Various inflammatory mediators are released by our immune cells during times when harmful agents invade our body. Long-term release of some of these inflammatory mediators has been observed in the cells of people with HD. An understanding of how these mediators work and how to block their release could be helpful in looking for ways to delay the progression of HD.
Our body must defend itself against many different disease-causing substances such as viruses, bacteria, and parasites, as well as tumors and a number of various harmful agents. To combat these disease-causing substances or events, our body has developed many mechanisms to defend itself against such an “attack.” One of the ways by which our body protects itself is by triggering an inflammatory response. Early scientists considered inflammation as our body’s primary defense system. However, inflammation is more than just a simple defense system, because when left unchecked, it could lead to debilitating diseases such as arthritis or even death. Long-term inflammation is also linked to the progression of neurological diseases such as Alzheimer’s Disease and Huntington’s Disease.
The development of inflammatory reactions is controlled by various molecules released by our body’s immune cells. Our immune cells act as the body’s “soldiers,” and they guard the body against attack by releasing “weapons” in the form of inflammatory mediators. One type of immune cell found to be present in extraordinarily high concentrations in the HD brain is the microglia. The microglia have been observed to release various inflammatory mediators that contribute to the long-term occurrence of inflammation in the HD brain, resulting in damage and cell death.
We will go over some of the most common inflammatory mediators released by the body’s immune cells in order to understand how the inflammatory response works. In general, most of the mediators that we will talk about in this section have one of two roles: amplification of the immune response, or destruction of the foreign substance.
Free radicals are atoms or molecules that are highly reactive with other cellular structures because they contain unpaired electrons. As free radicals react with cellular structures, they lead to cellular injury and eventually, cell death. Free radicals may also trigger activation of various proteins that in turn activate the inflammatory response.
Although the majority of the research on HD focuses on free radical generation due to impaired electron transport chain functioning, the concept of free radical toxicity actually has its roots in inflammation biology. (Click here for more information on free radicals and antioxidants.) The secretion of reactive oxygen and nitrogen free radical species by inflammatory cells is a major mechanism for attacking foreign substances. Large amounts of free radicals are produced by activated microglia, and chronic release of free radicals result in neuronal injury and cell death.
Excitotoxins such as glutamate and quilonic acid are excitatory molecules that are released by immune cells and are known to cause damage to the body. They can also result in cognitive impairment when found in increased concentrations in the brain. Glutamate has specifically been found to initiate various mechanisms that ultimately lead to cell death. (For more information on glutamate, click here.)
Complement is a set of many proteins activated in sequence when cells are exposed to a foreign substance. Once the proteins are activated, nine of them come together to form the membrane attack complex (MAC). When assembled on a cell membrane, MAC forms a ring-like structure that allows the movement of ions and small molecules into and out of the cell, disrupting the normal state of the cell.
The MAC creates a pore that allows the movement of various ions and substances into and out of the cell, resulting in cell damage.
The complement system is a potent mechanism for initiating and amplifying inflammation. One of the most damaging effects induced by the formation of MAC is the entry of calcium ions (Ca2+) into the cell. The Ca2+ ions are capable of activating various Ca2+-dependent proteins that contribute to cell death. If a sufficient number of MACs have assembled on the cell, cell death eventually occurs.
Studies have reported that a number of complement proteins are expressed at a higher level in HD brains compared to non-HD brains. The increased number of activated microglia induced by the altered huntingtin protein most likely causes the higher levels of complement proteins in HD brains.
Cytokines are proteins that are secreted by various types of immune cells and serve as signaling chemicals. The central role of cytokines is to control the direction, amplitude, and duration of the inflammatory response.
There are two main groups of cytokines: pro-inflammatory and anti-inflammatory. Pro-inflammatory cytokines are produced predominantly by activated immune cells such as microglia and are involved in the amplification of inflammatory reactions. Anti-inflammatory cytokines are involved in the reduction of inflammatory reactions. Table 1 lists some of the most common proinflammatory and inflammatory cytokines.
Pro-inflammatory cytokines
Anti-inflammatory cytokines
IL-1
IL-4
IL-6
IL-10
TNF-Alpha
IL-13
TGF-Beta
Table 1: List of common pro-inflammatory and anti-inflammatory cytokines
Prostaglandins are produced in most tissues of the body and have varying actions. They are short-lived, hormone-like chemicals that regulate cellular activities on a moment-to-moment basis. Prostaglandins fall into 3 series - PG1, PG2, and PG3. PG1 and PG3 are known to have anti-inflammatory effects as they decrease inflammation, increase oxygen flow, prevent cell aggregation, and decrease pain. PG2 are known to have pro–inflammatory effects, since their effects are opposite to those of PG1 and PG3. Table 2 shows a comparison of the effects of the different prostaglandins.
PG1 and PG3 (anti-inflammatory)
PG2 (pro-inflammatory)
Decrease pain
Increase pain
Increase oxygen flow
Decrease oxygen flow
Dilate airways
Constrict airways
Decrease inflammation
Increase inflammation
Table 2: Prostaglandins
Because of the negative effects of chronic inflammation, it is speculated that people with HD would most likely benefit from an increase in Series 1 and 3 prostaglandins and a decrease in Series 2 prostaglandins.
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-P. Chang, 5/6/03
For further reading:
Inflammation: http://nic.savba.sk/logos/books/scientific/node4.html This page contains detailed information about inflammation. It goes over all phases of the inflammatory response in a technical manner. Although not as easy to understand as other sites, this page has vast amounts of information for the person seeking to understand the many aspects of inflammation.
Click here to return to "Disease Mechanism II: Inflammation".
Last Modified: 5-6-03
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