HD and Inflammation
Disease Mechanism II: Inflammation

Studies of the HD brain indicate that long-term inflammation plays a significant role in the progression of HD. Given this finding, scientists are trying to understand the specific role of inflammation and are investigating the possibility of anti-inflammatory drugs as HD therapies.

The process of inflammation can be thought of as our body going into battle. Both inflammation and wars are responses to outside threats. Inflammation is a complex process that causes swelling, redness, warmth, and pain. It's our body's natural response to injury and plays an important role in healing and fighting infection. Similar to war, inflammation has its own troops: immune cells that secrete various molecules and enzymes that kill foreign invaders. Inflammation destroys and kills the injury-causing agent through a variety of mechanisms. Short-term inflammation protects the body from damage and disease. However, long-term or chronic inflammation, much like a drawn-out war, can lead to damage, not only to the foreign substances, but to the body itself as well.

Studies of the HD brain indicate that chronic inflammation plays a significant role in the progression of HD. Our body’s immune system has the ability to recognize foreign substances and launch various defense mechanisms to get rid of these potentially harmful substances. Scientists believe that the immune system recognizes the expanded glutamine tract in the altered huntingtin protein as “foreign” and tries to get rid of it, resulting in chronic inflammation and damage.

Studies have also shown that excitotoxic amino acids such as glutamate induce a direct activation and proliferation of cells involved in inflammation. Since glutamate activity is also implicated in the progression of HD, it is possible that the glutamate molecules in the HD brain induce an inflammatory response.

The inflammatory response results in the activation of various types of cells and the production of different molecules that can lead to cell death. An example of cells activated by the inflammatory response are the microglia (a type of immune cell) which have been found to be highly activated in the HD brain.

What are glial cells?

Nerve cell bodies and axons are surrounded by glial cells. Glial cells outnumber nerve cells by about five to one in the nervous system. Although their names come from the Greek word for glue, glial cells do not actually hold other cells together. Furthermore, glial cells do not conduct nerve impulses, and are thus not essential for processing information. Rather, they serve as supporting elements to the brain and act as scavengers, removing debris after injury or neuronal death. Two types of glial cells produce the fatty coating that covers large axons of the nerve cells.

There are many different types of glial cells in the nervous system. Glial cells such as the oligodendrocytes produce the fatty coating in nerve cells, the astrocytes maintain ionic balance, while the microglia get rid of unwanted substances.

Glial cells and HD

Research has shown that there is a marked increase in microglia in the HD brain. Microglia play the role of immune cells in the brain. They are sometimes called “brain macrophages” because they perform many of the same functions that macrophages in our body do. Macrophages are immune cells found all over our body that act as scavengers, engulfing dead cells, foreign substances, and other debris.

In the brain, the microglia act as macrophages, getting rid of unwanted substances by engulfing them and “eating” them.

Microglia are normally inactive. They become active in the brain following a variety of debilitating events such as infection, trauma, and decreased blood and oxygen flow. Once activated, the microglia are then able to remove dying neurons and other cells.

In the HD brain, an increase in activated microglia is found along the vicinity of nerve cells that contain neuronal inclusions (NIs) – accumulation of the huntingtin protein. This finding suggests that the huntingtin protein accumulation influences the activation of reactive microglia. Nerve cell injury due to excitotoxins such as glutamate also induces long-term microglial activation in the brain. Excitotoxins are excitatory amino acids found in increased concentrations in the nervous system and cause damage and cell death. (For more on excitotoxins, click here.)

Microglia and other inflammatory mediators

Aside from engulfing foreign substances, activated microglia are also capable of producing various substances that act as mediators of the inflammatory response. Although these mediators play an important role in inflammation, they are also potentially neurotoxic substances that can contribute to widespread central nervous system injury. Examples of inflammatory mediators include free radicals, proteases, excitatory amino acids, complement proteins, cytokines, and certain prostaglandins. These substances are the microglia’s “weapons:” they act to kill the foreign substance that invade our body. However, as stated before, chronic inflammation results in chronic release of these substances, which can eventually lead to considerable damage and cell death.

The exact mechanisms of these substances are not covered in this section. More information on each of the various inflammatory mediators can be found in various sources listed in the references section as well as in the chapter on Inflammatory Mediators.

These mediators each have different roles in the inflammatory response, but for our purposes, it is sufficient to know that all of them contribute to inflammation and are found in increased concentrations in the brains of people with neurological diseases such as HD and AD. Drugs that could lower the concentrations of these molecules are therefore attractive treatment agents for people with diseases where inflammation plays a prominent role.

Inflammation and disease

Inflammation, whether in the brain or in other parts of the body, is almost always a secondary response to some primary disease-causing substance or event. Despite the fact that inflammation is a secondary response, it is still an important mechanism that can protect or damage the cell, depending on its severity and length of occurrence. In head trauma, for example, the blow to the head is the primary event. However, what may be of greater concern is the secondary inflammatory response that will result from the primary event. When it continues for a long period of time, inflammation is likely to cause more neuron loss than the initial injury. Given that chronic inflammation has been reported in the brains of people with HD, anti-inflammatory compounds that will delay the inflammatory response or eradicate it altogether may be potential HD treatments to consider.

We hope you enjoyed this section of the HOPES website. To email this article to a friend, please click here. To leave feedback for the HOPES team, click here. Make sure to specify which article you're referring to.

-E. Tan, 9-21-01

For further reading:

1. Mulitple Sclerosis Glossary: http://www.albany.net/~tjc/gloss.html
   This page contains a glossary of words relevant to multiple sclerosis (MS) – an auto-immune disease that affects the nervous system. It is useful for looking up terms and concepts about the nervous system and immune system.
2. Neuroinflammation Working Group. "Inflammation and Alzheimer’s Disease." Neurobiology of Aging. 2000; 21: 383-421.
   This article contains detailed, comprehensive information on the inflammatory response and Alzheimer’s Disease (AD). It has information on the many studies done on the role of inflammation on the pathology of AD as well as the trials conducted on various anti-inflammatory compounds.
3. Sapp, et al. "Early and Progressive Accumulation of Reactive Microglia in the Huntington Disease Brain".Journal of Neuropathology and Experimental Neurology. 2001; 60(2): 161-172.
   This article contains information on a study done that investigated the presence of reactive microglia in postmortem brains of people with HD. The study reported that increased levels of reactive microglia are present in HD brains.
4. Singhrao, et al. "Increased Complement Biosynthesis By Microglia and Complement Activation on Neurons in Huntington's Disease." Experimental Neurology. 1999 Oct; 159(2):362-376.
   This article contains the full details on a study done to investigate the levels of inflammatory response proteins in HD nerve cells. The study reported that increased levels of those proteins are found in HD nerve cells.

Click here to return to "Disease Mechanism II: Inflammation".

Last Modified: 5-6-03

An educational product of HOPES, not to be used in place of medical care. For more information about HOPES, click on the Logo. To contact HOPES with comments or questions, click here.