The Interrelationship Between Psychopharmacology and Psychoneuroimmunology

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The background

The adverse effects of stress and depression, the effects of bereavement, unemployment and social isolation on mental and physical health have been known since antiquity. Aristotle advised physicians, ''Just as you ought not to attempt to cure eyes without head or head without body, so you should not treat body without soul.'' One of the fathers of modern medicine put it more scientifically in the 19th century when he recommended that when attempting to predict health outcomes from tuberculosis in patients, it is just as important to know what is going on in a man's head as it is in his chest.

These are two of the numerous examples, largely anecdotal, that document the complex and intimate connection between the mind and the body. In the past 20 years this has given rise to a new science of psychoneuroimmunology that is devoted to the study of the inter-relationship between the brain, behaviour and the immune system. Interest in this area of neuroscience has undoubtedly been due to the impact of acquired immune deficiency syndrome (AIDS) in which it has been estimated that at least 10% of these patients will develop mood, behavioural, cognitive and memory changes before they develop somatic signs of the illness. Similarly, studies have shown that 6 months before patients with pancreatic cancer develop clinical signs of the disease, a significant proportion develop depression. Such observations suggest that not only does the brain influence the immune system by way of the endocrine and efferent neuronal pathways but also that products of immune cell activity, such as the cytokines, play a role in modifying human behaviour by directly modulating central neurotransmitter pathways.

Basic structure of the immune system

It is not the purpose of this short introduction to psychoneuroimmunology to give a comprehensive view of the immune system, and readers are referred to the key references cited at the end of the book.

Most of the cells comprising the immune system can be divided into one of two categories depending on the targets of their action. Thus the immune cells are either primed to eliminate specific pathogens or to respond to any type of cell that is not recognized as being a normal body component. The first category of cells comprises the different types of lymphocytes which are divided into the B-lymphocytes (B cells) that are responsible for antibody production, and the T-lymphocytes (T cells) that directly phagocytose pathogens or release specific biologically active proteins, the cytokines, that regulate the activity of other cells in the immune system. Both T and B cells respond in a highly specific manner when attacking pathogens. In addition to these specific immune cells, there are phagocytic cells, such as the monocytes and neutrophils, that respond to any cell type or foreign molecule that is not recognized as being a normal constituent of the body.

The phagocytic cells such as the monocytes and neutrophils are basically scavenger white blood cells that ingest invading bacteria or viruses. Some of the monocytes also enter the tissues where they become macrophages. They can also provide signals enabling T cells to respond more efficiently to the pathogen. In this situation the antigen becomes attached to the monocyte membrane which is then presented to a T-lymphocyte together with the cytokine interleukin-1 (IL-1). This initiates a further activation of T-lymphocytes. Monocytes also produce mediators of inflammation, the complement proteins, which help to create a hostile environment for foreign organisms. In addition to complement proteins other mediators of the immune response include histamine (which acts as a local hormone to cause capillary dilatation), the prostaglandins and leukotrienes which act to initiate and terminate the activities of the macrophages and T cells.

Lymphocytes are derived from bone marrow but, whereas some of the cells remain in the bone marrow until they reach maturity (the B cells), others migrate early in their development to the thymus gland to become T cells. Thus B (from bursa) and T (from thymus) cells learn to distinguish between the normal constituent cells of the body and foreign objects, due to the presence of specific memory cells which are under genetic control. B and T cells circulate throughout the vascular system before concentrating in lymphoid tissue (spleen and lymph nodes) where they remain inactive until stimulated by specific antigens. Because of the specificity of function imparted on the T and B cells by the memory cells, the lymphocytes are highly selective in responding to relatively few antigens. The main

Table 18.1. The main properties of the immune cells that are altered in psychiatric illnesses

Natural killer cells (NKCs)

Phagocytes

T and B lymphocytes

Recognize changes on cell-membrane virus-infected and cancer cells and destroy the cells. NKCs bind to surfaces of target cells and inject cytotoxic molecules into the cell membrane, destroying the cells. There are several types of cells that have NKC activity Two major classes of WBCs are involved in removing invading microorganisms by a process of phagocytosis. These are polymorphonuclear leukocytes and mononuclear phagocytes, or monocytes. In tissues, monocytes differentiate into macrophages and, in the brain, into microglia Produced by lymphoid tissue. Lymphocytes represent about 20% of the WBCs in adults; they have a long life span (sometimes several years). They probably serve as memory cells for the immune system. These mononuclear cells may be small, agranular structures (T and B cells) or large, granular cells (NKCs). Different types of T cells may only be differentiated by their cell-surface markers (CD markers - clusters of differentiation). CD markers are identified using labelling antibodies properties of the immune cells that are altered in psychiatric illnesses are summarized in Table 18.1.

T cells exist in several different forms. Thus the T-helper cells (Th cells) play a regulatory role by facilitating the antibody production by B cells and also activate the macrophages. Other types of T cells can directly attack pathogens or normal cells that have been infected with a virus or bacterium for example. These are the cytotoxic T cells, or natural killer cells (NKCs). Not only can such cells destroy pathogens but they also secrete such cytokines as IL-1 which have a key role to play in orchestrating the immune system both peripherally and in the brain. The immunoglobulins (the most important in man being IgM, IgG, IgE, IgD and IgA) are produced following the activation of B cells by specific antigens.

Fever and sleep are important events which assist recovery following an infection by helping to destroy heat-sensitive foreign microorganisms. One of the key promoters of sleep and fever following an infection is IL-1. This cytokine can penetrate some areas of the blood-brain barrier and raise the temperature ''set point'' in the hypothalamus thereby producing a fever. Similarly IL-1 promotes slow-wave sleep and thereby facilitates tissue repair due to the secretion of growth hormone during that sleep phase. In addition to facilitating tissue repair, growth hormone can also boost the immune system. Whereas the precise mechanism whereby the cytokines can enter the brain and initiate subtle changes in brain function is uncertain, CNS changes initiated by peripherally produced IL-1 (and also by the microglial cells within the brain) provides convincing evidence that the immune system directly impacts upon the brain.

The endocrine immune relationship

One of the major pathways whereby the central nervous system regulates the immune system is via the hypothalamic-pituitary-adrenal (HPA) axis. Various neurotransmitters (e.g. serotonin, noradrenaline, acetylcholine) regulate the secretion of corticotrophin releasing factor (CRF) which controls the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH directly activates the adrenal cortex to produce glucocorticoids (e.g. cortisol). Following the rise in the plasma concentration of the glucocorticoids, a negative feedback mechanism normally operates to block the further release of ACTH from the pituitary. In depression, however, there would appear to be an insensitivity of the central glucocorticoid receptors to this feedback regulation. As a consequence, the plasma concentration remains elevated and cannot be easily suppressed by a potent synthetic glucocorticoid such as dexamethasone. This forms the basis of the dexamethasone suppression test (DST) which is often used as a biological marker of depression.

T cells are particularly sensitive to the inhibitory effects of the glucocorticoids. In particular, the nascent T cells, which represent about 90% of all T cells in the thymus gland, are very sensitive to the inhibitory effects of these steroids; high steroid concentrations can also prematurely induce the migration of T cells from the thymus to other immune tissues. This leads to a decrease in the size of the thymus gland. It should be emphasized that the effects of the glucocorticoids on the immune system are biphasic; in high concentrations they suppress major components of the immune system whereas in low concentration they activate it. In addition to glucocorticoid receptors, T cells also contain receptors for prolactin and growth hormones which suggests ways in which the endocrine system can directly affect the immune system.

The adrenal gland secretes glucocorticoids in a pulsatile rhythmical way with the highest plasma concentrations being reached during the day. It has been shown that the lowest plasma concentration of the glucocorticoids coincides with the time at which the lymphocytes respond most actively to antigens. As the hypersecretion of cortisol is a characteristic feature of depression and other psychiatric conditions, it is perhaps not surprising to find that components of the immune system are also abnormal in this condition.

Anatomical links between the brain and the immune system

What is the mechanism whereby the nervous system can influence the immune system? Two major routes serve to link the brain with the immune system. The first is via the HPA axis, already referred to. The second is via the autonomic nervous system.

It has been known for over 20 years that there were adrenoceptors on T cells, B cells and macrophages. In addition, noradrenergic fibres directly innervate the bone marrow, thymus, spleen, lymph nodes and virtually all other immune organs. These sympathetic nerve terminals not only release noradrenaline but also possibly neuropeptides as well. There is evidence that many sympathetic nerve terminals innervating the immune organs make direct contact with the parenchyma, ending adjacent to the cells of the immune system. In the spleen for example, the sympathetic terminals penetrate the areas that contain a high density of helper T cells and also cytotoxic and suppressor T cells. Electron microscopic evidence suggests that the sympathetic nerve terminals can form direct physical contact with T-lymphocytes and macrophages.

The functional connection between the peripheral sympathetic system and the immune system can be illustrated by the changes which take place in ageing. It is known that in the aged animal the sympathetic innervation of the spleen is dramatically reduced. This appears to be associated with deficiencies in T cell function and in cellular immunity. At the cellular level, immunosenescence is associated with a change in responsiveness of the immune cells and in their ability to regulate the beta adrenoceptors on their cell surfaces. Such changes appear to shift the metabolism of the sympathetic nervous system to a state that encourages apoptosis (or programmed cell death) possibly by inducing an increase in the production of cytotoxic metabolites. Experimental evidence suggests that the mono-amine oxidase-B (MAO-B) inhibitor deprenyl (selegiline) can reduce these neurodegenerative changes in the peripheral sympathetic system and lead to the restoration of sympathetic innervation of the spleen.

Figure 18.1 summarizes the inter-relationship between the nervous system and the immune system.

Stress and the immune system

All forms of stress result in the activation of the pituitary-adrenal axis, with a consequent rise in circulating catecholamines and glucocorticoid hormones from the adrenal gland. The secretion of ACTH from the pituitary gland, which is controlled by hypothalamic CRF, triggers the secretion of adrenal glucocorticoids, while stress-induced activation of

Brain

* Thymus

Brain

Neuroendocrine and autonomic pathways

* Thymus

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