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

• Published in: The Journal of experimental medicine Vol. 205; no. 8; pp. 1869 - 1877
• Main Authors: Björkqvist, Maria, Wild, Edward J, Thiele, Jenny, Silvestroni, Aurelio, Andre, Ralph, Lahiri, Nayana, Raibon, Elsa, Lee, Richard V, Benn, Caroline L, Soulet, Denis, Magnusson, Anna, Woodman, Ben, Landles, Christian, Pouladi, Mahmoud A, Hayden, Michael R, Khalili-Shirazi, Azadeh, Lowdell, Mark W, Brundin, Patrik, Bates, Gillian P, Leavitt, Blair R, Möller, Thomas, Tabrizi, Sarah J
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 04.08.2008
• Subjects: Animals; Basic Medicine; Case-Control Studies; Central Nervous System - immunology; Central Nervous System - pathology; Cytokines - blood; Cytokines - cerebrospinal fluid; Gene Expression; Humans; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - immunology; Huntington Disease - pathology; Macrophages - immunology; Macrophages - metabolism; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Transgenic; Microglia - immunology; Microglia - metabolism; Models, Immunological; Monocytes - immunology; Monocytes - metabolism; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - immunology; Nerve Tissue Proteins - metabolism; Neurosciences; Neurovetenskaper; Nuclear Proteins - genetics; Nuclear Proteins - immunology; Nuclear Proteins - metabolism; Trinucleotide Repeat Expansion
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20080178

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.