Have you ever wondered why you’re more prone to infection when sleep-deprived and sleepier when you have an infection? Do you know why people feel depressed during an acute illness? How is it possible that low socioeconomic status can heighten a person’s susceptibility to infection? Did you know that your memory could be impaired by infection?
The once anecdotal evidence to support these claims has been substantiated in recent years by rigorous scientific data. We have finally begun to recognize and understand the complex interplay between the endocrine, immune and nervous systems within the human body. This field of study, known as Psychoneuroimmunology (PNI), has emerged as a result of a change in the way that the scientific and medical communities view the human being: as a complex whole, rather than a conglomerate of unrelated parts. As it turns out, these systems can influence one another in multidirectional fashion. Very simply put – your behavior can affect your body and your body can affect your behavior.
Psychoneuroimmunology is a scientific demonstration of the unity of the organism but chiefly involves the immune, endocrine, and nervous systems. This integrative discipline was first described in 1980 by Robert Ader (Ader, 1981). It is “the study of behaviorally associated immunologic changes and immunologically associated behavioral changes that result from reciprocal interactions among the nervous, endocrine, and immune systems.” It is a novel field of scientific inquiry for which supporting evidence has exploded in the past 2 decades. Since J. Edwin Blalock proposed a theory in 1985 about shared mediators and shared receptors in the immune and neuroendocrine systems, the field of PNI has made significant progress (Blalock et al., 1985). There are now volumes of information available, some of which will be surveyed here.
The PNI Players
Immune System
The immune system is comprised of many different cell types and large molecules whose function is to maintain the integrity of the organism and fight pathogens. It is the interface between the organism and microscopic adversaries. The skin is the most obvious component, but the liver, thymus, spleen, lymph tissue, and bone marrow play substantial roles as well. At the cellular level, immunoglobulins, granulocytes, T-cells, B-cells, natural killer cells, and chemicals called cytokines and chemokines, keep infection at bay. However, the immune system does not function autonomously. There are hormones and peptides released by the endocrine glands that impact the immune system. This is one of the foundational principles of PNI.
Endocrine System
The endocrine system is essential for maintaining life and consists of the hypothalamus, pituitary gland, thyroid, parathyroid and adrenal glands, reproductive organs, pancreas, pineal gland, and the thymus (also considered part of the immune system). The hormones and factors produced and secreted by these organs are numerous and involved in virtually every aspect of the organism. A partial list includes the following: oxytocin, dopamine, thyroid-stimulating hormone, growth hormone, prolactin, estrogen, thyroid hormones, insulin-like growth factor, epinephrine, and beta endorphin. The release of hormones by the endocrine glands is largely under neural control, is subject to negative feedback, and is influenced by other hormones. We now know that substances first discovered in the immune cells (e.g., cytokines) can alter endocrine activity and are now known to be released by pituitary cells, endothelial cells, and cells of the nervous system (neurons and glial cells). Furthermore, leukocytes (a type of white blood cell that is crucial to fighting infection) have been shown to produce pituitary hormones and various other peptides that may influence neuroendocrine activity.
The complexity and multitude of reciprocal influences between the endocrine and immune systems help explain the abundance of pathways for neuroimmune communication. However, they also reinforce the notion that a simple model of hormonal immune effects does not exist.
Nervous System
The nervous system is composed of two major parts: the central nervous system (brain and spinal cord) and the peripheral nervous system (all neural elements outside of the brain and spinal cord). The peripheral nervous system (PNS) consists of sensory and motor pathways carrying information to and from the tissues of the body. The sensory pathways transmit signals FROM visceral organs, muscles, tendons, and skin. The motor pathways carry signals TO the muscles and the visceral organs.
The visceral neural outflow is also known as the autonomic nervous system (ANS) which is divided into the sympathetic and parasympathetic branches. Another major component of the ANS is the enteric nervous system (ENS), which is contained within the walls of the gastrointestinal tract. Simply put, the components of the ANS are not under voluntary control. The ANS controls things like sweating, constriction/dilation of blood vessels, and how quickly food moves through the gut. This is in contrast to the somatic nervous system which is under voluntary control and aids us in the use of our muscles.
The Game Plan
The interplay of these systems is exceedingly complex. It is also incompletely elucidated. The following points illustrate a sample of the known interactions.
Evidence that the Nervous and Immune Systems Communicate
- Ader and Cohen showed the effect of taste-aversion conditioning on antibody immune response, which indicated that behavior influenced immunity and immunity influenced behavior (Ader and Cohen, 1975).
- Besedovsky and Del Rey (Besedovsly et al., 1977; Besedovsky et al., 1983) showed that the activated immune system was able to release a substance that caused a change in the firing rate of neurons within the brain (hypothalamus). The significance was that the hypothalamus is the brain region that controls activation of organ system pathways that allow for the brain to communicate with the periphery. The organ system pathways include the sympathetic nervous system (SNS) which releases the neurotransmitter, norepinephrine, from nerve terminals and epinephrine from the adrenal glands (immune-nervous-endocrine interaction); the other pathway is the hypothalamic-pituitary-adrenal axis which releases a number of different hormones including corticosteroids.
- Besedovsky and Del Rey also demonstrated that the SNS was able to regulate the magnitude of an antibody response by stimulating a receptor that could bind norepinephrine.
Evidence that the Endocrine and Immune Systems Communicate
- The specificity of the hormonal influences on thymic function is supported by the discovery that thymic epithelial cells and thymocytes contain receptors for many hormones and peptides.
- Production of cytokines and thymic peptides is influenced by the hormonal milieu of the micro environment, which is a reflection of both blood levels and local release of hormones in the tissues.
- Hormonal influences coordinate the distribution of metabolic resources between the immune system and other life-sustaining tissues; they modify immune activity and responsiveness during perceived periods of threat to the organism.
The Role of Psychoneuroimmunology in Disease
In effect, PNI supports early ideas about the fundamental unity of the organism and the notion that health rests on proper balance. To disrupt that balance in any way imposes a stress on the organism that creates disequilibrium within the bodily systems that sustain life. It is during such times that the organism may demonstrate vulnerability to disease or effective response to the challenge.
Psychosocial stress has neuroendocrine and immune effects in humans. The effects start in the CNS and are transmitted to the PNS and endocrine system. Peripheral neuroendocrine activity that results from the stress will feed back to modulate CNS activity. This helps impact future psychosocial inputs to which the individual may be exposed.
Disease is a form of stress that starts within microenvironments. Microenvironments may refer to DNA segments of a gene, the region around a single cell, or a small amount of tissue with a few interacting cells. This is particularly true of cancer, but also with allergic and infectious agents as well as autoimmune responses. At the level of the microenvironment, a complex interplay takes place between environmental irritants and gene expression in the cells in that area. The nutritional state of the organism influences the microenvironment as do signals from the endocrine system and local innervations by the PNS. Psychosocial factors, in turn, modulate neural and endocrine signals in the area. The cascade of events increases the likelihood that pathologic change will ensue with clinically significant symptoms.
Essentially, an individual’s state of health is a function of genetic characteristics, age, and specific organ function as a response to the challenges posed by the environment. In this way, PNI underscores the need for an integrative approach to health care. It is paramount that patients understand the natural healing process and be educated in a way that is aligned with their individual beliefs about the situation. How patients think about disease must be discussed in the therapeutic effort. Communication sets expectations in motion, and nocebo effects are just as powerful as placebos. Expectation of negative outcomes can facilitate such outcomes, so messages to patients must be carefully constructed.
Psychoneuroimmunology demonstrates the interconnectivity of bodily systems and the need for an integrative view of the individual. The pathways that interconnect the endocrine, immune, and nervous systems are complex and multidirectional. Attempts to understand disease by seeking isolated causes in a reductionistic way ignore the intricacies at all levels as well as the dynamic response to any intervention. There is still a great deal to be learned about Homo sapiens, but this will need to happen by implementing research in two ways: (1) the traditional reductionistic approach to identify the details and mechanisms of disease and (2) the integrative approach that views individuals in their natural environment in a longitudinal manner.
References
Ader, R. (Ed.) (1981) Psychoneuroimmunology. San Diego: Academic Press.
Ader, R., and Cohen, N. (1975). Behaviorally conditioned immunosuppression. Psychosomatic Medicine, 37, 333-340.
Besedovsky, H., Sorkin, E., Felix, D., and Haas, H. (1977). Hypothalamic changes during the immune process. European Journal Immunology, 7, 323-325.
Besedovsky, H., Del Rey, A., Sorkin, E., Da Prada, M., Burri, R., and Honegger, C. (1983). The immune response evokes changes in brain noradrenergic neurons. Science, 221, 564-566.
Blalock J.E., Harbour-McMenamin D., and Smith, E.M. (1985). Peptide hormones shared by the neuroendocrine and immunologic systems. J. Immunology, 135, 858s-861s.
Daruna, J.H. (2004). Introduction to Psychoneuroimmunology, London: Elsevier Academic Press.