Psychoneuroimmunology




Introduction

Health psychologists are concerned with the effects that psychological states and processes have on health and disease. Credible scientific enquiry into these connections began with Dunbar and Alexander, both of whom proposed that specific psychological factors caused or predisposed individuals to specific diseases, giving rise to the theory of specificity. Engel subsequently described the multifactorial approach, in which diseases have multiple determinants, including psychological factors. Finding correlational evidence that disease and health states are affected by psychological factors necessitates the investigation of processes mediating such links. Psychoneuroimmunology (PNI) is concerned with these processes, examining in particular the bidirectional relationships between the mind and the immune system, through nervous system and endocrine system pathways.

This article provides a basic introduction to the field of psychoneuroimmunology. This includes a brief overview of the immune system followed by a description of nervous and endocrine systems, which provide the channels of communication between the mind and the immune system. Some of the most commonly used methods that have been used to assess these interactions are examined. Conditioning of immunity and the effects of stress on the immune system are then discussed, and finally the clinical applications of PNI are considered, including the importance of PNI for understanding the course of immune-mediated disorders.

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The Immune System

The immune system is a highly complex system whose intricate workings are described elsewhere in this text. This section seeks only to set out the basic principles of the system in order to familiarize the reader with key terms and processes.

Self-versus Nonself

The immune system has one basic function: to seek and destroy foreign agents (pathogens). To achieve this, the body must first discriminate between itself and the pathogen. This recognition is achieved first by phagocytes recognizing patterns on the surface of the cell in question. This is termed innate recognition.

Once an agent is recognized as nonself, the system begins a process in which there is a cascade of cells to attack and destroy the specific pathogen. Such defenses are brought about through monocytes and lymphocytes: T cells and B cells. B cells are principally responsible for the production of antibody, which binds to the pathogen to aid in its destruction. There are several types of T cells, including cytotoxic T cells, T suppressor cells, and T helper cells, all of which have specific roles in immune function. The cascade of cells and their functioning is mediated by the presence of certain chemicals, called cytokines, including the interleukins, interferons, and colony-stimulating factors. Alterations in their concentrations regulate immune functioning.

Channels of Communication between Brain and Immune System

The physiological processes that form the pathway between the brain and the immune system are the nervous and the endocrine systems, both of which are controlled by an area of the brain called the hypothalamus. These are briefly introduced in turn.

The Nervous System

The nervous system consists of two branches: the central nervous system (CNS), which comprises the brain and the spinal cord, and the peripheral nervous system (PNS), which comprises the remainder of the nerves. The PNS is further divided into the autonomous and somatic nervous systems. The somatic system is connected to voluntary muscles, whereas the autonomic system is the one of interest in PNI because it is connected to the involuntary muscles, such as lungs, stomach, and liver, regulating the processes essential for survival. The somatic system is subdivided into the sympathetic and parasympathetic systems. Both systems innervate the same organs, but they have different, but not mutually exclusive, actions. The sympathetic nervous system is concerned with arousal of systems, increasing blood supply to facilitate the activation of a system or organ, and as such is associated with increased heart rate and blood pressure. The parasympathetic nervous system reduces arousal and activation and as such slows down heart rate and reduces blood pressure.

The Endocrine System

The action of the endocrine system is complementary to that of the nervous system and acts through the release of hormones into the bloodstream through a series of glands. The most widely investigated of these are the adrenal glands, which consist of the adrenal medulla and the adrenal cortex. Following stimulation of the sympathetic nervous system, the adrenal medulla secretes epinephrine and norepinephrine (also known as adrenaline and noradrenaline, respectively). Norepinephrine functions like the sympathetic nervous system by extending arousal. Epinephrine has similar effects and is particularly effective in stimulating the heart. The adrenal cortex is stimulated through the release of adrenocorticotropic hormone (ADTH) from the pituitary, which in turn has been stimulated through the release of corticotropin-releasing factor (CRF) by the hypothalamus. When stimulated, the adrenal cortex secretes corticosteroid hormones. There are two basic forms of corticosteroids; mineral corticoids, which affect the utilization of minerals and electrolyte regulation in the blood, and glucocorticoids, which aid in regulation of glucose in the blood. In humans, the main glucocorticoid is Cortisol.

Mind-Body Connections

The first experiments linking psychological events with physiological responses were conducted by Selye in 1946 and gave rise to the theory of the general adaptation syndrome (GAS). In basic terms, GAS proposes that exposure to a stressor elicits a nonspecific adrenocortical response in three stages: alarm reaction, resistance, and exhaustion. Alarm reaction occurs as an animal recognizes a stimulus as a stressor; resistance occurs as an animal attempts to cope with the stressor, and is characterized by increased adrenocorticol activity; and exhaustion occurs when the stress caused by the stressor is not alleviated, and leads to adrenocortical exhaustion and disease or death. Although simplistic (it is clear that the adrenal cortex is not the only mechanism between stress and health), this research demonstrated that external events could influence physiological processes, that the effect was hormonally related, and that this had direct consequences for immune functioning.

These experiments led to the understanding of two important systems responsible for coping with stressors: the active (fight/flight) system and the passive (conservation/withdrawal) system. The pathways for these systems will be set out in turn. They are important in understanding health and disease because they both culminate in the release of hormones that can and do influence immune functioning.

The Sympathomedullary Pathway (SAM)

The SAM pathway is the pathway for the active system, and involves activation of the sympathetic nervous system and then the adrenal medulla. As previously discussed, this results in the release of epinephrine and norepinephrine.

The Hypothalamic-Pituitary-Adrenocorticol (HPA) Pathway

The HPA corresponds to the passive system, where stress activates the hypothalamus, which secretes CRF, stimulating the pituitary. This activates the adrenal cortex, and culminates in the release of Cortisol.

Hormones involved in both of these pathways affect the immune system and therefore influence the body’s ability to respond to disease. Some of the evidence linking the SAM, HPA, and immune system is summarized as follows:

SAM and the Immune System

In general, activation of the SAM axis has been associated with an upregulation of the immune system. For example, an early study involving injections of norepinephrine found that this hormone results in the redistribution of lymphocytes from storage into circulation while reducing the efficacy of the cells (Crary et al.) Norepinephrine has also been associated with increased natural killer (NK) cell activity (Locke et al.) and a decrease in gamma interferon (Malarkey et al.). Indeed, Cohen and Kinney, in a recent review of the interactions between the nervous and immune systems, state that there is compelling evidence to support a bidirectional relationship between these systems. This includes evidence that the nervous system is connected to parts of the immune system by nerve fibers and that components of the immune system, in turn, have receptors specific for norepinephrine that respond to norepinephrine released by the sympathetic nervous system.

HPA and the Immune System

In general, the activation of the HPA axis has been associated with a downregulation of the immune system. Most HPA studies have examined the effects of Cortisol on immunity and have found that Cortisol can kill lymphocytes (Borysenko & Borysenko) and can affect the ability of NK cells and lymphocytes to respond to pathogens (Strausbaugh & Irwin). In a more recent study, Gruzelier and colleagues showed, by using hypnosis to reduce stress in students during examination periods, that changes in Cortisol correlate positively with changes in NK cells.

Further description of the relationships among the nervous, endocrine, and immune systems are explored in details in other texts (e.g., Ader et al.).

Before examining the evidence linking psychological processes with immune function, we consider how these relationships are typically measured. This includes an overview of approaches to measuring the immune system and stress.

Measurement Issues in Psychoneuroimmunology

Measuring Immunocompetence

The dramatic increase in PNI research has resulted in a plethora of techniques to measure the effects that psychological states might have on immunity. The breadth of techniques leads to difficulty in interpreting PNI data because direct comparisons among studies cannot easily be drawn. This section presents some of the most commonly used techniques and briefly discuss their pros and cons. Vedhara and colleagues provide a more in-depth review of available measures and their relative usefulness.

Immunocompetence can be measured in vivo and in vitro. In vitro assessment is the most common and tends to focus on the presence, quantity, and function of individual parts of the immune system. In vivo assessment is much less common and focuses on how the system works as a whole when presented with a specific immune challenge. Both types of technique have advantages and disadvantages. In vivo techniques tell us much about the outcome of the immune response, but little about the underlying processes, whereas in vitro techniques tell us about the minutiae of processes within the system, but a limited amount about what impact those processes will have on the functioning of the host. Both approaches involve enumerative and dynamic or functional measures.

Common Enumerative Measures

Enumerative measures involve measuring the amount of a chosen immune substance, for example, total lymphocyte numbers, or numbers of T cells. Adequate functioning of the immune system might depend on adequate numbers of cells. However, it should be noted that cell numbers do not always correspond to cell function. Anesi and colleagues, for example, in a study with people with depression, found that although T cell numbers were not altered, T cell responses were reduced. Additional difficulties arise from variations in cell numbers brought about through physiological events, other than stress or psychological changes, such as circadian rhythms.

Other enumerative measures include the measurement of cytokine and antibody levels. Cytokines up- and downregulate the immune system, and therefore measurement of cytokine levels can be useful in understanding underlying mechanisms for immune dysfunction. Kiecolt-Glaser and colleagues reported that stress in caregivers was associated with poor antibody response to influenza vaccine. Through measurement of several cytokine levels, they were able to speculate on the possible mechanisms underlying this poor response.

Measurement of antibody levels is popular in PNI research, with investigators assessing both total antibody levels or levels of specific types of antibody. Of these, the measurement of total antibody levels is the perhaps the most limited because only a proportion of any circulating antibody will respond to any pathogen, and thus total levels are imprecise in determining functional immunocompetence. Responses to specific pathogens are favored, but even these have difficulties, in particular the fact that antibody levels decrease quickly once the pathogen is removed. Many researchers have circumvented this through focusing on latent viruses (i.e., viruses that are always present in the body).

Common Functional Measures

Functional measures typically involve assessing the immune system in action. One of the most common techniques involves measuring the extent of proliferation in immune cells in response to a pathogen. Despite the widespread use of these proliferation assessments, there is no proof of a linear relationship between proliferation and efficacy of the immune response, and it is not always clear which lymphocytes are responding to the pathogen.

Measurement of the ability to kill pathogens (cytotoxicity) also provides a measure of immune system efficacy. Active killing or cytotoxicity can be carried out by T cells and NK cells. The assays for measuring this inform us about the T or NK cells potential for killing. However, cytotoxicity assays only inform us about the endpoint—that cytotoxicity is affected. Such an end result could be the result of many different changes, such as decreased proliferation.

Integrated in Vivo Measures

The foregoing methods of measuring immunocompetence provide indications of how specific parts of the immune system are functioning. However, there is little empirical evidence associating such methods with clinical outcomes. Methods of measuring immunocompetence in vivo offer outcomes of the greatest clinical significance because evidence concerning how the system works as a whole offers the most accurate way to judge the efficacy of the system. As previously mentioned, there are very few in vivo methods that have been used in this field, largely due to the ethical difficulties in exposing human participants to immune challenges. Those that have been used include delayed hypersensitivity tests and responses to live or attenuated virus preparations. These are briefly discussed here.

Delayed Hypersensitivity Test. Hypersensitivity is an exaggerated immune response leading to tissue damage. There are four types, but only type IV or delayed hypersensitivity has been adopted as an index of immunity in PNI. In this response, lymphokine release following T cell-pathogen interaction causes inflammation. In humans this test is often used to determine whether previous exposure to a particular pathogen has occurred. Although this method provides an indication of a system working in context, it does not illustrate where the immune impairment has taken place or provide an easily quantifiable immune response.

Response to Live or Attenuated Virus Preparations. This method involves healthy individuals being given a vaccine and different responses, most commonly the antibody response, being examined. This has clear advantages because the pathogen is naturalistic and the ethical difficulties of introducing a pathogen into a participant are removed. The only caveat with such methods is that previous exposure to pathogen can have a profound effect on immune response to current assault, and therefore any results from such studies should be interpreted with this in mind. Vaccination studies tend to use populations who would be receiving vaccinations without involvement in a study; for example, influenza viruses are commonly examined in older adults, who receive the vaccination in winter, and hepatitis B vaccinations are often examined in medical students, who receive this vaccination before beginning clinical work involving potential exposure to blood.

Psychoneuroimmunology and Psychological Applications

Conditioning of Immunity

Ader and Cohen in the 1970s conducted a revolutionary experiment in which they paired a saccharin solution (the conditioned stimulus) with an immunosupressant drug (the non-conditioned stimulus) in a classical conditioning paradigm. In classical conditioning a stimulus that will naturally affect a specific response (the nonconditioned stimulus) is given at the same time as a stimulus that by itself would produce no response (the conditioned stimulus). Conditioning occurs when the stimulus that would typically produce no response begins to produce the response that is associated with the other stimulus. Ader and Cohen were able to show that immunosuppression could be conditioned because the saccharin solution given without the immunosupressant drug began to produce immunosupressant effects. These findings have been replicated many times using various paradigms, and it is now widely accepted that the immune system can be conditioned, although robust findings have only been shown in T cell conditioning, not B cell conditioning.

Exton and colleagues showed that immunosuppression could be conditioned in rats that had undergone heart grafts to prevent rejection of the graft and prolong survival. They proposed that this occurred by inhibiting the release of cytokines in the spleen, imitating and supplementing the action of the standard drug treatment, which also works in this way.

Most studies have used pharmacologic agents to elicit immunosupression, but perhaps of even more interest to health psychologists are experiments using nonpharmacologic stimuli to elicit a conditioned immune response. Sato and colleagues, for example, found that if mice were stressed using electric shock, a conditioned immunosupression related to the stress of the shock could be elicited.

The conditioning of immunoenhancement has also been the subject of only limited research. Most studies have used conditioning of enhancement of NK cell activity, and most have been carried out using animals. One exception to this is the work of Ikemi and Nakagawa, who elicited a conditioned skin inflammatory response in a sample of four participants. Although not being beneficial in itself, this work showed that the immune system could be upregulated as well as downregulated by conditioning.

Stress and Immune Functioning

The relationship between stress and immunity is perhaps the most researched area of PNI within health psychology. Experiments have considered the effects of both acute and chronic stress in animals and humans and in healthy and diseased populations, including people with HIV, cancer, rheumatoid arthritis, and multiple sclerosis. These studies have employed many paradigms to assess the efficacy of the immune response, including response to vaccine, wound healing, and progression of disease.

With regard to experimental acute stress, Bachen and colleagues found that experimentally induced acute stress, caused by a 21-min Stroop test, was associated with a reduction in lymphocyte numbers and their proliferation in response to pathogen. Illustrating the importance of appraisal of stress, Sieber and colleagues found that participants who reported a noise stressor as less controllable had a higher reduction in NK cell activity than those who perceived they did have control over the noise, and were therefore probably less stressed.

Examination stress is the most widely used naturalistic acute stress paradigm. For example, Glaser and colleagues found that students had a lower percentage of CD4+ cells and reported more infectious illnesses during exam periods. More recently, Marucha and colleagues used a within-subject design to compare wound healing in students during examination and vacation periods. They found that each individual student healed more slowly during their examination period and that the time to heal was an average of around 40% longer during this time.

In terms of chronic stress, evidence for downregulation of immunity due to chronic stress has been found in hospitalized groups, people with clinical depression, people who have been bereaved, and caregivers. These studies have shown reductions in NK cell activity and T cell percentages and increased antibody levels (indicating increased viral activity) and increased plasma Cortisol, indicating activation of the HPA system. Kiecolt-Glaser and colleagues (1987) examined the immune function of the caregivers of people with Alzheimer’s disease. They noted a decline in T cell percentages, a decline in the number of T helper cells, and an increase in antibody levels to Epstein-Barr virus (the virus responsible for glandular fever). In a more recent study with caregivers, Kiecolt-Glaser and colleagues (1995) gave caregivers punch biopsy wounds, and observed that healing times were approximately 25% longer than those of controls.

There is now a large body of literature on the effects of stress on the progression of disorders such as HIV infection. Whether stress can mediate the course of a disease is a difficult question to answer, given the multifactorial nature of disease aetiology. However, investigations using a wide range of research designs appear to suggest that stress may indeed be a significant cofactor in the progression of such illnesses.

Cross-Sectional, Longitudinal, and Long-Term Survivor Studies: HIV Infection, an Example

In a cross-sectional study of HIV-positive men, Goodkin and colleagues found greater NK cell cytotoxicity in participants with an active coping style. Longitudinally, Weiss found that greater anger and less suppression of anger in HIV-positive men was associated with more rapid disease progression as evidenced by CD4+ decline over a 5- to 6-year follow-up. In a key study in the area of HIV infection, Soloman and colleagues retrospectively compared people who had died with AIDS-related Pneumocystis corinic pneumonia and those still alive. Survivors were found to have made more use of problem-solving social support and had significantly higher scores on the control dimension of Kobasa’s hardiness measure. Interviews with long-term survivors revealed the presence of active coping associated with realistic acceptance and adjustment to their diagnosis. These studies suggest that psychological variables, in particular coping styles, might influence the course of immune-mediated diseases such as HIV infection.

Psychoneuroimmunology Intervention Studies

Despite the fact that the field of PNI is in its infancy, it has been possible to give persuasive evidence that conditioning, stress, and other psychological factors can influence immune function. However, researchers have also examined how such immune changes can be used in clinical applications to improve health.

In a study of hypnosis and relaxation in a healthy student population, Kiecolt-Glaser and colleagues (1987) found that during examination periods, those in the intervention group had an increase in the number of T helper cells. More recently, Petrie and colleagues examined the effect of emotional disclosure on medical students. Emotional disclosure is a technique in which people are encouraged to write about traumatic or upsetting experiences usually for around 20 min a day on four consecutive days. Petrie found that the disclosure group had significantly increased antibody levels in response to hepatitis B vaccine, indicating enhanced immune functioning.

A classic study investigating interventions in a clinical population was that of Spiegel and colleagues, who examined the effect of 1 year of weekly group therapy sessions and self-hypnosis in a group of women with breast cancer. The women involved in the groups lived an average of 18 months longer than women not in the groups. Similarly, Stanton and colleagues investigated the effect of emotional disclosure on a group of women with breast cancer. They found that the participants in the emotional disclosure group attended clinics for illnesses related to their cancer, and self-reported symptoms at 3-month follow-up significantly less than the control group. However, Rosenberg and colleagues in a pilot study with 30 men with prostate cancer found that although emotional disclosure was linked to improved psychological outcomes, there was no evidence that immunity was affected.

Conclusions

PNI is a burgeoning area of research. The research endeavor has provided compelling evidence of a potent bidirectional relationship between psychological factors and physiological and immunological functioning. The challenges that lie ahead include gaining a greater understanding of the mechanisms underlying these relationships, exploring the clinical relevance of the observed effects on immunity, and developing interventions to harness the effects of the mind on the body.

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