Stanley M. Bierman MD, F.A.C.P. (C2004)

    Patients could, if they wish, view themselves as simply a network of mechanical systems (reproductive, motor, digestive, circulatory, and nervous), each element of which possesses its own particular design and purpose. One is "healthy" when all the component parts function properly and harmoniously. However, each system carries the potential for malfunction, and when this occurs; individuals may be presumed as being "sick." While genetic influences, environmental factors, diet and chronologic aging are critical elements impacting on health, there are intrinsic mechanisms in the body that are essential to regulate these separate components.

    In recent years, it has become increasingly clear that the lubricant that keeps these systems functioning smoothly, and that helps to maintain a sense of fitness and well-being, is closely tied to the immune function of the host. Speaking metaphorically, we know that the healthy body possesses a "department of defense" with armies of cells designed to recognize and destroy potentially dangerous intruders that upset normal homeostasis. The immune system is a critical link in the overall network relating to susceptibility to infection, if not cancer surveillance. An understanding of the immune system's function, regulatory mechanism, and association with the central nervous system is of fundamental importance in formulating an approach to good health.

    It is natural to speculate on the means whereby individuals can promote the immune system to more efficiently fight infection, in the same manner that correct nutrition and exercise can minimize the risk of heart attacks. Can adherence to proper diet boost immunity and build resistance to every infection from the common cold to AIDS? Will ingestion of food supplements from the health food store help in this respect? What about taking the appropriate vitamin and minerals? Does exercise boost immunity? Do physicians know of drugs and immune adjuvant to enhance resistance? Will chanting the correct mantra prevent cancer? More seriously, and to the point, how can your own particular emotional health and sense of well-being influence immune function?

    To understand how emotional health impacts on host resistance, entails a brief review of the manner in which your body fights infection. The subject of immune function is highly complex given the broad range of its separate elements which must act in concert with one another. These relationships are associated with a trigger mechanism, next a cascade of cellular events, which in turn, generate additional chemical mediators. The interrelations of these various components can be viewed as a jigsaw puzzle with individual and disparate elements coming together to eliminate, destroy or inactivate the invading organism. The outcome also involves a "memory" of the experience, such that the host will be better prepared next time it is confronted with the infection.

    It is nearly impossible to understate the range of the immune system's capabilities as a barrier to invasion by hostile intruders such as viruses, fungi, bacteria, foreign cells or tissues. Foremost amongst the function of this marvelous biological system is the ability of its individual components to distinguish "self" from "non-self." The non-self elements consist of the hostile intruders or microorganisms cited above. To deal with these infective organisms, the body manufactures specialized white blood cells known as phagocytes, along with other blood elements such as lymphocytes and monocytes which are assigned to recognize and counteract foreign invasion.

    If one views the heart as the central organ of the circulatory system, and the brain as the center of the nervous system, the immune system lacks a general headquarters, albeit there are regional offices in nearly every part of the body. Various segments of the immune system reside in the tonsils, adenoids, spleen, thymus, lymph nodes as well as the small intestine and bone marrow. Perhaps the first line of defense against infection is the skin and mucous membrane which act as an obstacle against invasion by foreign elements. When there is a disruption of this barrier such as by a wound, signals are sent to the immune system by chemical mediators, and then white blood cells are alerted. These cells comprise an intelligent communicative network whose members help organize the immune response. Hundreds of thousands of cells are marshalled by a specific signal from the skin, and are attracted to the local site or sites where they can render aid and defense to the host.

    Most mature white cells are highly specialized. One element consisting of the T cell lymphocyte (T for thymus-derived) has various functions, among which is the capacity to switch on various aspects of the immune system. The T lymphocyte also possesses the important quality of switching off the reaction. Another lymphocyte known as the B cell (B for bone marrow-derived) manufactures antibodies. These antibodies which are comprised of gamma globulin help immobilize and neutralize the invading organism. Once the B or T cell have met and conquered an invading antigen, the white blood cells develop a "memory" of the encounter, so that in addition to other capabilities, the immune system possesses something resembling a repository of prior infective exposures. Once it "remembers", antibodies or T lymphocytes are developed against certain microorganisms, and the host remains relatively immune for life.

    Another type of white cell that fights infection is called a phagocyte or macrophage. These blood and tissue elements act like scavengers to eat and engulf tissue debris, as well as alert certain T cells to the presence of antigens. In addition, there are killer, suppressor and helper T cells. Killer T cells, stimulated by helper T cells are responsible for zeroing in on cells infected with antigens, or turning on the body's own cells when, as in the case of cancer, they begin to proliferate in an uncontrolled manner. Another class of lymphocyte killer cells is called "natural", because unlike T and B cells, it does not require a trigger by a specific antigen. Most healthy cells are of little interest to natural killer cells, but cancer cells invaded by viruses may be vulnerable to their search and destroy missions.

    The above is only a sketchy description of the complex system that comprises the immune function. Although our immune system isn't perfect, it is very efficient and has many built in fail-safe systems that, at least in theory, rarely fail. In actuality, the immune system can malfunction in several ways. For some individuals, inhalant elements such as dust, pollens or animal hair can trigger inappropriate deployment of the immune system. This response, which we refer to as an allergic reaction, causes the host to go into "alert" over an intruder that normally causes no harm. In rare instances, the immune system can mistake the body's own cells and tissue as "non-self" and attack them. Rheumatoid arthritis would be considered a prototype of this autoimmune phenomenon, where the host's own cells attack joint tissue to cause swelling and pain. The immune system will also reject and kill potentially lifesaving organs and tissue transplants; this is why physicians employ strong anti-immunity drugs such as cortisone and chemotherapeutic agents to circumvent the graft rejection. For reasons not fully understood, the host normal immune functions can be compromised and fail to deal successfully with cancer cells. In other instances, it can be simply overwhelmed by the numbers and toxicity of invading microorganisms such as in fatal cases of pneumonia or AIDS infection.

    It is now clear that the brain and hypothalamus consist of an important link and play a pivotal role in the infrastructures that govern immune surveillance. Tucked away in the anterior hypothalamus, which is located at the base of the brain, is a network of autonomic nerve endings that radiate throughout the body. In addition, the hypothalamus is the site of production of neurohormones that are known to modulate the activities of peripheral white blood cells. During periods of emotional well-being, the normal immune system is capable of confronting and eliminating deadly invading foreign elements. Newly emerging evidence suggests that anxiety and personal life stress may change this homeostatic balance. Responding to stressful events, the hypothalamus may trigger release of selective neurohormones or send neural messengers to special end organs. The hypothalamus may influence and operate through the adrenal gland, or may directly impact on T cell function. Studies by Swiss immunologists have shown a fourfold increase in electrical activity in rat brains coinciding with elaboration of antibody producing cells following immunization.

    Proof of a psychoneuroimmunologic axis in humans has been proposed based on a number of interrelated phenomena and observations: (1) emotional stress can be shown to alter the incidence and severity of select diseases in which there is known immunologic resistance, and those associated with immunologic deficiency states {such as AIDS}; (2) strong emotional disturbance in individuals is often accompanied by measurable immunologic abnormalities; (3) hormone regulation by the central nervous system (neuroendocrines such as ACTH) have demonstrable and direct influence on peripheral immune function; (4) peripheral T cells have receptor cites for these brain neurohormones and neurotransmitters which, when activated, retard or hinder the capacity of these cells to fight infection; (5) experimental manipulation of appropriate portions of the hypothalamus have demonstrable immunologic consequences; (6) finally, it has been shown that activation of the immune system is accompanied by feedback mechanisms within the central nervous system.

    Once relegated to faith healers and practitioners of folk medicine, the idea that the conscious mind can influence the onset and outcome of various diseases is now widely accepted by the medical community. The central premise of this theory suggests that emotional stress may increase vulnerability to infection through operatives in the brain which impact on immune function of lymphocytes: psycho-neuro-immunology. While lacking strong scientific support, it is also possible that these same mechanisms may influence cancer surveillance, and render the system less efficient in fighting cancer. Whether or not this is a reasonable conjecture, the fact still remains that a better understanding of the mechanisms how emotions influence immune function may have a profound effect on our lives and life styles.

    I first became aware of the premise of psychoneuroimmunologic connection with health and well-being at a medical conference in the 1970s. I vividly recall an almost electric brain storm that I experienced when Jonas Salk discussed the notion that there was a link between emotions and immunity. Salk was borrowing on the precepts and theory laid down by George Solomon who first articulated the concept of psychoneuroimmunology in 1964. Since this time, there have been several books, myriads of scientific articles, specialized journals and a new medical discipline devoted to this field of investigation.

    Before proceeding further in the discussion, it is important to define certain words and notions that are part of the lexicon of psychoneuroimmunology. Stress is familiar to most individuals who function in today's fast-paced society. Stress, as we all know, can be maladaptative and noxious (distress), but it also can be productive, creative and tonic to the host (eustress). It is not pleasant, and surely stressful, to be falsely accused of a crime. Conversely it is equally stressful, yet quite pleasant, to win the California Lotto jackpot. Most of us recall reading in our college textbooks about Claude Bernard's studies in the 1800s on homeostasis. We may also recall Walter Canon's 1914 demonstration that epinephrine was the mediator of stress, and made it the basis of his hypothesis that the hormone mobilized the organism for "fight or flight." Years later Hans Selye enunciated his "General Adaptive Syndrome" (1946) which was mainly concerned with responses to physical and psychologic stress that would stimulate ACTH from the pituitary and cortisone secretion from the adrenal cortex. To many, these views of stress in laboratory animals were not exactly applicable to the human experience.

    It is quite clear to most individuals that stress alone is not harmful to our personal well-being. Many of us thrive and are productive despite considerable work-related and personal-life stress. When we become sick or diseased because of overwhelming, intolerable, and unendurable stress, illness does not normally happen overnight. There are, in place, a number of protective devices and safeguards that shield us. Were one to reduce the equation to its most fundamental components, the outcome of disease is influenced by both intrinsic and extrinsic determinants. Intrinsic host factors would relate to elements of age, sex, genetic and hormonal factors, previous microbial experience, and native and acquired immune competence, and emotional well-being. Extrinsic factors would pertain to hygiene, sanitation, medication, nutrition, environmental elements, alcohol-smoking-obesity and psychologic stress. Other major categories relating to the outcome of disease would bear on social support systems and coping mechanisms of the host.

    Renee Dubos suggested that the absolute quantity of stress is less significant in the long run than the temperamental orientation of the individual. Thus we must avoid simplistic notions that stress and psychologic experience are the "cause" of disease. Rather one should view stress as having complex interactions within the personality and biology of the host, and hence influencing susceptibility to disease. The timing of stress, individual coping mechanisms, and social support systems are important determinants our resistance, as are intrinsic and extrinsic host factors described above.

    Some of the early studies on stress and immune function were performed in laboratory animals. In 1957 Rasmussen demonstrated that stressful events or the simple administration of epinephrine could activate latent Herpes simplex in animals. Electric shocks, restraints, overcrowding or exposure to predators would make animals more prone to a wide variety of infectious viral agents. There were a number of animal studies in the 1970s that established close links between stress and decreased cellular immunity, the results of which cannot be addressed because of constraints and limitations in this newsletter; however Monjan's report in 1977 is illustrative. He administered high intensity sound stress to laboratory animals and demonstrated a 50% decrease in mitogenic response of B and T cells (mitogenic response constitute a test tube reaction to white cell stimulants) which lasted two weeks. He also showed a simultaneous rise in plasma cortisone production that paralleled the immune suppression. In 1981 Keller documented that incremental administration of stress by electrical currents to rats resulted in proportional reduction in lymphocyte response to mitogens.

    The neural regulation of the immune response has been widely investigated. Fessel in 1963 demonstrated that electrical stimulation of the lateral hypothalamus leads to increased gamma globulin production, while destruction of the same areas leads to decreased gamma globulin production. Another example of the feedback loop between the immune system and the hypothalamic-pituitary-adrenal axis is the observation that serum cortisol level rise in response to antigenic stimulation. Afferent pathways have been demonstrated between the peripheral initiation of an immune response and the hypothalamus by Besedovsky in 1977. Stein in 1982 demonstrated a decrease immunologic recall to specific antigens following electrical lessoning of the hypothalamus.

    Lymphokines derived from T cell lymphocytes also play an important role in the immunologic regulatory system that binds the immune system and the brain. Skin cells are known to produce interleukin 1 and may also contribute to this mechanism. There is a market basket of endogenous hormones that can be factored into the equation, and enkephalins, endorphins, vasoactive intestinal peptides, substance P, bombesin are some of the neuropolypeptides that impact on the immune system. Receptor sites of these neuropeptides are regularly found in brain centers (limbic system) that mediate emotional responses.

    Stress and immune responses in man have a long and detailed history which can be highlighted by Rimsey's 1975 study of sky lab astronauts in which he showed a decrease T cell response to mitogens after splashdown. Palmblad demonstrated that with sleep deprivation during a 77 hour vigil, there were decreased mitogenic responses of lymphocytes, deceased phagocytic function, altered adrenal, thyroidal and growth hormone production. To my way of thinking, the landmark study was Bathrop's investigation published in Lancet (1:834-836, Apr 16, 1977) into the immunological consequences of bereavement. The New South Wales physician demonstrated a ten fold decrease in T cell response eight weeks (though not at two weeks) following the death of a spouse. More recently Stein obtained similar results with bereaved persons. The results point unequivocally to an association of depression with immune function.

    Psychologic intervention has been demonstrated to positively impact on immune function, and even hypnosis has been reported to improve cell mediated immunity. Biofeedback, behavior therapy such as operant and aversive conditioning, and insight-oriented psychotherapy have been shown to benefit patients because of their particular positive influence on the immune system.

    Since cancer is a prime example of the failure of immune surveillance, patients with malignancies have been the subject of many studies correlating disease with psychologic status. Robert Ader's 1981 book on "Psychoneuroimmunology" (Academic Press) devotes a full chapter to laboratory and human studies into the relation of stress to cancer. Some of the criticisms leveled against these reports relate to the fact that many studies have been retrospective. Borysenko has pointed out that physical changes occurring secondary to cancer may themselves produce depression. It is of interest to note that depression is the initial presenting symptoms in 75% of patients with pancreatic cancer. Urban blacks are known to have a higher death rate than controls, according to the American Cancer Society, based on an attitude of fatalism and societal perception that cancer is a death sentence.

    Once patients become ill with cancer, the temperament which has been associated with the longest survival and deemed most successful in fighting the disease can be described as combative: the feisty cancer patients who do not passively accept the disease seem to live the longest. Indeed fostering this attitude is the basis for the controversial psychologic program promoted by Carl Simonton, M.D. of Fort Worth, Texas. Simonton, a radiologist, and his wife Stephanie, a psychologist, believe that patients with cancer can partially control their disease through their thought processes. The Simontons's book entitled "Getting Well Again" outlines a program where, in addition to conventional anticancer treatment, patient are encouraged to draw pictures of what they think their cancer looks like, to depict how chemotherapy and radiation are affecting the tumor, and especially, to depict their idea as to how the cells of the immune system are destroying the aberrant cells.

    The most ambitious prospective study of emotional factors preceding premature disease and death was initiated in 1946, and is still in progress, by Carolyn Bedell Thomas, M.D. of Johns Hopkins University. Surveying 17 consecutive medical school classes and 1,337 students as to nervous tension, family attitudes, and general behavioral habits, along with Rorschach tests and questionnaires, a baseline has been established. Thomas has correlated certain traits with higher incidence of disease. Specifically, adverse family attitudes seemed to be associated with major forms of cancer, mental illness and suicide. While she found that certain isolated personality characteristics could predict the future health of an individual to some degree, the overall pattern of genetic and ever-changing environmental factors is a greater determinant of outcome. However, it was clear that good early psychologic health preceded good physical and mental health in middle age. The characteristics which Thomas found which were most important for a healthy personality included good self-esteem; a warm relationship with parents; an optimistic approach to life; a spontaneous, outgoing temperament; minimal nervous tension; minimum depression and anxiety under stress; and a lack of morbid, frightening undertones on the Rorschach test.

    It is important to note that there are contrary views to suggest that "psychological stereotyping and assumption of diagnosis-specific emotional responses appear neither tenable nor clinically meaningful" (B. Cassileth et al. Psychosocial Status in Chronic Disease. N Eng J Med 1984; 311:506-11). In a study of five groups of chronically ill patients, psychosocial adaptation among individuals seemed remarkably effective and fundamentally independent of the diagnosis. The same author(s) reported social and psychological factors individually, or in combination, do not seem to influence the length of survival of cancer. Flying in the face of dogma and commonly held belief, Cassileth claimed that the biology of cancer seems to predominate and override the potential influence of life-style once the disease process is established (Psychosocial Correlates of Survival in Advanced Malignant Disease? N Engl J Med 1985; 312:1551-5).

    What emerges from a brief review of the influence of emotional stress on health is that authorities hold contrary opinions on the matter. Nevertheless, common sense, personal life experiences, and an overwhelming scientific literature on the subject do seem to add strength to the thesis that emotional stress has a deleterious effect on our lives. Perhaps my opinions and attitudes have been profoundly influenced by the writings of Norman Cousin, who's widely read "Anatomy of An Illness" has impacted on all who are familiar with his thesis. Likewise I have attended a number of UCLA Conferences, the most notable of which has been Robert Ornstein, Ph.D.'s "The Healing Brain." Together with Jon D. Levine, M.D. and Davis S. Sobel, M.D. these authors have provided overwhelming evidence of the complex interaction between the brain and body function as well as articulating the characteristics that distinguish those who remain healthy in the face of stress.

    What then is the upshot of all that has elucidated to this point in writing? What practical messages does this study impart to the reader? While space constraints do not provide a means to document select recommendations, one can start by stating that there seems to be no magical or "right" diet to follow. It is clear that nutritional deficiencies can impair immune response, but most of us follow a reasonable diet. There is no scientific evidence that massive doses of vitamin C will fight viruses or prevent cancer, notwithstanding Linus Pauling's claim to the contrary. In fact, massive doses of ascorbic acid many actually protect cancer cells from immune surveillance; likewise excess minerals such as zinc can depress this function. Protein supplements, enzymes, and a whole range of health-food nostrums that claim to boost immunity, cannot and do not. If you can find a double-blind scientific publication to this effect, then I will acquiesce. But to date, my assertion has remained unchallenged.

    It may be that very high intensity exercise can depress immunity, but the problem for most individuals is too little, rather than too much. There is little published material in the scientific literature on this matter, but regular, vigorous exercise is known to be associated with good health, longevity, and will benefit your cardiovascular system.

    Medicine has been actively engaged in investigating vaccines and drugs that can enhance immunity. The effects of active immunization against viral diseases has been known since Jenner's time, and today it can be safely said that smallpox has been eradicated, while many viral diseases, if not a number of bacterial diseases such as pertusis, tetanus and diphtheria have been conquered. Certainly we are all looking forward to a time when a vaccine for AIDS or Herpes simplex infection will be available. While it is well known that drugs such as Cimetidine, Thymosin, Transfer Factor, Gamma Globulin, Levamisole and lithium salts have demonstrable influences of cellular and humoral immunity, this fact has not necessarily translated out in "cures" for cancer or remedies for overwhelming infection. Some as yet unanswered questions relate to whether these drugs, which have known immune enhancing influences, would be best administered early in the course of disease, rather than during the terminal phase of illness.

    It then appears that the best means for enhancing natural immunity is to concentrate and direct attention to personal stress. To reiterate a previous underlined observation, one must view stress as having complex interactions within the personality and biology of the host. It would be naive and simplistic to assert that a change in emotional temperament will prevent infection and/or cancer. It is not, however, unrealistic to suggest that by diminishing life stress, the body can better function to deal with these matters, no longer encumbered by the immune suppressive influences of stress.