Psychoneuroimmunology and Stress

Psychoneuroimmunology: laugh and be well

Psychoneuroimmunology and Stress

The idea that a positive outlook on life and a cheery disposition help to stave off illness is as old as the hills. Perhaps surprisingly, this adage is much more than an old wives’ tale.

Share on PinterestThe implications of psychoneuroimmunology cover the length and breadth of medical research.

Over the last few decades, the intriguing and pervasive links between neuroscience and the immune system have slowly been uncovered.

What might seem, at first, an uneasy marriage between the brain and immunity has steadily grown into a fully fledged interdisciplinary area of study.

This field is known as psychoneuroimmunology (PNI).

It is well established, in the minds of most people, that stress can induce illness and that, conversely, a fun-filled occasion with loved ones can soothe aches and pains and stave off the very same illness.

What might have been referred to as pseudoscience a few decades ago now finds strong support from many quarters. PNI has deep ramifications for the future of medical research, the treatment of diseases and our attitude toward handling stress.

In this article, we will take a look at the birth of PNI, how the immune and nervous systems interact and some of the ways in which these communication pathways affect us all.

First, we will take a very brief look at a few examples of how psychology has been shown to influence the immune system:

  • Bereavement: stories of recently bereaved individuals dying soon after their partner are common. These tales are not just apocryphal. A study that followed 95,647 recently widowed individuals found that during the first week after bereavement, mortality was twice the expected rate. There is more to this than a metaphorical “broken heart”
  • The gut: it is now fairly well established that there is a strong association between sustained stressful life events and the onset of symptoms in functional gastrointestinal disorders, inflammatory bowel disease and irritable bowel syndrome
  • Cancer: health professionals working with cancer patients know only too well that a patient’s outlook and their quantity and quality of psychological support can hugely impact the outcome of their disease
  • HIV (human immunodeficiency virus): studies have found significant evidence that elevated levels of stress and diminished social support accelerates the progression of HIV infection
  • Skin complaints: psoriasis, eczema and asthma are all known to have psychological aspects to them. A stressful day at the office can have you scratching as you reach for the asthma pump
  • Wound healing: the speed at which a surgical patient heals has been linked to psychological factors. For instance, increased levels of fear or distress before surgery have been associated with worse outcomes, including longer stays in the hospital, more postoperative complications and higher rates of re-hospitalization. In one study on patients with chronic lower leg wounds, those who reported the highest levels of depression and anxiety showed significantly delayed healing.

Despite first-hand accounts of stressful or exhausting psychological events negatively impacting physical well-being, the scientific evidence behind these stories was not initially forthcoming.

How could neural activity influence the activity of the immune system? The immune system’s classical messaging system – the lymph system – is not present in the central nervous system, so conversations between the two were considered impossible.

What sounds medieval quackery is now considered science fact; the mechanisms that underpin immune-brain interactions are steadily being uncovered.

As with so many scientific discoveries, it was a chance observation that got the ball rolling.

Robert Ader is widely considered to be the father of modern PNI. His early research, involving conditioning in rats, opened the floodgates for the study of brain-immune communication.

Share on PinterestExperiments into psychological conditioning accidentally stumbled upon the brain-immune interaction.

Ader, a psychologist by trade, worked closely with Nicholas Cohen, an immunologist.

Their specialties made them the perfect team for the job, even though they did not realize it at the time.

Their landmark discovery was courtesy of science’s old friend – serendipity.

Ader was working on variations of the classic Pavlov’s dogs experiment: salivation in dogs was conditioned by an auditory stimulus – such as a metronome – before they were fed each day. Consequently, the stimulus induced salivation without the presence of food.

In Ader’s version of the experiment, he fed rats different quantities of saccharin solution and simultaneously injected them with Cytoxan – a drug that induces gastrointestinal distress and suppresses the immune system. The rats were conditioned to avoid drinking the solution, as predicted.

Ader then ceased injecting the rats but continued to present the saccharin-laced water. The rats avoided the solution but, strangely, some of them died. He noted that the avoidance response and the level of mortality varied depending on the amount of saccharine water they had been presented with.

The results intrigued Ader; it seemed that the avoidance response had been conditioned as expected, but, unexpectedly, so had the corresponding drop in immunity. In an interview in 2010, he explained:

“As a psychologist, I was unaware that there were no connections between the brain and the immune system, so I was free to consider any possibility that might explain this orderly relationship between the magnitude of the conditioned response and the rate of mortality.

A hypothesis that seemed reasonable to me was that, in addition to conditioning the avoidance response, we were conditioning the immunosuppressive effects [of Cytoxan].”

His next study, published in 1975, proved beyond doubt that his hunch, although surprising and openly mocked by other scientists, was spot on.

The game truly had changed. A neural signal (taste) had managed to trigger a conditioned reduction in the immune system. The results were replicable, and although the theory received more than its fair share of flack, there seemed no other way to explain it.

All of a sudden, the central nervous system and immunity were bedfellows.

Following on from those seminal experiments, science began to build a picture of this new and unexpected interaction.

Share on PinterestThe brain and immune system are now known to have a myriad of functional connections.

If the immune system was in cahoots with the nervous system, there must be points where they intersect. Soon, this too was demonstrated.

In 1981, David Felten made the next major discovery. He uncovered a network of nerves that led to blood vessels and, importantly, cells of the immune system.

Felten’s team found nerves in the thymus and spleen that terminated near clusters of important immune system components: lymphocytes, macrophages and mast cells.

In 1985, Candace Pert found neurotransmitter and neuropeptide receptors on the cell walls of the immune system and the brain. This discovery showed that the communication chemicals of the nervous system could also speak directly to the immune system.

What made this finding particularly fascinating was the discovery of neuropeptide links to the immune system.

Neuropeptides are the latest molecules to join the ranks of the neurotransmitters. Neurons use them to communicate between themselves and, to date, more than 100 distinct neuropeptides appear to be utilized by the nervous system.

Rather than classic neurotransmitter’s relatively short-lived action, neuropeptides have longer-lasting effects and can influence a number of operations, from gene expression to the building of new synapses.

Interestingly, neuropeptides are implicated in a wide array of functions involving an emotional aspect. For instance, neuropeptides are known to play a part in reward-seeking, social behaviors, reproduction, memory and learning.

As the field of PNI grows and develops, many discrete pathways of chatter between psychology and immunity are being discovered.

Over the past few decades, the depth of integration between the nervous system and immune system has slowly been unpicked.

For the sake of brevity, we will mention just one of the better-understood networks at play: the hypothalamic-pituitary-adrenal (HPA) axis and the impact that psychological stress has on that particular network.

Hypothalamic-pituitary-adrenal axis

The HPA axis involves three small endocrine glands – glands that secrete hormones directly into the blood. The glands in question are the hypothalamus and the pituitary, which are neurological neighbors, and the adrenal glands, situated on top of the kidneys.

This triumvirate of tissues control reactions to stress and regulate processes including digestion, the immune system, sexuality, mood and energy usage.

Share on PinterestThe hypothalamic-pituitary-adrenal axis plays a vital role in immune-brain interaction and stress.

One chemical of note involved in the HPA axis’ work is corticotropin-releasing hormone (CRH). The hypothalamus releases CRH in response to stress, illness, exercise, cortisol in the blood and sleep/wake cycles. It peaks soon after waking and slowly declines throughout the rest of the day.

In a stressed individual, however, cortisol levels are elevated for prolonged periods of time.

During stress, the body believes it is in imminent danger, so cortisol triggers a number of metabolic changes to ensure that enough energy is available in case a fight or flight is necessary.

One of these energy-saving tactics is to suppress the metabolically expensive immune system, saving vital glucose for the approaching life-threatening event.

Of course, in modern humans, stress levels can soar for a number of reasons. Very few of these situations involve a genuine threat to life, but the HPA axis evolved long before dissertation deadlines and job interviews.

In this way, ongoing stress can reduce the capabilities of the immune system as the body saves its energy for a physical exertion that never comes.

Conversely, there is some evidence that oxytocin, produced during positive social interactions, helps dampen the activity of the HPA axis. This has been shown to promote health benefits, such as increasing the speed of wound healing.

The interaction between the hypothalamus, pituitary and adrenal glands is complex, as is the influence of other brain centers on each of them. Although we have a picture of some of its workings, we are a long way from charting the entire range of influences and influencers. And, the HPA axis is but one of the systems PNI has uncovered.

A meta-analysis of 300 empirical studies found that certain types of stress altered different aspects of the immune system. They compared brief stressors, exams, with chronic stressors – events that change a person’s entire life, caring for a partner with dementia.

Brief stressors tended to suppress cellular immunity (the type that deals with cellular invaders, viruses) while preserving humoral immunity (normally dealing with pathogens outside of cells, such as parasites and bacteria).

Chronic stressors tended to suppress both types of immunity.

Stress has a measurable effect on the strength of the immune system and therefore its ability to protect us. In a very real way, managing levels of stress can help maximize the virility of your immune system.

Research has shown time and time again that people in stressful situations have measurable changes in physical responses to injury. Whether it is slowed wound healing, a higher incidence of infection or a worse prognosis for cancer survival.

It rams home the message that managing stress is an important ability to learn and that supporting those in stressful situations is just as important.

For many years, the immune system was considered a stand-alone, autonomous mechanism. This, as we now know, is not the case. The brain speaks regularly and eloquently to the cells of the immune system and vice versa.

Stress is both psychological and physical.


What is Psychoneuroimmunology?

Psychoneuroimmunology and Stress

Did your mother ever tell you to be sure to bundle up properly in the winter so you would not get sick? Well, mine did, but I never listened because I thought only germs, not being cold, could make me sick. Yet every time I shivered with an inadequate coat, I got sick. A new science is proving all those moms right.

Psychoneuroimmunology (PNI) – and its newer name psychoneuroendoimmunology (PNEI) – is an exciting subject in health today but that jaw-breaker of a name is daunting. Let's break it down, and you'll see how simple it is:

  • 'psycho-' means thoughts and emotions
  • '-neuro-' means that the physical brain is involved
  • '-endo-' brings in the endocrine system
  • '-immunology' explains how your immune system protects you from illness

PNI researchers study how your emotions and thoughts impact your brain, hormones, and nervous system and also your immune system's ability to protect you. It can also work the other way – changes in the immune and endocrine systems create changes in your nervous system which lead to changes in your emotions. Let's see how this interaction works.

Why Are Researchers Excited About Studying PNI?

For a long time, the idea that your emotions could impact your physical health was considered a myth believed by people who supported holistic health in place of traditional medicine. Over the past 25 years, solid research has proven that prolonged stress and specific traumatic experiences change the biochemistry of your brain and your hormones.

Stressful emotions also reduce the numbers and effectiveness of immune system cells, including

  • The inflammation response which is part of your non-specific protection
  • The t cells that directly attack invaders and the Natural Killer (NK) t-cells that rid you of cancers
  • The macrophages that also attack directly
  • The cells and processes, including cytokines, that fuel chronic inflammation – a risk factor for cardiovascular disease and cancer

People who were abused or neglected as children can have permanent changes in their brain chemistry and immune response as a result. Trauma survivors, military veterans, natural disaster and assault victims, and those who work in first responder roles, have higher than expected incidences of both infectious illnesses (because their immune response to viruses is reduced) and cancer.

Even loneliness can be the cause of immune system suppression that can lead to illness. PNI also studies how positive emotions can bolster both immune and endocrine system responses.

The interactions work in the other direction as well, with many disease sufferers prone to developing clinical depression in response to lowered hormone levels and chronic inflammation.

Studies of cancer victims and other disease-sufferers who receive psychotherapy and group support show that these interventions in emotional health can have an impact on physical health.


Psychoneuroimmunology and Stress

Psychoneuroimmunology and Stress

Psychoneuroimmunology is defined as the examination of the interactions among psychological, behavioral, and social factors with immunological and neuroendocrine outcomes. It is now well established that psychological factors, especially chronic stress, can lead to impairments in immune system functioning in both the young and older adults.

In several studies of older adults, those who are providing care for a relative with dementia report high levels of stress and exhibit significant impairments in immune system functioning when compared with noncaregivers.

Stress-induced changes in the immune system may affect a number of outcomes, including slowing the wound healing process and increasing susceptibility to infections.

What is stress?

Stress is a feeling you get when faced with a challenge. In small doses, stress can be good for you because it makes you more alert and gives you a burst of energy.

For instance, if you start to cross the street and see a car about to run you over, that jolt you feel helps you to jump the way before you get hit. But feeling stressed for a long time can take a toll on your mental and physical health.

Even though it may seem hard to find ways to de-stress with all the things you have to do, it’s important to find those ways. Your health depends on it.

Chronic Stress

We all have stress sometimes. For some people, it happens before having to speak in public. For other people, it might be before a first date. What causes stress for you may not be stressful for someone else.

Sometimes stress is helpful—it can encourage you to meet a deadline or get things done. But long-term stress can increase the risk of diseases depression, heart disease and a variety of other problems.

A stress-related illness called post-traumatic stress disorder (PTSD) develops after an event war, physical or sexual assault, or a natural disaster.

If you have chronic stress, the best way to deal with it is to take care of the underlying problem. Counseling can help you find ways to relax and calm down. Medicines may also help.

How Stress Affects your Health and What You Can Do About It

Stress—just the word may be enough to set your nerves on edge. Everyone feels stressed from time to time. Some people may cope with stress more effectively or recover from stressful events quicker than others. It’s important to know your limits when it comes to stress to avoid more serious health effects.

Stress can be defined as the brain’s response to any demand. Many things can trigger this response, including change. Changes can be positive or negative, as well as real or perceived.

They may be recurring, short-term, or long-term and may include things commuting to and from school or work every day, traveling for a yearly vacation, or moving to another home. Changes can be mild and relatively harmless, such as winning a race, watching a scary movie, or riding a rollercoaster.

Some changes are major, such as marriage or divorce, serious illness, or a car accident. Other changes are extreme, such as exposure to violence, and can lead to traumatic stress reactions.

How does stress affect the body?

Not all stress is bad. All animals have a stress response, which can be life-saving in some situations. The nerve chemicals and hormones released during such stressful times, prepares the animal to face a threat or flee to safety.

When you face a dangerous situation, your pulse quickens, you breathe faster, your muscles tense, your brain uses more oxygen and increases activity—all functions aimed at survival. In the short term, it can even boost the immune system.

However, with chronic stress, those same nerve chemicals that are life-saving in short bursts can suppress functions that aren’t needed for immediate survival.

Your immunity is lowered and your digestive, excretory, and reproductive systems stop working normally. Once the threat has passed, other body systems act to restore normal functioning.

Problems occur if the stress response goes on too long, such as when the source of stress is constant, or if the response continues after the danger has subsided.

How does stress affect your overall health?

There are at least three different types of stress, all of which carry physical and mental health risks:

  • Routine stress related to the pressures of work, family and other daily responsibilities.
  • Stress brought about by a sudden negative change, such as losing a job, divorce, or illness.
  • Traumatic stress, experienced in an event a major accident, war, assault, or a natural disaster where one may be seriously hurt or in danger of being killed.

The body responds to each type of stress in similar ways. Different people may feel it in different ways.

For example, some people experience mainly digestive symptoms, while others may have headaches, sleeplessness, depressed mood, anger and irritability.

People under chronic stress are prone to more frequent and severe viral infections, such as the flu or common cold, and vaccines, such as the flu shot, are less effective for them.

Of all the types of stress, changes in health from routine stress may be hardest to notice at first.

Because the source of stress tends to be more constant than in cases of acute or traumatic stress, the body gets no clear signal to return to normal functioning.

Over time, continued strain on your body from routine stress may lead to serious health problems, such as heart disease, high blood pressure, diabetes, depression, anxiety disorder, and other illnesses.

Stress and Stressors

Even though there is little consensus among psychologists about the exact definition of stress, mainstream scientists define stress as the process by which we perceive and cope environmental factors that are appraised as threatening or challenging by our brains. Those factors, known as stressors, could be either physical or psychological in natural.

A stressor can be the presence of flood after a storm or nervousness about SATs. According to the theory of Richard Lazarus, a psychologist from UC Berkeley, there are three types of stressors (also known as stimuli): major cataclysmic changes that affect large numbers of persons; major changes affecting one or several persons; and daily hassles.

(Lazarus, 1984)

The first type of stressors may refer to phenomena that are outside anyone’s control. natural disasters, wars or uprooting and relocation, they are universally stressful. The stressors themselves could be ephemeral, but the physical and psychological aftermath is long-term.

The second category of stressors happen to relatively few people or to individuals. These are events the individual’s control, the death of loved ones, a robbery, or the process of taking exams.

The daily hassles are little things that distress or irritate: a quarrel with parents, a losing sports game or too much homework.

The above listed stressors all seem to have negative effects and impacts to our life, however, stressors can be positive as well. According to Hans Selye, the father of stress study, there are two types of stress: eustress and distress. Eustress refers to stress that actually allows the body to function as well or better than it does while unstressed.

Learning Activity

  • Go to Stress Assessment to rate your own stress level.
  • Were the results what you expected? Why or why not?


How Psychoneuroimmunology Sheds Light on Stress and Overall Health

Psychoneuroimmunology and Stress

4FR / Getty Images

Psychoneuroimmunology, also known as PNI, is an important, relatively new field that lends solid research to our understanding of the mind-body connection.

In a nutshell, PNI studies the connection between psychological processes and the nervous and immune systems of the body. A more detailed description of PNI was given in an interview with Dr.

Robert Ader, a Distinguished University Professor at the University of Rochester School of Medicine and Dentistry, and one of the pioneers of this rapidly growing branch of research.

It reads as follows:

“Psychoneuroimmunology refers, most simply, to the study of the interactions among behavioral, neural and endocrine (or neuroendocrine), and immunologic processes of adaptation. Its central premise is that homeostasis is an integrated process involving interactions among behavior and the nervous, endocrine, and immune systems.”

The field grew from the work of Russian psychologist Ivan Pavlov and his classical conditioning model.

Pavlov was able to condition dogs to salivate when they heard the ring of a bell by ringing a bell when they were given food.

Eventually, they came to automatically associate the sound of the bell with the act of eating, so that when the food was no longer given, the sound of the bell would automatically cause them to salivate.

With PNI, Russian researchers conducted a series of experiments that showed that the body’s other systems may be altered by conditioning as well. Although their research does not live up to today’s rigorous standards, they were able to cause immunologic reactions in animals in much the same way that Pavlov created salivation in his dogs.

American researchers Ader took the research further in the United States, and we now know for certain that immune responses can be enhanced or suppressed with a wide variety of conditioned cues. We also have a deeper understanding of the placebo effect—some researchers are beginning to believe that it might be a conditioned response as well.

Psychoneuroimmunology research sheds a great deal of light on many aspects of wellness and provides important research on stress. PNI studies have found may correlations between life events and health effects.

As PNI has gained greater acceptance in the scientific community, the finding that emotional states can affect immunity has been an important one, and research in this area helps us to gain a clearer understanding of stress and its effects on health. We are gaining a clearer understanding of the links between lifestyle and personality factors and immunity as research continues.

Stress and Health Research includes studies that exemplify what we have learned so far through the field of PNI and supply us with important information on the link between stress and health.

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  • Freeman, L. W. (2009). Mosby’s complementary and alternative medicine. (3 ed.). St. Louis, MO: Mosby.


Psychoneuroimmunology: Definition, Research, and Examples

Psychoneuroimmunology and Stress

Psychoneuroimmunology (PNI) is a relatively new field of study that looks at the interactions between your central nervous system (CNS) and your immune system. Researchers know that our CNS and immune system can communicate with each other, but they only recently started to understand how they do it and what it means for our health.

The nerves in your brain and spinal cord make up your CNS, while your immune system is made up of organs and cells that defend your body against infection.

Both systems produce small molecules and proteins that can act as messengers between the two systems. In your CNS, these messengers include hormones and neurotransmitters.

Your immune system, on the other hand, uses proteins called cytokines to communicate with your CNS.

There’s plenty of existing research about the effects of stress on the immune system. Many of these studies focus on the release of cytokines in response to both physical and psychological stress.

A cytokine is a small protein that’s released by cells, especially those in your immune system. There are many types of cytokines, but the ones that are generally stimulated by stress are called pro-inflammatory cytokines.

Under normal circumstances, your body releases pro-inflammatory cytokines in response to an infection or injury to help destroy germs or repair tissue. When you’re physically or emotionally stressed, your body also releases certain hormones, including epinephrine (adrenaline). These hormones can bind to specific receptors that signal for the production of pro-inflammatory cytokines.

Here’s a look at some of the recent research and discussions around PNI in the medical community:


  • A 2016 review of existing studies found that stressful experiences during childhood can increase the release of cytokines by your immune system. This is associated with an increased risk of mental illness in adulthood. Researchers believe that this early release of cytokines may cause changes in the brain that increase a person’s risk of developing a mental illness later in life.
  • A 2015 article noted that rats produced different types of cytokines depending on the type of stress they experienced. For example, an injury produced one type of pro-inflammatory cytokine. Meanwhile, exposure to a social stressor, such as separation from a close family member, released a different type of pro-inflammatory cytokine.
  • Another 2016 review found that both sleep disturbances and sleeping too much seemed to trigger the release of pro-inflammatory cytokines.
  • A 2011 review exploring the link between stress and the immune system found that stress may play a role in conditions that affect the immune system, such as cancer, HIV, and inflammatory bowel disease.

What does all of this new knowledge mean for our health? Keep reading to learn more about the role that PNI plays in several common conditions.


Psoriasis is a great example of how your immune system, CNS, mental health, and stress levels are all intertwined. It’s a chronic condition that causes your skin cells to grow too quickly. Your body usually sheds extra skin cells, but if you have psoriasis, these extra cells build up on your skin’s surface. This can lead to intense itching and pain.

The overgrowth of skin cells in psoriasis is due to the release of cytokines from your immune system. We know that psychological stress may worsen or trigger episodes of psoriasis. Indeed, people with psoriasis tend to have increased levels of cortisol, a stress hormone.

Your hypothalamus, which is part of your CNS, is responsible for cortisol production. When it senses stressors, it signals your nearby pituitary gland, which signals for cortisol production. This, in turn, can trigger the release of pro-inflammatory cytokines by your immune system. These cytokines then trigger an overgrowth of skin cells.

In addition, people with psoriasis often report having psychological conditions, such as depression, increased stress, and suicidal thoughts. Previous research has linked an increase in cytokine levels with major depression.

There’s currently no cure for psoriasis, but new developments in the field of PNI could change this in the future. In the meantime, here’s how to manage it at home.


A 2013 review of many studies exploring the relationship between PNI and cancer found evidence to suggest that:

  • Women with genetic risk factors for developing cancer showed immune system abnormalities in response to stress.
  • There appears to be a link in people with breast cancer between depression, the quality of social support they have, and immune cell activity.
  • People with breast, cervical, or ovarian cancer who reported feeling stressed or lonely had abnormalities in their immune systems.
  • Communication between the immune system and brain may impact symptoms that are related to cancer treatment, including fatigue, depression, and difficulty sleeping.
  • Stressful experiences and depression may be associated with a poorer survival rate for several types of cancer.

Coronary artery disease

A review from 2010 looking at the relationship between stress, immune function, and coronary artery disease echoed other studies suggesting that psychological stress increases the production of pro-inflammatory cytokines.

This increase in pro-inflammatory cytokines is associated with an increase in heart rate and blood pressure. In addition, the production of cytokines by your immune system promotes feelings of sickness or fatigue. According to this review, this reaction isn’t immediately harmful. However, long-term stress and cytokine production may contribute to the development of cardiac disease.

PNI is a rapidly growing field of study that looks at the relationship between your CNS and immune system. While some of the research has raised more questions than answers, researchers now know that both physical and emotional stress can have a very real effect on your immune system.

The future of PNI will ly look at how this relationship impacts certain conditions, including cancer and psoriasis. It may even point researchers in the direction of long-awaited cures for both of these conditions, along with many others.


(PDF) The Psychoneuroimmunology of Stress in Pregnancy

Psychoneuroimmunology and Stress

The Psychoneuroimmunology of Stress in Pregnancy 327

support women who are at risk for stress-related preterm birth

and other adverse outcomes. An additional research priority is

developing interventions to reduce maternal stress, alleviate

the maladaptive biological changes that may be associated

with it, and, ultimately, improve birth outcomes. Progression

from the current state of knowledge to the development of reli-

able interventions will take time, but psychological science

and psychoneuroimmunological research are already provid-

ing a strong foundation for achieving this goal.

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Coussons-Read, M. (2012). (See References). A chapter providing a

review of the effects and mechanisms of prenatal stress in preg-

nancy and infant development.

Dunkel Schetter, C. (2011). (See References). An accessible review

of research examining psychosocial stress in pregnancy.

Giscombe, C. W., & Lobel, M. (2005). (See References). An examina-

tion of the role of racism and stress in adverse pregnancy outcomes.

Declaration of Conflicting Interests

The author declared that she had no conflicts of interest with respect

to her authorship or the publication of this article.


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Psychoneuroimmunology and Stress

Psychoneuroimmunology refers to the study of the interactions among behavioral, neural and endocrine, and immune functions. It is, perhaps, the most recent convergence of disciplines that has evolved to achieve a more complete understanding of adaptive processes.

Until recently, the immune system was considered an independent agency of defense that protected the organism against foreign material (i.e., proteins that were not part of one's “self”). Indeed, the immune system is capable of considerable self-regulation.

However, converging data from the behavioral and brain sciences now indicate that the brain plays a critical role in the regulation or modulation of immunity.

This new research indicates that the nervous and immune systems, the two most complex systems that have evolved for the maintenance of homeostasis, represent an integrated mechanism for the adaptation of the individual and the species.

Thus, psychoneuroimmunology emphasizes the study of the functional significance of the relationship between these systems–not in place of, but in addition to the more traditional analysis of the mechanisms governing the functions within a single sys-tem-and the significance of these interactions for health and disease.

Brain-Immune System Interactions

Evidence for nervous system-immune system interactions exist at several different biological levels.

Primary (thymus, bone marrow) and secondary (spleen, lymph nodes, gut-associated lymphoid tissues) lymphoid organs are innervated by the sympathetic nervous system, and lymphoid cells bear receptors for many hormones and neurotransmitters.

These substances, secreted by the pituitary gland, are thus able to influence lymphocyte function. Moreover, lymphocytes, themselves, can produce neuropeptide substances.

Cytokines produced by macrophages and activated lymphocytes (and by cells of the central nervous system) are critical elements in the cascade of immune responses to antigenic stimulation and also serve to energize the hypothalamic-pituitary-adrenal axis.

Thus, there are anatomical and neurochemical channels of communication that provide a structural foundation for the several observations of functional relationships between the nervous and immune systems.

Lesions or electrical stimulation of the hypothalamus, for example, can alter antibody- and cell-mediated immune responses, and elicitation of an immune response results in an increase in the firing rate of neurons within the ventromedial hypothalamus at the time of peak antibody production. Changes in hormonal states can influence immunologic reactivity and, conversely, the immune response to antigenic challenges includes the release of cytokines which influence the neural regulation of psychophysiological processes and is also associated with changes in circulating levels of hormones and neurotransmitter substances.

Stress and Immunity

Data suggesting a link between behavior and immune function include the experimental and clinical observations of a relationship between psychosocial factors, including “stress,” and susceptibility to or progression of disease processes that involve immunologic mechanisms.

There are, now, abundant data documenting an association between stressful life experiences and changes in immunologic reactivity. The death of a family member, for example, is rated highly on scales of stressful life events and, depending on gender and age, is associated with depression and an increased morbidity and mortality.

Bereavement and/or depression are also associated with changes in some features of immunologic reactivity such as reduced lymphoproliferative responses (a general measure of the physiological status of T (thymus-derived) and B (bone marrow-derived) lymphocytes and impaired natural killer cell activity, lymphocytes capable of destroying cancer and virally-infected cells without having had prior contact with the foreign material. Changes in immunity are also associated with the affective responses to other “losses” such as marital separation and divorce. Other, less severe, naturally occurring stressful experiences such as taking examinations result in transient impairments in several parameters of immune function in medical students. In students that are seropositive for Epstein-Barr virus (EBV), for example, there are elevated EBV titers, interpreted as a poorer cellular immune response control over the latent virus, during examination than control periods. It should be emphasized, however, that the association between stressful life experiences and disease and the association between stressful life experiences and changes in immune function do not, in themselves, establish a causal link between “stress,” immune function, and disease.

In animals, a variety of stressors can, under appropriate experimental circumstances, influence a variety of immune responses in a variety of species – in a variety of ways.

Stressful circumstances can also alter the host's defense mechanisms allowing an otherwise inconsequential exposure to a pathogen to develop into clinical disease.

Our understanding of the interactions between neuroendocrine and immune function under normal and stressful conditions, however, is incomplete.

Glucocorticoids secreted by the adrenal cortex, a common endocrine feature of the stress response, are, in general, immunosuppressive and there are numerous examples of stress-induced, adrenocortically-mediated changes in immunity.

However, there are numerous other observations of stress-induced changes in immunity that are independent of adrenocortical activation. It is evident from the available literature that the immunologic consequences of stressful experiences involve complex neural, endocrine, and immune response interactions. Since immune responses are, themselves, capable of altering levels of circulating hormones and neurotransmitters, these interactions probably include complex feedback and feedforward mechanisms, as well.

In sum, the direction, magnitude, and duration of stress-induced alterations of immunity are influenced by: (a) the quality and quantity of stressful stimulation; (b) the capacity of the individual to cope effectively with stressful events; (c) the quality and quantity of immunogenic stimulation; (d) the temporal relationship between stressful stimulation and immunogenic stimulation; (e) sampling times and the particular aspect of immune function chosen for measurement; (f) the experiential history of the individual and the existing social and environmental conditions upon which stressful and immunogenic stimulation are superimposed; (g) a variety of host factors such as species, strain, age, sex, and nutritional state; and (h) interactions among these several variables.


Central nervous system involvement in the modulation of immunity is dramatically illustrated by the classical (Pavlovian) conditioning of the acquisition and extinction of suppressed and enhanced antibody- and cell-mediated immune responses.

Using a one-trial taste aversion conditioning situation, a distinctively flavored drinking solution, the conditioned stimulus (CS), was paired with an injection of the immunosuppressive drug, cyclophosphamide, the unconditioned stimulus (UCS).

When subsequently immunized with sheep red blood cells, conditioned animals reexposed to the CS showed a reduced antibody response compared to nonconditioned animals and conditioned animals that were not reexposed to the CS.

The acquisition and the extinction (elimination of the conditioned response by exposures to the CS without the UCS) of the conditioned enhancement and suppression of both antibody- and cell-mediated immune responses–and nonimmunologically specific host defense responses, as well–have now been demonstrated under a variety of experimental conditions. For example, the immunological effects of “stress” have been conditioned, and still other studies have demonstrated conditioning effects using antigen, itself, as the unconditioned stimulus. The hypothesis that conditioned alterations of immunity are merely a reflection of stress responses, notably, adrenocortical secretions, is not supported by the available data. In keeping with the bidirectional nature of nervous and immune system interactions, it is also possible to condition the physiological effects elicited by the products of an activated immune system.

The biological impact of conditioned alterations in immunity is illustrated by experiments in which conditioning operations were applied in the pharmacotherapy of spontaneously developing systemic lupus erythematosus in New Zealand mice.

In conditioned animals, substituting CSs for active drug on some of the scheduled treatment days delays the onset of autoimmune disease using a cumulative amount of immunosuppressive drug that is ineffective by itself in altering the progression of disease.

Similarly, reexposure to a CS previously paired with immunosuppressive drug treatment prolongs the survival of foreign tissue grafted onto mice.

These dramatic results address the clinical implications of the behavioral component of research in psychoneuroimmunology, but they have yet to be experimentally verified in human subjects or patients.

Again, in keeping with the reciprocal nature of the relationship between neural and endocrine and immune responses, there are data indicating that immune status influences behavior. For example, emotional and cognitive changes are associated with lupus in human patients and there are changes in the behavior of animals that accompany the progression of their autoimmune disease.


We cannot yet describe the mechanisms underlying the functional relationships between the nervous system and the immune system illustrated by conditioned and stressor-induced modulations of immune functions.

It is assumed that different conditioning and stressful experiences induce different patterns of neuroendocrine changes that define the milieu within which immunologic reactions occur.

This milieu is influenced by neural and endocrine signals to the immune system and signals from the immune system that initiate further neural and endocrine changes–and by regulatory feedback loops between as well as within these “systems.

” An elaboration of the integrative nature of neural, endocrine and immune processes and the mechanisms underlying behaviorally-induced alterations of immune function is ly to have important clinical and therapeutic implications that will not be fully appreciated until more is known about the extent of these interrelationships in normal and pathophysiological states.