By William Collinge, Ph.D.

Table of Contents

Chapter 4. Your Immune System:
How It Works, and How It is Affected in CFS

OVERVIEW OF THE IMMUNE SYSTEM
     There are many ways to tell the story of immunity, and they all must grapple with its complexity. To attempt to describe the immune system requires us to artificially separate it from the rest of the body and the myriad other systems with which it relates. Of course, none of your body's systems exist in isolation. In fact, they literally flow into one another like a seamless garment, and you can not really find where one system ends and another begins. Nonetheless, I will describe what are considered to be the main elements of the immune system.

The Sea of Microbes
     Our environment is an ocean of life. This ocean is teaming with millions of viruses, bacteria, fungi, and other micro-organisms, and this abundance of living organisms does not stop at our skin. It is normal for us to have many different kinds of organisms living inside our bodies. Some are good for us, such as certain kinds of bacteria that live in our intestinal tract and help maintain healthy digestion. Others have the potential to cause symptoms of dis-ease or imbalance in how our bodies function. These latter organisms are called pathogens. 
     Usually we think of the surface of our skin as a boundary between us and our environment. In a sense, the skin serves as an interface between us and what is outside us--self and nonself. When we touch a tree, our skin is a boundary, the point where we, or the self, and the tree, or non-self, meet. But because our bodies are permeable, many microscopic organisms are able to penetrate our boundaries. 
     Hence we need another level of protection inside the body to distinguish self from non-self. This is the function of the immune system--to provide internal protection from non-self organisms or materials that penetrate our boundaries. The immune system is our internal interface between self and non-self. As we shall see, the immune system is able to distinguish between friend and foe, and to protect us from materials which do not belong.

The Balance of Nature
     The notion of the balance of nature means that we are living in balance or harmony with life around us. However, it does not apply only to the grand scale of ecological crises and endangered species in the outer world. It also applies to the environment inside our bodies. In fact, many definitions of health often refer to living in balance. This implies that all of our internal life processes are somehow in harmony or rhythm with each other. 
     Within our bodies, as in outer nature, one of the principles for maintaining balance is that of predators and prey. Certain organisms perform the function of limiting the growth of other organisms which could upset the balance, and could ultimately lead to the demise of the entire system. In the human body this principle takes the form of the immune system hunting down and destroying pathogens. The immune system is predatory, with its white cells literally hunting down and preying upon pathogens such as viruses, bacteria, and fungi. 
     Because we are constantly immersed in this sea of life, it is normal for us to have these organisms within us, and it is normal for the immune system to routinely detect and destroy them, usually without our ever being even aware of it. It is normal for us to have cancer cells arise, and again, for our immune system to quietly destroy them before any noticeable pathology could ever develop. We are in a state of dis-ease when  the balancing principle has somehow been interfered with or the immune system has been unable to respond as needed to maintain the balance.
     With these principles in mind, let us now consider the major parts of the immune system.

The Bone Marrow
     The marrow has been often used as a powerful symbol in poetry and literature, referring to the deepest recesses of one's being. There is perhaps a universal understanding that to penetrate to the marrow is to penetrate to the core. This symbolism is certainly an accurate one when considering the human body, for without the marrow we could not live.
     The marrow is a spongy tissue that fills the hollow spaces in our bones. You can think of the marrow as a vast vineyard, with billions upon billions of vines bearing fruit. The vines represent what are called stem cells. These are the cells which continuously bear fruit in the form of red cells and white cells. They give birth to the red cells and platelets of your blood. They also give birth to all your white cells, which do the work of your immune system. As these offspring of your stem cells mature and ripen, they detach and are carried out into the body by your circulatory system.

The Thymus Gland
     After your white cells leave the bone marrow, about half of them migrate directly to the thymus gland. The thymus is a small, walnut-sized gland located behind the breast bone. Only in recent years has it been understood as an integral part of the immune system. It serves as an incubator for certain white cells. Those cells which migrate to the thymus become "T" cells -- "T" for "thymus-derived." There are basically four types of T-cells, which will be discussed later. These include T-helper cells, T-suppressor cells, T-killer cells, and T-memory cells. Each of these performs a vital function in your immune system.

The Spleen
     The spleen is another region of spongy tissue, located deep in the abdomen between your stomach and left kidney. It too is not completely understood, but it serves as a reservoir for immune cells to be stored and to interact with each other. As we shall see later, communication among white cells is an important function of the immune system, and the spleen assists with this. Damage to the spleen can result in increased vulnerability to infection. 

The Immune Cells
     Finally we have the immune cells themselves, also called white cells. There are many different types of white cells, which can be lumped into a few broad categories. If you can bear with this explanation, you will see that the immune system is an incredibly intelligent, well-organized system.

     T-helper cells. One of the most important functions of the immune system is performed by the T-helper cell. That function is to turn on or arouse the immune response. The T-helpers receive information from other white cells that tells them of the presence of a threat. The T-helpers then release messenger molecules, called cytokines, into the bloodstream. These messages are received by the other white cells, which in turn respond with heightened activity, mounting a response to the offending material, whether it is a virus, bacteria, cancer cell, toxic substance, or other threat.
     The T-helper cell is considered the trigger of the immune response. Unfortunately, it is one of the primary targets of the human immunodeficiency virus in AIDS. If the T-helper cell is injured or killed, then the person's immune response will be compromised, and they will be more vulnerable to infections. This of course is how AIDS becomes a life threatening illness. People who suffer from AIDS do so as a result of infections that would not be such a threat in a normally aroused immune system.

     T-Suppressor Cells. These are the cells which turn off the immune response after a threat has passed. The T-suppressors also release chemical messengers into the bloodstream to the other white cells. These chemicals have the effect of announcing that the battle is over and it is safe now to relax the defense forces and move back into a state of routine surveillance.
     Immunologists have found that the ratio of T-helper cells to T-suppressor cells is an indication of the health of the immune system. The normal T-cell ratio is approximately 1.8 T-helper cells for each T-suppressor cell. This is the ratio in which the immune system is in balance and runs most harmoniously. 
     There are many diseases in which the ratio is out of balance, one way or the other. For instance, some lymphomas may have a ratio of 4:1 or higher, and multiple sclerosis may range from 2.5:1 to 2.8:1. AIDS, on the other hand, may be 1:1 or less, because of the toll the AIDS virus takes on T-helper cells. In the Tahoe study reported earlier, CFS patients were found to have a ratio of 3.16:1, a clearly abnormal ratio.

     T-Killer Cells. There are several types of white cells which do the work of actually killing or removing unwanted material. The T-killer cell is one of these. It has receptors on its surface which receive the chemical message from the T-helper cell. The receptor is like a satellite dish, which accepts the message and processes it. After this communication has taken place, the T-killer knows what kind of target to look for and springs into action.
     It is not entirely clear how T-killer cells find their targets, but it is probably through some kind of electrochemical attraction. Once they encounter the unwanted tissue, they use chemical warfare to destroy it. This means they literally come up against the surface of the offending organism and inject poison into it. The poison dissolves a hole in the wall of the offending cell, its insides spill out, and it dies. Once the battle is over, the T-killer cell receives the message from the T-suppressor to retreat, and it returns to a mode of surveillance.

     T-Memory Cells. As I stated earlier, the immune system is intelligent. This means it communicates, has senses, and also has memory. The T-memory cells perform the function of storing information about past encounters with disease-causing agents. This enables the immune system to respond to an invader more quickly, because it does not have to go through the work of drawing up a profile and identification of the offender. In a sense, the information is already filed in the memory bank, enabling more rapid recognition and analysis of the offender to take place, and an overwhelming immune response may be mounted more quickly. This is the principle on which immunizations and inoculations are based.

     Macrophages. As stated earlier, only about half the white cells leaving the marrow become T-cells. The other half become macrophages, natural killer cells, and B-cells. 
     Macrophages are the largest cells of the immune system. Their name literally means "the great eaters." Their function is to roam throughout the body picking up debris, digesting it, and removing it. They keep the body clean, in a sense, constantly on the look out for diseased, dying, or dead tissue. Occasionally a macrophage will encounter a pathogen such as a virus, bacterium, or other invader. When this happens, the macrophage will take a piece of material from this invader and bring this evidence to the attention of the T-memory cell for identification. In this way, macrophages play an essential role in surveillance of the body. They are also involved in eating and removing diseased or dead tissue, including the remains left by the work of killer cells.
     As do all the other white cells, macrophages do have certain vulnerabilities. One is that sometimes they can be penetrated by a dangerous virus, such as HIV. In this instance, rather than killing its host cell, HIV may simply live within the macrophage and go along for the ride. Unfortunately this is one of the routes by which viruses may penetrate through the blood-brain barrier and gain entry into brain tissue. Once in the brain, they can cause symptoms. Many of the symptoms of CFS are thought to be caused by the effects of viral activity on brain tissue.

     Natural Killer Cells. If there is to be a hero in the immune system, the natural killer (NK) cell is a good candidate. This is because NK cells are extremely powerful and important. They are thought to play a major role in the destruction of both cancer cells and cells which are infected by viruses.
     The NK cell functions like a free spirit. Since it is not part of the T-cell network, it is not dependent on messages from the T-helpers or T-suppressors to regulate its activity. On their own, NK cells are able detect the presence of a cancerous or virus-infected cell, and destroy it. The killing process is the same as that described earlier for the NK's close cousins, the T-killer cells.
     Because they are free spirits, NK cells play an important role in diseases where T-helper function is deficient. It is believed that long-term AIDS survivors do well because their NK cells are compensating for a deficient number of T-helper cells. This demonstrates one of the important features of the immune system, called redundancy--the ability of other parts of the system to pick up the slack and compensate when one part is having difficulty. Overall, the NK cell is considered a symbol of the fighting spirit of the immune system.

     B-Cells. So far we have been discussing the activity of white cells which directly encounter and confront unwanted organisms--in a sense, cell-to-cell combat. Those activities described comprise what is called "cellular immunity." This refers to the activity of individual cells in defending the body directly.
     There is another kind of immune activity, however, which is called "humoral immunity." Humor refers to blood, and humoral immunity involves the circulation throughout your body, of substances which are produced by your white cells. 
     This type of immune response is directed by B-cells. These cells tend to cluster around your lymph nodes, where they can easily monitor foreign materials, for example viruses, which may be circulating through the body. The B-cell is alerted to the presence of a virus, either by a macrophage or by T-helper cells, and rather than attacking the virus directly it begins producing antibodies for that virus. 
     Another name for antibody is immunoglobulin (Ig). The antibodies are released into the blood stream where they attach themselves to viruses, neutralizing them until a macrophage comes along and devours the antibody and virus together. In a sense the antibody acts like a ball and chain to the virus, rendering it unable to penetrate a cell and cause disease.
     The B-cells manufacture millions of antibodies for viruses which have been detected in the body, and each type of antibody is tailor-made for a specific type of virus. Each type of virus you have been exposed to in your life is remembered by your immune system, and each has a corresponding template stored in the memory of your B-cells. Should a given virus from your past be detected again, the response of your B-cells will be swift in mounting the antibody response. Should it be an encounter with a new virus, the response will be slower because of the time needed to design the new antibodies. Finally, the B-cells respond to the level of viruses in the body, and adjust their output accordingly.
     In summary, there are several qualities your immune system has which give reason for hope. These include the fact that it is intelligent, it communicates, it has memory, it has senses, and it is creative. In addition, it has certain qualities of redundancy and compensatory mechanisms--that it, it has several alternative ways of responding to a problem, and if one part of the system is having difficulty, other parts can pick up the slack.

An Open System
     The immune system cannot be considered in isolation. In fact, it can be thought of as part of a larger system which could be called the healing system. This larger system also includes the mind and attitudes, the brain, the nervous system, and the endocrine system. The interaction among all these systems is the subject of the science of psychoneuroimmunology (PNI). One of the most important messages of this new field is that the immune system is an open system--that is, it does not act alone, but is very much influenced by communication with these other systems.

     The Neuroimmune Network. How does this communication take place? One the most important insights of PNI is that the brain is a gland. As such, it releases chemicals into the bloodstream which communicate with the white cells. As mentioned earlier, white cells have receptors--like satellite dishes--on their surfaces which receive these chemical messages, decode them, and use the instructions to influence the behavior of the cell.
     Another means of communication between the brain and white cells are the nerve endings reaching from the brain all the way into the bone marrow, thymus, and the other organs of the immune system. These nerve endings can stimulate the production of white cells in the marrow. They are also able to stimulate the activity of the thymus gland and other organs. 
     The nervous system also has receptors embedded in the organs of the immune system, along the walls of the blood vessels, and in the brain. These receptors are able to receive chemical messages released by the white cells, and send this information back to the brain. These signals can tell the brain about the status of the immune system and its activity. The brain can in turn respond with further release of chemicals or nerve impulses to stimulate the immune responses in the desired way. Hence there is constantly two-way communication between the immune and nervous systems. 
     These two modes of communication--chemical messages and nerve impulses--are the means the brain uses for mind/body communication. These are the means by which mind/body techniques such as imagery, for example, are able to influence immune activity. As we will see below, the immune system is indeed responsive to our input.

     Influences on immune responsiveness. Your immune system's responsiveness can range along a continuum, from sluggish to hyper-active, depending upon a multitude of factors. These factors include the psychological and emotional aspects of our lives. For instance, research has shown that depression can have an adverse effect on immunity. 
     A good example of this kind of research is a study in which NK cell activity was compared in depressed patients, schizophrenic patients, and staff in a psychiatric hospital. The patients with major depressive disorder had significantly lower NK functioning than schizophrenic patients and normal controls.
     Or consider the findings of a study of recently divorced people. Those who wanted the divorce, for whom it brought relief, were found to have better immunity than those who did not want the divorce.
     One of the leading authorities in the study of emotions and health is Dr. Lydia Temoshok, a health psychologist and PNI researcher with Walter Reed Army Hospital., In her highly detailed research, she found emotional expressiveness to be directly related to the thickness of tumors, as well as disease progression, in a study of 59 malignant melanoma patients. In fact, emotional expressiveness turned out to be a significant predictor of the progression of melanoma. In discussing the role of emotion in immunity and cancer progression she states, "If there is a hero in this, it's probably emotional expression." 
     Temoshok has pioneered the notion of the "type C" personality as a cancer-prone personality. The qualities of a type C person include a pattern of emotional constraint, particularly in times of stress, and a sense of helplessness and hopelessness with depressive tendencies. This person is a cooperative, unassertive patient who suppresses negative emotions, particularly anger, and who accepts or complies with external authorities. This is the polar opposite of the "type A" personality, which has been shown to be predictive of coronary heart disease.
     I would not suggest that there is such a thing as a CFS prone personality. I have seen too much diversity in the kinds of people with this syndrome. Still, it is worth considering that one's patterns of emotional expression may be a piece of the multicausal pie.
     Chronic stress may be another factor. It is a widely accepted principle, though perhaps not very well understood, that stress plays a role in immunity. Specifically, certain chemicals are produced by the body when you are in a state of stress. You may recognize the "adrenalin rush" or the heightened state of alertness and perhaps strength you have when in an emergency or an anxiety-provoking situation. Indeed, there is a whole set of physiological responses taking place, which scientists call the stress response. 
     The chemicals produced in the stress response are both good news and bad news. The good news is that they help prepare you for fight or flight, or to function at a higher degree of effectiveness in a crisis. The bad news is that these same chemicals have a wearing or suppressing effect on your immune responses. The stress response is usually transitory, and no ill effects occur on immunity. For example, someone unexpectedly cuts in front of you on the freeway, and you may feel a very strong physiological reaction. But within a few minutes the reaction subsides, and by the time you reach your destination the trauma of the situation has pretty much left you. 
     However, if stress is chronic, then chronically suppressed immunity can of course have ill effects. Both chronic stress and situational stress are of concern in CFS.
     It is interesting to note that many of the studies of the stress response have studied NK cell activity and herpes viruses, such as the Epstein Barr virus, to document the effects of stress on immunity. These studies offer a lot of insight into the role of stress in CFS. For example, significant drops in NK cell activity were found in a group of 75 medical students during an exam period, as opposed to one month before the exams. 
     This drop in NK cell activity was reproduced, and a significant reduction in numbers of NK cells was also found, in two other studies involving exam stress., 
     Other immune functions are also affected by stress. A study of 34 first year medical students found the percentage of T-helper cells in the blood to be significantly lower during exam periods, compared to a month earlier. Likewise, a study of 40 second year medical students during final exams found similar decreases in the percentage of T-helper cells.
     In terms of herpes viruses, the studies of exam stress showed elevated antibody titers to the Epstein Barr virus. Elevated antibody titers are believed to reflect poorer cellular immune system control over the latent virus. For example, patients on immunosuppressive therapies such as cancer chemotherapy, or patients with AIDS, typically show elevated herpesvirus antibody titers.
     The vulnerability to herpes infections is not limited to short term stressors, like the medical student exam periods. One study followed West Point cadets for four years. The cadets chosen had never had an acute EBV infection and began the study as EBV seronegative. 
     Of those who converted to EBV positive over the four years, there was an interesting connection between stress and degree of illness with EBV infection. Both the length of hospitalization for clinical infectious mononucleosis, and elevated antibody titers among those who did not need hospitalization, were associated with the same psychosocial risk factors. Those factors were high motivation for a military career, and poor academic performance--a combination likely to create a state of chronic stress. This is consistent with the findings of two other studies in which greater unhappiness was associated with poorer control over latent herpes viruses.,
     The studies cited above offer a sampling of the findings describing how stress can compromise immunity. But there is also evidence that when we feel love and joy, our immune functioning measurably improves. One study involved 132 college students to determine the effects of two kinds of emotional arousal on salivary immunoglobulin A (S-IgA) levels. S-IgA is the body's first line of defense against viruses, bacteria, or other pathogens entering through the mouth or nose. 
     Half the students were shown the film Triumph of the Axis in World War II. This film was selected for its content dealing with themes of power, domination, persecution, fear and conflict. The other half were shown the film Mother Theresa, a documentary of a Roman Catholic nun serving the poor, diseased, and dying in Calcutta. This film deals with themes of unconditional love, selfless service, and compassion. 
 Before and immediately after watching the films, the subjects' S-IgA levels were tested. There was no significant change for those who watched Triumph of the Axis. However, those who watched Mother Theresa showed significantly increased S-IgA concentrations, indicating heightened immune responsiveness. 
     Fortunately, research in the field of PNI points the way to how we can use the pathways of mind/body communication being illustrated by all the above studies. As will be discussed in later chapters, deep relaxation and certain other self-help strategies such as meditation, imagery, and emotional expression can all take advantage of these pathways to help us heal. 
     While psychological states can obviously be a major influence, it is also known that nutrients can affect immunity, positively or negatively. Caffeine and refined sugar suppress the immune system, while zinc and vitamin C are among the raw materials of which it is constructed, and which it requires to perform.
     We will discuss the enhancement of immunity at greater length later. For now, the conclusion I invite you to consider is this: because your immune system is an open system, there is potential for you to have an impact on your healing process by how you choose to live each day.

     Compensatory Mechanisms. One interesting and perhaps life-saving aspect of immunity is that your immune system has "compensatory mechanisms." This means that there is enough overlap or redundancy built in to the system that when certain parts do not function properly, other parts can pick up the slack. 
     Why is it that a person with AIDS can appear to hold of infections, even though the level of T-helper cells is extremely low? Because fortunately, not all immune functions are dependent on T-helper cells. 
     As mentioned earlier, NK cells are a strong line of defense against viral infection, and are not dependent on T-helpers for their instructions. Macrophages, as well, are not part of the T-cell network and have a degree of free-spiritedness. There is enough redundancy and flexibility built in to the immune system that there are a variety of ways the system can respond to a disease process. 

TYPES OF IMMUNE-RELATED ILLNESS
     With this explanation of the immune system, let us know turn our attention to the various types of illness to which it responds. This will help give us a perspective on CFS in relation to other illnesses. There are four broad types of immune-related illness. 

Type One
     One involves an insufficient immune response to an external pathogen, such as in a viral or bacterial infection. The pathogen enters the body and is not met with an appropriate immune response. Either the immune system is suppressed for some reason, or the pathogen is somehow able to deceive the immune system and slip through the defenses. This is thought to be the case in HIV, for example, where the virus changes form and keeps a step ahead of the immune system's ability to manufacture appropriate antibodies. In more common viral conditions, however, the immune response follows a normal course, and after an initial flare-up, it catches up with the numbers of viruses and eliminates them from the body.

Type Two
     A second type of illness is where there is an insufficient response to an internal pathogen, such as cancer cells. In this case, the cancer cells are growing and reproducing at a rate faster than the immune system is recognizing and destroying them. Again, the problem may be related to suppressed immunity, but it also may be related to some cancer-causing substance simply overwhelming the body's ability to respond.

Type Three
     The third type of illness involves an over-active response to an external pathogen. This occurs in allergies and food sensitivities, where the immune system misinterprets a substance as being harmful to the body when in fact it is not. As a result it is fighting an unnecessary battle, and the bi-products of this battle create unpleasant symptoms.

Type Four
     Finally, some illnesses involve an over-active immune response to internal tissues. These are called autoimmune diseases. Here again, the immune system is malfunctioning and mounting a misguided attack against the body's own healthy tissues. This occurs in multiple sclerosis, rheumatoid arthritis, lupus, and Graves' disease, for example.

CFS: A DISEASE IN SEARCH OF A CATEGORY
     Where does CFS fit in? Interestingly, CFS does not fit neatly into any of the above types of illness. Rather, it has some of the qualities of each. This is one of the reasons why mainstream medicine has had such reluctance to acknowledge the syndrome as a distinct disease--it simply does not fit any of our familiar categories.
     We now know that CFS involves both brain dysfunction (encephalopathy, lesions, neurological problems) and immune dysfunction. It is not known whether one precedes the other, or whether they develop simultaneously. According to Byron Hyde, M.D., Chair of the Nightingale Research Foundation, brain dysfunction is a requirement in defining the syndrome. The area of the brain affected varies from one person to the next, although almost all are found to have injury to the left frontal lobe. Damage to this area of the brain is responsible for several of the disturbances of memory, concentration, and other cognitive symptoms of CFS.
     The involvement of the central nervous system is further supported by Dr. Paul Cheney, who describes CFS as a disease of cognition dysfunction involving such unusual impairments as difficulties with memory sequencing, spatial disorganization, trouble giving and following directions, processing problems, intellectual speed, and processing visual and auditory information.
     While the involvement of the nervous system is a major part of the syndrome, the heart and soul of making a diagnosis, according to Cheney, remain to be immunologic testing. He describes "all manner of unusual phenomena" going on in the great majority of patients. The most common pattern is chronically heightened T-cell activation, elevated levels of cytokines such as interferon and interleukin II, immunoglobulin deficiencies, and severe natural killer (NK) cell functional deficiency. In fact, NK cell dysfunction is so central to the condition that in Japan the disease is called "Low NK Syndrome."
     One leading CFS immunologist, Nancy Klimas, M.D., of the University of Miami, believes this NK deficiency is a central feature of CFS, and qualifies the syndrome as an acquired immune deficiency. She states that her findings, based on a patient population of 500, show higher than normal numbers of natural killer cells in CFS, as if the immune system is trying to respond to something, but very low functionality. The ability of those NK cells to kill was the lowest of any group studied, including among people in early stages of HIV infection, people with ARC (AIDS-Related Complex), and in intravenous drug users.
     According to Dr. Klimas, "The most compelling finding was that natural killer cell cytotoxicity in chronic fatigue syndrome was as low as we have seen in any disease... These cells seem to feel the way that CFS patients do--they're exhausted." Other researchers have observed that NK cell numbers rise during the acute stage of CFS, and then return to normal after recovery.
     These various dysfunctions help explain how the person may have elevated activity levels of viruses such as Epstein-Barr (EBV), cytomegalovirus (CMV), human herpesvirus number 6 (HH6), herpesvirus types I or II, or other viruses.
     These immune dysfunctions are part of a broader picture which also includes immune system up-regulation. It is the chronic, high state of immune activation that appears to be the real cause of most of the symptoms. In fact, Dr. Klimas and her colleagues have also identified a cytokine abnormality that has not been sen before in any disease. In about 35% of their patients, they are seeing interleukin-1 (IL-1) levels that are 50 times higher than normal. Klimas reports that in studies of mice with similarly high levels, the mice develop muscle weakness, lassitude, generalized inflammation, cardiac tachycardia, decreases in cardiac output and peripheral neuropathies--all symptoms found in severe cases of CFS. 
     Dr. Jay Levy of the University of California, San Francisco, considered by many as the first to have actually located and isolated the AIDS virus, has proposed that the syndrome be renamed "Chronic Immune Activation Syndrome." It is indeed unfortunate that the syndrome was named for merely one of its many symptoms, fatigue, rather than being given a name which represents more accurately the disease process itself. Paul Cheney, M.D. has made the comment that this is like calling pseumonia "chronic cough syndrome."
     According to Levy: "We believe that there is an infectious agent that enters the host and activates the immune system... some individuals, because of their genetic makeup or because of their state at the time of infection, will not be able to turn off that activated state... (and) the immune system never returns to a normal resting state. So, these people are in a state of chronic immune activation."
     If the retrovirus being studied by Dr. DeFreitas at the Wistar Institute and by Dr. Martin at U.S.C. is found to be the culprit, it may be that it triggers the disturbance in the immune system and then is either eliminated or goes into hiding, leaving behind a disturbed immune response. One theory is that it is some kind of a hit-and-run virus, leaving the immune system firing away at no specific target.

The Real Cause of Symptoms
     Even if the dysregulation of immune functioning is found to be caused by a virus, however, it is apparent that the symptoms with which most people suffer are not caused by viral activity itself. Rather they are caused by the chemical by-products being churned out by the immune system. 
     Some of those products, the cytokines, are known to be potent virus- and cancer-fighters. However, they also cause the very symptoms people with CFS have. In cancer, research has shown that some of these substances have been an effective treatment for certain cancers. They include interleukin I and II, and interferon, well-known cancer treatments. The cancer research also shows, however, that patients using these treatments can expect certain side effects, which go away when treatment is discontinued. These side effects, which cancer patients are told to expect, fit the symptom picture of CFS almost perfectly.
     The picture which is emerging is that CFS clearly involves an immunologic disturbance. The immune system is stuck in a state of hyper-activation, churning out cytokines whose role normally is to fight viruses, but which, when overproduced, cause a plethora of symptoms and injure brain tissue. If the areas of the brain that are damaged are involved in regulation of the immune response, then it is even more difficult to restore the proper relationships between these two systems, and a pattern of chronic illness results.

Breaking the Rules
     As we can see from this discussion, CFS has elements of all four major categories of immune-related illness, as illustrated in Figure 7 below. With regard to insufficient response to an external pathogen, most likely it involves a virus entering the body from the environment. The immune system has not successfully defended against the invader. The virus gets a foothold, penetrating certain immune cells, and triggers the dysregulation.

Figure 6. CFS in Search of a Category

     The second category, insufficient response to an internal pathogen, generally relates to the growth and spread of cancer cells. CFS has been linked statistically to a slightly increased incidence of certain kinds of cancer such as Burkitt's lymphoma and nasopharyngeal carcinoma. This by no means implies, however, that people with CFS are in general at greater risk of cancer. At this stage of our knowledge, it is simply an interesting statistical association.
     With regard to the third category, over-active response to external pathogens, people with CFS typically have increased problems with allergies, and may even have totally new onset of allergies. An allergic response is an extreme immune response. Sensitivities to foods and other substances in the environment such as perfumes, smoke, paint, carpeting, and certain construction materials create serious problems for CFS patients, all as a result of the immune system's heightened sensitivity.
     With regard to the fourth category, overactive response to internal tissues, the immune system is not targeting the host's tissues as it would in more common autoimmune diseases. However, the chemical by-products of the disease process do adversely affect neurological tissue in many patients, causing brain lesions and serious disability. It is only in this indirect sense that CFS has some semblance to an autoimmune disease.

CFS and AIDS
     The question often arises as to whether CFS has any association with AIDS. This is a logical question, because both conditions involve difficulties in immune functioning. However, in reality they are very different syndromes. CFS is actually opposite to HIV in terms of immune system activation. To compare the two is like comparing apples and oranges. The symptoms in CFS are directly caused by the over-activity of the immune system, flooding the body with toxins which have ill effects. In AIDS, the symptoms are indirectly caused by the under-activity of the immune system, allowing what would normally be innocuous infections to take hold.

THE GOOD NEWS
     CFS presents us with a unique challenge. We must abandon many of our old concepts of health and illness, and rededicate ourselves to the quest for understanding how harmony can be restored among multiple bodily systems. 
     The good news is that in spite of our limited understanding and our lack of a medical cure, people do recover their health. The fact that many have recovered in the absence of medical treatment is evidence that the body has the inherent ability to heal such immune dysfunction. The cells and tissues of the immune system, because of their genetic programming, remember what harmony is and how to restore it. It takes time. Medical treatment and lifestyle change can accelerate the healing process, but the resiliency and intelligence of the immune system are what make such healing possible.

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