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

By M. Björkqvist, E. Wild, J. Thiele, A. Silvestroni, R. Andre, N. Lahiri, E. Raibon, Richard V. Lee, C. Benn, D. Soulet and 12 more. Journal of Experimental Medicine, 2008

668 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e5d09a79819eba4e95f9b85f33e2ab910e07478b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. T. Wyss‐Coray
2. T. Johansen
3. Sangram S. Sisodia
4. R. Ransohoff

In Molecular Biology

1. V. Deretic
2. T. Wyss‐Coray
3. T. Johansen
4. Kurt M. Lucin
5. R. Ransohoff

Citations in the corpus

• Interleukin-6, a Major Cytokine in the Central Nervous System (2012, background): “IL-6 expression is dramatically elevated in the striatum of HD patients, and in general these patients show clear signs of abnormal immune activation, IL-6 being one of the cytokines affected and monocytes, macrophages and microglia (from both HD and mouse HD models) being overactive upon stimulatio”
• Heterogeneity of CNS myeloid cells and their roles in neurodegeneration (2011, background): “Arguing in favor of altered myeloid cell function in individuals with Huntington's disease, the circulating monocytes of affected individuals were shown to overexpress inflammatory cytokine”
• TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation (2012, positive): “We first tested whether the Rab8b phenotype was exerted via Htt as a putative effector (known to functionally affect peripheral myeloid cells in Huntington’s disease patients [Björkqvist et al., 2008]).”
• Immune activation in brain aging and neurodegeneration: too much or too little? (2009, background): “Similarly, changes in patterns of soluble immune mediators and other communication factors in the periphery have been linked to AD, HD, and PD and were used to predict disease progression (Bjorkqvist et al., 2008; Ray et al., 2007; Scherzer et al., 2007).”