Hyperactive white blood cells link the brain and blood in Huntington’s disease

In our previous work, we described an altered innate immune response in Huntington’s disease (HD) throughout the disease course (Bjorkqvist et al., JEM, 2008), demonstrating that pro-inflammatory cytokines such as IL-6 and TNF-alpha were significantly increased in the striatum, plasma and CSF of HD patients. We also identified innate immune cell hyperactivity with elevated IL-6 production in mutant htt expressing myeloid cells of the central (microglia) and peripheral innate immune system (monocytes and macrophages), both in HD patients and mouse models. This work represents a significant advance in our understanding of the role of the mutant Huntingtin gene and the pathogenesis of HD, suggesting that altered myeloid cell function may be relevant to HD pathogenesis and opens new avenues for research into biomarkers and disease-modifying therapies.

Our current work aims to characterise the mutant huntingtin-dependent abnormal cell function of peripheral myeloid cells isolated from HD patients in greater detail. Cell migration, cytokine production and phagocytosis are some of the functions we are looking at. In addition we are examining alterations in signalling pathways possibly responsible or related to these changes.

Recently, we described a migration defect in both murine and patient myeloid cells. Microglia, monocytes and macrophages are impaired in their migration towards chemotactic stimuli in vitro and in vivo, which may contribute towards the chronic low-grade inflammation observed in our previous studies.

We have also identified an overactivation in the NFkB pathway, a master regulator of the innate immune response and pro-inflammatory cytokine release, as a result of cell-intrinsic effects of mutant htt expression. We demonstrated a direct interaction of mutant htt with components of the NFκB pathway, whereby it interacts with IKKγ, leading to increased degradation of IκB and subsequent nuclear translocation of RelA. Glucan-encapsulated small interfering RNA particles were used to lower htt levels in human HD monocytes/macrophages, resulting in a reversal of htt-induced elevated cytokine production and transcriptional changes. This work is currently being translated to patient treatment with a clinical trial testing the effects of Laquinimod, a novel immune suppressant, on HD symptoms (see Legato HD trial).

Understanding the systemic nature of HD is important to developing models of disease pathogenesis and to designing disease modifying therapies that can be peripherally administered. Our work hopes to help us understand neural-immune cross-talk in HD, and how these interactions both centrally and peripherally contribute to disease pathogenesis.

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

This paper first described the role of the innate immune system in the pathogenesis of HD, now recognised as a major disease modifier. We report that abnormally high levels of molecules called cytokines – key to the body’s immune response – were present in the blood of people carrying the HD gene many years before the onset of symptoms.

Finding these cytokine levels in the blood of HD gene carriers so long before they exhibit symptoms could be an important clue to some of the earliest changes caused by the HD gene. The combinations and levels of cytokines, easily measured from a blood test, could be useful markers to help measure the severity of HD, making it easier and quicker to test new drugs.

In addition, we showed that white blood cells from HD patients were hyperactive, due to the presence of the abnormal HD protein (huntingtin) inside the cell. This hyperactivity was also seen in microglia (the brain’s immune cells) suggesting that abnormal immune activation could be one of the earliest abnormalities in HD, and that its signature in the blood could offer a glimpse into the effects of the disease in the brain. Abnormal immune activation could be a target for future treatments aimed at slowing down HD.

A new pathway of cellular damage?

Professor Sarah Tabrizi, UCL Institute of Neurology, led the research. She said: “Finding increased cytokines in the blood was interesting, but the idea that the mutant protein could be causing immune overactivity directly from within the white blood cells is important, because if the same thing is happening in the brain, cells that are there to protect neurons could be damaging them instead.”

“It looks like we’ve unearthed a new early pathway in HD by which the mutant protein could cause damage, through abnormal overactivity of the immune system. What’s more, this new pathway is quite easy to detect in the blood of patients, so we may have found a unique window from the blood into what the disease may be doing in the brain.”

Worldwide collaboration

This work was the result of a major international collaboration, involving teams from:

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Bjorkqvist M, Wild EJ et al. Journal of Experimental Medicine 2008: jem.20080178.

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Updated January 11, 2010