Chapter 3

The Immune-Brain Connection

Early Concepts, Pre 1950.

Fifty years ago, biomedical scientists were certain that there was an impervious barrier between the immune system and the brain. The barrier, called the blood-brain barrier, was thought to protect the brain from any effects of the immune system. It was not thought possible for immune cells to migrate from the blood, through the blood-brain barrier and into the brain. According to the prevailing view of the time, immune cells did not reside in the brain either. The concept of the immune system releasing chemical messengers which traveled through the blood and into the brain had absolutely no scientific support. The notion of immune cells secreting chemical messengers of any sort was immunological heresy. As a result, a model of the immune system communicating with the brain was never proposed or discussed because it was considered biologically impossible.1

Communicating in the other direction, that is, from the brain to the immune system, was considered impossible also. For one thing, neuroanatomists could not find nerves extending from the brain to cells or structures of the immune system. For another, there were no reports of the brain secreting chemical messengers which could regulate the immune system. Without chemical messengers or nerve connections, the brain could not send vital information to the immune system.

Consequently, before 1950, there were no biological concepts of a functional connection between the immune system and the brain. The biological dogma of the time was: 1). The immune system cannot communicate with the brain or control any brain function; 2). The brain cannot communicate with the immune system or control any immune system functions. In short, there was no hypothesis of an immune-brain connection before 1950.2

From 1950 to 1978


During the 1950's the pituitary gland became known as the Master Endocrine Gland. Scientists discovered that the pituitary gland controlled the adrenals and its many hormones, the sex glands and all the sex hormones and the thyroid and its hormones. The title, Master Endocrine Gland was well deserved.

The pituitary is a small pea shaped gland at the base of the forebrain (above the roof of the mouth). It is lies next to the brain, directly adjacent to a small brain structure called the hypothalamus. The pituitary looks like a brain appendage. Endocrinologists and brain scientists were intrigued by the close relationship between the pituitary and the hypothalamus.

Between the pituitary and the hypothalamus is a space called a cleft, so the two structures don't actually touch. In the late 1950's biologists began to report evidence of a chemical linkage between the hypothalamus and the pituitary. By the beginning of the 1960's, a conceptual revolution was in the making based on an exciting neurochemical discovery: the hypothalamus secretes hormones into the cleft between the pituitary and the hypothalamus. Indeed, the hypothalamic hormones regulated the pituitary. By the late 1960's, a revolutionary conclusion was unavoidable: The hypothalamus controls the pituitary! Since the hypothalamus is part of the brain, the brain, in fact, controls the pituitary.

Also in the 1950's, biologists discovered that hormones help regulate the immune system. Cortisol (also called hydrocortisone) is the best known example of hormonal control of the immune system. It is an anti-inflammatory and immunosuppressive hormone made by the adrenal cortex. The production of cortisol is governed by the pituitary and the pituitary is controlled by the hypothalamus. Therefore another revolutionary conclusion: the brain, via its control over cortisol and other hormone secretions, helps regulate the immune system.

Many hormones influence the immune system. In fact, most of them do. The hypothalamus, for example, secretes many potent hormones (See table 2) and a number of them help control immune cells. The pituitary secretes many different hormones (see table 3) and these hormones help regulate immune cells. In like manner, sex hormones secreted by the ovaries and testes influence immune cells. So do thyroid hormones.

The brain and peripheral nerves release numerous neurotransmitters and other chemicals called neuropeptides (see table 5). Neurotransmitters and neuropeptides are not usually called hormones, but they do have hormone like properties, that is, they are chemical messengers. Most neurotransmitters and neuropeptides influence immune cell activities.3 As you can see, there are many hormones, neurotransmitters and neuropeptides released by the brain or by structures controlled by the brain which regulate the immune system.


In addition to the extensive ability to chemically (i.e. via hormones, neurotransmitters and neuropeptides) regulate the immune system, the brain can also directly control important parts of the immune system through its network of nerves. Starting in the 1960's, neuroanatomical investigations began finding direct nervous links between the brain and the immune system.4 There are nerves going directly from the brain to important immune organs like the thymus, bone marrow, spleen, lymph nodes and gut associated lymphoid tissue.5 By having nerves connected to these important immune organs, the brain is able to directly regulate immune system activities. Extensive animal studies have shown that the brain, via its nerve connections, does exert significant control over these immune organs.6

Thus, from 1950 to 1978, a radically changed view of the immune-brain connection developed. Massive hormonal and neuroanatomical evidence made it clear that there was a connection between the brain and the immune system. The brain, through its direct nerve connections to the immune system and its control over the extensive hormone network, helped govern the immune system. A new biomedical discipline, called psychoneuroimmunology, grew up around these discoveries.7

In 1978, the paradigm for the immune-brain connection was: 1). The brain, in a very complex way, regulated the immune system. The direction of the control was from the brain to the immune system, that is, Brain→Immune System. 2). There was no evidence the immune system could control the brain, therefore the immune-brain connection was a one-way street, Brain→Immune System, and not a two-way street, Brain↔Immune System.

The Brain→Immune System Paradigm

The one-way street model of the Brain→Immune System linkage encouraged psychologists, psychiatrists and popular writers to find examples showing that the human brain has an ability to consciously and unconsciously control the immune system. For example, happy, positive thoughts along with loving and serene emotions are claimed by many 'new age' writers to result in a healthier, more effective immune system.8 On the other hand, negative, depressing thoughts along with hostile emotions are thought by these writers to result in a hobbled and less effective immune system. These writers assure us that good health, to a great extent, is merely a matter of thinking good thoughts and feeling good emotions.

The high incidence of serious physical illness in patients diagnosed with depression appears to support the theory that thoughts and emotions can affect physical health. Depressed persons not only have more physical illnesses than happy people, but their illnesses are more serious, with more complications and higher death rates. Furthermore, several measures of immune system function appear to be impaired in depressed persons, including reduced natural killer cell activity.

The one-way model of the Brain→Immune System connection appears to explain the high co-incidence of depression, physical illness and a suppressed immune system. The explanation goes something like this: The negative thoughts and unhappy emotions of depressed patients causes the brain to send immunosuppressive messages and immunosuppressive hormones to the immune system. The suppressed immune system fails to protect the body against serious physical illnesses like cancer, pneumonia, infection and heart disease.

The one-way model of the Brain→Immune System linkage was the state of the art before the scientific acceptance of cytokines in 1979. Yet, to this day, the one way model has remained very popular and influential even though it has been scientifically incorrect since 1979. Indeed, current paradigms of depression typically incorporate a one-way brain-immune system model (see Chapter 2). One reason for its continued influence is its seductively simple solutions for preventing and treating serious health problems. What could be simpler than thinking happy thoughts and having loving emotions as a method to prevent cancer, heart disease or ulcers? What could be more attractive than thinking optimistic, healthy thoughts as a method to treat cancer, heart disease or ulcers? In the next section an alternative explanation for the high incidence of physical diseases occurring with depression will be presented.

From 1979 to 1998


Brief History Two American researchers, A. R. Rich and M. R. Lewis, in 1932 published the first evidence of immune cells releasing water-soluble hormone-like substances. They reported that the liquid from cultured immune tissue inhibited the movement of other immune cells. Thirty-four years later, in 1966, several investigators claimed to have isolated Rich and Lewis's water-soluble factor. By 1979 biologists had isolated over 100 different hormone-like factors released by activated immune cells.9

What started in 1932 as an obscure observation, by 1979 had turned into a "tower of immunological babel." There was great confusion and skepticism concerning the bewildering number of water-soluble "factors". Since the myriad factors were poorly characterized and often with conflicting claims, most immunologists remained unconvinced that activated immune cells released hormone-like substances.

On May 27, 1979, over 200 immunologists from all over the world met in Switzerland to address the "soluble factor" chaos in immunology. The meeting was a turning point for immune cytokines. The expert immunologists created order out of chaos. Instead of over 100 different factors, the immunologists realized that there were far fewer, more like 10 or 15 factors. Each factor had many different functions, which accounted for much of the chaos. At the end of the meeting there was a general scientific consensus that immune cells do secrete molecules which regulate other immune cells. These molecules were given the general name cytokine. Since the 1979 consensus, there has been an explosion of biomedical research on cytokines, resulting in unprecedented advances in the scientific understanding of human physiology in both health and disease. Much of the explosion of research was dependent on developments in genetic engineering occurring about the same time. Recombinant DNA technology made it possible to program yeast cells to produce usable quantities of pure cytokines. Sufficient quantities of pure cytokines were available for researchers around the world to investigate cytokines in cells, animals and humans.

Properties Cytokines are water soluble protein molecules made and secreted in very small amounts by activated immune cells and various other cell types. Cytokines have hormone like properties at extremely low concentrations. Immune cells are stimulated to make various cytokines by infectious agents whether they are bacteria, virus, fungi, amoebae or other pathogens. Most foreign proteins and many allergens stimulate cytokine production. So do malignant cells, dying tissue and injury. Essentially, when immune cells sense any kind of biological danger, they begin secreting cytokines.

If very small amounts of cytokine are secreted by activated immune cells, then the effects are usually localized. On the other hand, if somewhat more cytokine is secreted by immune cells, then some cytokine will migrate into the blood, thereby provoking a systemic (i.e. whole body) effect. A systemic effect can be profound, since cytokines can affect almost every tissue, organ and gland in the body. Extensive cytokine research on animals and humans has shown than during serious illness, cytokines are adjusting every tissue and organ in the body. Thus, the profound alterations in body function which occur in diseased states, are primarily due to the effects of cytokines on the body. These discoveries are major insights into understanding the symptoms and signs of diseased states. Before the discovery of the extensive effects of cytokines, the profound changes in body chemistry and physiology during disease were deep mysteries.

At first, since immune cells were the focus of cytokine research, immune cells were thought to be the only producers of cytokines. During the 1980's it became evident that other cells produce these same molecules. Endothelial cells, fibroblasts and tumor cells make various immune cytokines. So do astrocytes, mast cells, fat cells and muscle cells.10 Nevertheless, immune cells usually initiate the production of cytokines and produce the largest amounts.

The 1979 international meeting on cytokines concluded that the immune system secreted about 10 or 15 messenger molecules. Since that time, many more cytokines have been discovered. Also a more general definition of cytokine has been gradually accepted. At the present time, any protein messenger molecule (except for messengers already identified as hormones, such as, insulin, ACTH and various hypothalamic and pituitary hormones) secreted by immune cells or any other cell type is classified as a cytokine. Using the general definition of cytokine, there are over 100 protein messenger molecules included as cytokines.11 Most of these cytokines are not made by immune cells and do not target immune cells.

In this book we will use the original, immunological definition of cytokine. Therefore in this book, cytokine includes any protein messenger molecule secreted by immune cells that help regulate the immune system. Within the immunological definition, there are 28 different cytokines (see table 1). The majority of the immune cytokines are called interleukins (i.e. they send messages between leukocytes or white blood cells-another name for the immune cells found in the blood). The interleukins were named in order of discovery. Thus, interleukin-1 (IL-1) was the first interleukin discovered. IL-2 was the second and so on up to IL-16. The interferons are another group of immune cytokines. There are three different interferons, interferon-alpha (IFN-α), interferon-beta (IFN-β) and interferon-gamma (IFN-γ). Tumor necrosis factor (TNF), lymphotoxin and the colony stimulating factors are also immune cytokines.

Most cytokines have a very wide spectrum of effects, that is, each cytokine has multiple functions (this property is called pleiotropy). Another very important property is redundancy, meaning that many different cytokines can have the same function. For example, IL-1, IL-6 and TNF do many of the same things, such as, stimulate the liver to make different proteins, cause muscle wasting and stimulate the hypothalamus to make stress hormones.12 (See table 2)

At the present time, most cytokines have not been investigated for their ability to communicate with the brain. The ones that have been investigated are IL-1, IL-2, IL-6, TNF and the three interferons (see table 3). These are the cytokines we will discuss in this book. Hopefully in the future other cytokines will be investigated for their roles in regulating the central nervous system. Nevertheless, the evidence on the few cytokines investigated so far makes a very powerful and persuasive case for the involvement of the immune system as a fundamental player in depression and brain function.

Cytokines and the Immune-Brain Connection After the scientific acceptance of cytokines in 1979 and the availability of pure recombinant cytokines, it became apparent over the next few years that the immune system can send powerful chemical messages to the brain. Receptors for IL-1, IL-2, IL-6 and a few other cytokines were discovered throughout the brain. These cytokines were found to be able to travel in the blood, through the blood-brain barrier and into the brain.13 When animals or humans were given various cytokines intravenously, dramatic changes in behavior and brain function occurred. The above observations demonstrate the ability of cytokines to pass through the blood brain barrier and profoundly influence brain function.14

Recent investigations have revealed peripheral nerves as another pathway for cytokines to deliver messages to the brain. Many peripheral nerves have receptors for cytokines. In animal experiments, IL-1 activates peripheral nerves, thereby forcing the nerves to send messages directly to the brain.15

These cytokine experiments indicate that activated immune cells in the skin, stomach, throat or any other site, can send urgent, powerful messages to the brain by secreting cytokines into the blood or into tissue spaces near certain peripheral nerves. This explains why an infection or other pathology in the throat, bladder, liver, stomach (ulcers, for example) or any site can profoundly affect brain function and behavior. Any pathology that activates the immune system can affect brain function and behavior.

Before the remarkable discoveries on cytokines, it was assumed to be impossible for the immune system to communicate with the brain. Like no other previous discovery, cytokines have revolutionized our understanding of the communications link between the immune system and the brain. The one direction pathway model is now untenable. It is simply wrong. Instead, we now know the communications pathway is bi-directional, that is, it is a two-way street: Immune system↔Brain. There is a continuous information loop going from the immune system to the brain and from the brain back to the immune system.16 Thus, the immune system can control the brain and the brain can control the immune system.

The Immune System as a Sensory Organ The two-way communications model has permitted immunologists to look at the immune system in completely new ways. One very novel way is to view the immune system as a sensory organ.17 This shouldn't be surprising, since immune cells are constantly on alert to detect dangerous bacteria, viruses, fungi, foreign proteins, antigens, harmful chemicals, poisons, malignant cells, damaged tissue, dying cells and abnormal cells. In other words, the immune system is constantly 'sensing' for danger at the chemical and cellular level.

The immune system's sensory function goes on 24 hours a day. In every tissue, including throat, lung, liver, stomach, brain, skin, kidney and blood, immune cells are constantly on alert for danger. When immune cells sense danger, they become activated and start secreting various cytokines to inform neighboring cells about the danger. Nearby peripheral nerves, if they have cytokine receptors, will carry the cytokine message to the brain. In addition, if enough cytokine is secreted to spill into the blood, then every tissue and organ in the body, including the brain, will be directly informed of the danger.

The Brain's Response Once the brain is alerted to the impending danger (via cytokines), whether it is infection, cancer, heart attack or trauma, it can help coordinate the defense of the body against the potentially life threatening danger. One way the brain helps the immune system is by sending direct messages through nerves to lymph glands, thymus, bone marrow and spleen. The functioning of these fundamental immune organs is greatly influenced by the brain.

The other way the brain helps regulate the immune system is by altering hormone levels in the body. After the brain is exposed to cytokines, the hypothalamus begins secreting more of a key hormone called corticotrophin releasing factor (CRF). CRF stimulates the pituitary to release adrenocorticotropic hormone (ACTH). The adrenals are stimulated by ACTH to release more cortisol. CRF, ACTH and cortisol are three of the main hormones released in response to cytokine exposure. They are called stress hormones because they are elevated during biologically stressful conditions like infection, trauma, cancer and ischemic events. Psychologically stressful conditions also raise stress hormone levels.

The Sixth Sense In high school biology we all learned (or should have learned) about the five senses. They are: seeing, hearing, taste, smell and feeling (somatosensory sense, i.e. body sensations like heat, cold, pain, pleasure etc.). Our five senses are constantly sending information to our brain for processing. Then the brain can respond to what it sees, hears, tastes, smells or feels by having us walk, jump, think, plan, run, talk, laugh, cry or any number of complex behavioral responses.

For the most part we are conscious of the sensory information being delivered to our brain by the five senses, that is, we are consciously aware of seeing, hearing, feeling, tasting and smelling. The traditional five senses could be called our conscious senses.

Since the immune system is a sensory organ and is distinct from the traditional five senses, it can be considered our sixth sense. The sixth sense is constantly on alert, trying to detect foreign proteins, dangerous microorganisms, dying cells, dangerous chemicals, malignant cells and other dangers at the chemical and cellular level. If the immune system senses danger, then it sends messages to the brain by silently secreting cytokines. No bells, words, whistles, pictures, tastes or smells flash to the brain when cytokines are delivering their urgent messages. Instead, cytokines are silent, unconscious chemical messengers. Thus, our sixth sense could be called our unconscious sense.

Eventually, hours, days or sometimes weeks later, the somatosensory sense (i.e. how your body feels) begins to make us conscious of the silent cytokine secretion. Fever, malaise, fatigue, depressed mood, lack of interest, anorexia and pain are typical delayed conscious sensations of immune activation. Curiously, IL-2 given in high doses to human volunteers produces visual and auditory hallucinations. This suggests that cytokines can provoke two other conscious senses, i.e.. sight and hearing.

The Immune-Brain Connection & The Six Senses The two-way model (Immune System↔Brain) shows that both systems can communicate with each other, but it doesn't indicate which system initiates the communication. Most likely the immune system sends the first message since the immune system is a sensory organ and it is the function of sensory organs to send new information the brain. Then the brain would respond to the new sensory information by sending messages back to the immune system. The messages from the brain would help the immune system coordinate its defense of the body. This crosstalk cycle could be repeated over and over again. Each cycle would be purposeful, with the immune system sending new, urgent information to the brain on chemical-microbiological dangers and the brain responding with information to help coordinate the defenses against the dangers. In diagram form the information flow would be:

6th Sense (Immune System) → Brain ↔ Immune System

The diagram emphasizes the important direction of the information flow between the immune system and the brain, that is, from the 6th sense to the brain. This paradigm makes all pre-cytokine thinking about the immune-brain connection obsolete. Essentially, immune cells detect or "sense" pathogens or other chemical-biological dangers. The immune cells become activated and release cytokines to alert the brain and other organs of the impending danger. The brain then adjusts the body and fine tunes the immune system defenses in order to save the body from destruction by pathogens, malignant cells, noxious chemicals or the activated immune system.

It is possible for the brain to send messages to the immune system based on information it receives from the other senses. For example, if a person was entering a dangerous situation where bodily harm was likely, then it would be reasonable for brain to send urgent messages to the immune system, telling it to prepare for bodily harm. Consistent with this scenario are the reports on psychological stressors causing immune activation in both animals18 and humans.19 Sudden severe pain is another situation where the brain would initiate urgent messages to the immune system. In diagram form the information flow would be:

Five Senses → Brain ↔ Immune System

A more general diagram would include all six senses:

Six Senses (includes immune system) → Brain ↔ Immune System

Further Evidence For An Immune-Brain Connection

Monocytes and macrophages Monocytes are inflammatory, phagocytic cells of the immune system (phagocytes eat other cells-especially bacteria, viruses, malignant and dying cells). They are made in the bone marrow, released into the blood where they circulate for several days. After a few days, monocytes invade tissues and then transform into larger, more complex cells called macrophages (big eater).20

For most of this century it was believed that blood monocytes could not pass through a healthy blood-brain barrier. This long held belief has been proven incorrect. One of the first papers to demonstrate this was published in 1988.21 They used animals with brain tumors. In the animals, activated blood monocytes readily passed through the blood-brain barrier and then began attacking the brain tumor. Activated macrophages in the brain secrete cytokines, including IL-1, IL-6 and TNF, directly into the brain. Cytokines secreted into the brain are fundamental players in most, if not all, brain diseases, such as Alzheimer's Disease, Parkinson's Disease and multiple sclerosis.22

Studies of the neurological and psychiatric symptoms of AIDS provide another striking example of monocytes passing through the blood-brain barrier. One of the first events in the development of AIDS is the attempt by blood monocytes to ingest and destroy any AIDS virus (human immunodeficiency virus-HIV) found in the blood. Blood monocytes ingest HIV but they are unable to destroy it. HIV remains hidden and dormant in the monocytes. After a few days, the HIV infected blood monocytes invade tissues, where they turn into macrophages. One of the main tissues invaded by the HIV infected monocytes is the brain. They pass thorough the blood-brain barrier with their load of hidden HIV inside. Monocytes literally carry the AIDS virus into the brain! Once inside the brain, the HIV infected macrophages may remain dormant for some time. Eventually, during the progression of the disease, they become activated and begin secreting cytokines, including IL-1 and TNF. These cytokines don't have to pass through the blood-brain barrier, because they are secreted directly into the brain by the infected macrophages. Excessive IL-1 and TNF are two of the main causes of the neurological and psychiatric symptoms of AIDS.23

Microglia Surprisingly, most of the cells in the brain are not nerve cells. Glia cells outnumber neurons 9 to 1 and take up over half the volume of the brain.24 Early biologists thought these cells were the glue that held the brain together (glia comes from the Greek word for glue). There are several different types of glia cell: oligodendrocytes-these cells wrap around neurons forming the white myelin sheath. The myelin sheath permits nerve impulses to travel much faster; astrocytes-these are believed to be the nurse cells for the neurons; microglia-these are the resident macrophages in the brain. They are derived from monocytes.

Microglia are found in the brain at a very early stage of development. By the fifth month of pregnancy, monocytes have already invaded the growing human brain and begun to form a immense network of microglia throughout the brain. The microglia appear to help destroy excessive nerve cells produced during early brain development. They also influence nerve cell growth and help shape the blood supply to the brain. Clearly, microglia play an important role in brain development.25

There are a vast number of microglia in the adult human brain-at least 5 billion and very likely many more. They have a distinctive shape: a small cell body from which numerous long, thin, branching arms arise. Microglia are distributed in a regular pattern in every brain structure. They are layered in such a way that no two of them touch or intertwine. The long branching arms have enormous surface areas, with each microglia in contact with huge numbers of nerve cells. The network of layered microglia may be in contact with every nerve cell in the brain! The intimate relationship between microglia and neurons in the brain is an extrordinary example of the profound connection between the immune system and the brain.26

Under normal conditions microglia are in a resting state. They are very difficult to study in a resting state because almost any manipulation activates them. Whether resting microglia have anything but a watching and waiting function is still being debated, hence nothing is known about microglia's influence on normal brain function. This is a vast, exciting area to explore for future research.

A good deal is known about microglia function during pathological conditions in the brain. For example, if the brain is injured, then microglia near the injury site become activated and begin secreting cytokines. These cytokines have intense effects on brain and immune system function. In addition, many devastating brain diseases like multiple sclerosis, Alzheimer's Disease and Parkinson's Disease have extensive involvement of activated microglia.27, 28

Astrocytes Astrocytes, being the most numerous cell type in the brain, are found everywhere in the brain. They are considered care-givers for nerve cells, providing nutrients, growth factors and clean-up service when excessive chemicals are present. There is evidence that astrocytes have special communication links with nerve cells. Some researchers suspect that astrocytes may participate, along with neurons, in memory and information processing.29

Astrocytes have receptors for IL-1, TNF and the neurotransmitter norepinephrine. Both IL-1 and TNF induce astrocytes to produce the powerful immune cytokine IL-6. In addition, norepinephrine, which is only secreted by nerve cells, induces astrocytes to release IL-6. This means astrocytes can receive messages from the nervous system (via norepinephrine) and the immune system (via IL-1 and TNF) and astrocytes can send messages via IL-6 to the immune system and the nervous system. This is another example of a powerful but complex communication link between the immune system and the brain.30

Lymphocytes The varied and complex lymphocytes form a major arm of the immune system, the lymphoid arm. They are found in the blood, lymph, lymph glands and major immune organs like the spleen, thymus and intestine, but they do not normally reside in the brain. Resting lymphocytes are blocked from going into the brain by the blood-brain barrier. Nevertheless, activated T-lymphocytes can readily pass through the blood-brain barrier and then roam around the brain searching for problems. T-lymphocytes can secrete a variety of cytokines if they meet up with a situation needing their assistance. If they don't encounter any difficulties needing their attention, then they exit the brain and return to the blood.31 Activated lymphocytes are another example of a powerful, complex communication link between the immune system and the brain.

Next chapter: The Immune System -- Briefly

Chapter 3 References

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