Activation of the immune system in HD

HD Lighthouse Contributing Editor's Comment: 

Two teams of researchers, working separately and then combining their results for an important journal article, provide evidence of an activated immune system in both the blood and brain of HD patients and HD mice.

The involvement of the immune system in HD is not a new finding. Studies of inflammation in neurodegenerative disorders have been tracked on the Lighthouse since 2001. What's exciting about the new research is that specific cytokines (proteins secreted in response to a pathogen) were identified which are elevated years before the disease is manifest in the patient and which increase with the disease progression. They are measurable in the blood and parallel what is happening in the brain.

Researchers at the University of Washington and researchers at the University College of London used a variety of methods to study the immune system, examining blood plasma and cerebrospinal fluid in HD patients, premanifest gene carriers, and controls as well as in multiple mouse models.  In addition, brain tissue samples from autopsy were analyzed as were samples from the mice.

They found that certain cytokines, proteins which are secreted as part of an immune system response, were elevated in both plasma and the brain.  These cytokines were elevated in those who were gene positive but not showing clinical symptoms as compared to a control group of individuals without the HD gene. Strikingly, these elevations were found in premanifest gene carriers who were an average of 16 years from their predicted age of onset.  Levels were elevated still further in HD patients as compared to premanifest gene carriers.  

It appears that the presence of the HD protein causes the cells to be over-responsive when the immune system is activated.  The researchers stimulated isolated white blood cells from people and YAC128 mice and found that the cells produced more of the cytokine IL-6 then did cells from normal controls.  They repeated the experiment with microglia cells from the R6/2 mice and got the same response.

In the blood, the cytokine elevation was associated with white blood cells.  In the brain it was associated with microglia.  The microglia are often said to be the immune cells of the brain, but their function is a little more complicated than that.  The microglia, like glia cells, function to protect and support neurons, but they also function as immune cells.  

However, they are not as powerful as the immune cells in the blood because neurons are too fragile to withstand a response of that intensity.

The role of microglia in HD is not fully understood but it is believed that they contribute to pathology since microglial activation is associated with the areas of the brain affected by HD and is found early in the brain in premanifest gene carriers, and because it increases with the severity of the disease.  The theory is that activated microglia could lead to excitoxicity, the production of free radicals and oxidative damage, and caspace activation and apoptosis.

The new research is helpful in three ways. First, this identifies a possible new target for fighting the disease. Second, it helps to identify when the treatment should be started once it's available. Elevated levels of the cytokines were found an estimated sixteen years before the expected onset of the disease. Third, as Lighthouse readers know, the search for a set biomarkers is to more precisely measure the progression of the disease and shorten clinical trials is underway. Cytokine levels could become part of a set of biomarkers.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 08-17-2008

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

Maria Björkqvist, Edward J. Wild, Jenny Thiele, Aurelio Silvestroni, Ralph Andre, Nayana Lahiri, Elsa Raibon, Richard V. Lee, Caroline L. Benn, Denis Soulet, Anna Magnusson, Ben Woodman, Christian Landles, Mahmoud A. Pouladi, Michael R. Hayden, Azadeh Khalili-Shirazi, Mark W. Lowdell, Patrik Brundin, Gillian P. Bates, Blair R. Leavitt, Thomas Möller, and Sarah J. Tabrizi.

press releases from the University of Washington and University College of London combined:

Researchers link Huntington's disease to overactive immune response in the brain

The damage to brain tissue seen in Huntington's disease may be caused by an overactive immune response in the bloodstream and the brain, according to new findings from two teams of researchers at the University of Washington in Seattle and University College London. The findings will be published online July 14 in the Journal of Experimental Medicine.

Working separately, the two teams found evidence in both brain cells and the bloodstream suggesting an important link between the immune system's response and Huntington's disease. Together, the findings may help scientists find biological markers for monitoring the disease progression earlier and with more accuracy, and could help them develop new treatments for the disease. Huntington's is a fatal inherited neurodegenerative disorder for which there is currently no effective treatment.

The UW team, lead by Dr. Thomas Moeller, research associate professor of neurology, had previously studied the role of inflammation and immune response in neurodegenerative diseases like Huntington's and ALS, also known as Lou Gehrig's disease. In this study, they found that patients with Huntington's had higher levels of immune-system signaling molecules, called cytokines, in their brain tissue.

The UW researchers then looked at a mouse-based model of the disease, studying the response of microglia, the immune cells of the nervous system. When the microglia were treated with a molecule triggering an immune response, the microglia from Huntington's mice produced much higher levels of cytokines, the immune system molecules. That finding suggests that the protein produced by the Huntington's disease genetic mutation, a protein called huntingtin, is causing the immune cells to be overactive. The researchers think that overly strong immune response may be the mechanism through which the disease causes damage to neurons in the brain.

"When we found increased levels of cytokines in the brains of Huntington's disease patients, we were very excited," Moeller said. "Inflammation in the brain has been increasingly recognized as an important component in other neurodegenerative diseases such as Alzheimer's or Parkinson's disease. These findings might open the door to novel therapeutic approaches for Huntington's disease that target inflammation."

The team at University College London focused their work on immune cells in the bloodstream, and found similar results linking the disease to the body's immune response.

Dr Sarah Tabrizi led the research for the UCL Institute of Neurology team. She said, “Finding increased cytokines in the blood was interesting, but the idea that the HD gene 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 by which the HD gene 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.”

The immune response in the blood may also help researchers use immune-system molecules as biological markers for the disease, which can be difficult to diagnose in early stages. Better tracking of Huntington's disease progression may help researchers to fine-tune interventions aimed at slowing the disease before it has affected as much brain tissue.

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.

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Source: Journal of Experimental Medicine 2008 Jul 14. [Epub ahead of print]