Blair R.3,Möller Thomas4,Tabrizi Sarah J.2

Affiliation:

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

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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