Immunity, Hormones And The Brain
The language of immunology, with its emphasis on memory, tolerance, self and non-self, is reminiscent of that of neurology; indeed, the immune system has been referred to as a ‘mobile brain’. Soluble ‘messenger’ molecules , the cytokines (see Figs 23 and 24), are used by immune cells to communicate with each other at short range across ‘immunological synapses’ closely parallelling the role of neutrotransmitters. Other long-range cytokines recall the hormone-based organization of the endocrine system, which is itself linked to the brain via the hypothalamic–pituitary–adrenal axis. Thus, it has been suggested that all three systems can be seen as part of a single integrated network, known as the psychoneuroimmunological, or neuroendocrinoimmunological, system.
Evidence to support this comes from several directions. Stress, bereavement, etc. are known to lower lymphocyte responsiveness, and the same can be achieved by hypnosis and, some claim, by Pavlovian conditioning. Lymphoid organs receive a nerve supply from both sympathetic and parasympathetic systems, and the embryonic thymus is partly formed from brain, with which it shares antigens such as theta. Lymphocytes secrete several molecules normally thought of as either hormones or neuropeptides (see bottom right of figure), while the effect of cytokines on the brain is well established (see Fig. 24).
The ability of the immune system to affect neurological and endocrine function is clearly established, and has a central role in several important diseases (see opposite page). The influence of the brain on immunological function remains more controversial and immunological opinion is divided as to its significance. At one extreme are those who dismiss the connections as weak, trivial and irrelevant. At the other are the prophets of a new era of ‘whole body’ immunology, stretching from the conscious mind to the antibody molecule, which would have significant implications for medical care. A middle-of-the- road view would be that such effects are the fine-tuning in a system that for the most part regulates itself autonomously. Time will tell who is nearest the truth.
Cortex The outer layer of the brain in which conscious sensations, language, thought and memory are controlled.
Limbic system An intermediate zone responsible for the more emotional aspects of behaviour.
Hypothalamus The innermost part of the limbic system, which regulates not only behaviour and mood but also vital physical functions such as food and water intake and temperature. It has connections to and from the cortex, brainstem and endocrine system.
Pituitary gland The ‘conductor of the endocrine orchestra’, a gland about the size of a pea, divided into anterior and posterior portions secreting different hormones (see below).
RH Specific releasing hormones produced in the hypothalamus stimulate the pituitary to release its own hormones, e.g. TRH (TSH- releasing hormone).
Neuropeptides Small molecules responsible for some of the transmission of signals in the CNS. The hypothalamus produces several that cause pain (e.g. substance P) or suppress it (e.g. endorphins, enkephalins).
In general, sympathetic nerves, via the secretion of noradrenaline (norepinephrine), excite functions involved in urgent action (‘fight or flight’) such as cardiac output, respiration, blood sugar, awareness, sweating. Parasympathetic nerves, many of which travel via cranial nerve X (the vagus), secrete acetylcholine and promote more peaceful activities such as digestion and close vision. Most viscera are regulated by one or the other or both. Massive sympathetic activation (including the adrenal medulla, see below) is triggered by fear, rage, etc. – the ‘alarm’ reaction, which if allowed to become chronic shades over into stress.
Adrenal medulla The inner part of the adrenal gland, which when stimulated by sympathetic nerves releases adrenaline (epinephrine), with effects similar to noradrenaline but more prolonged.
Adrenal cortex The outer part of the adrenal gland, stimulated by corticotrophin (ACTH) from the anterior pituitary to secrete aldosterone, hydrocortisone (cortisol) and other hormones that regulate salt– water balance and protein and carbohydrate metabolism. In addition, hydrocortisone and its synthetic derivatives have powerful anti- inflammatory effects.
Thyroid Stimulated by thyrotrophin (TSH) from the anterior pituitary to release the iodine-containing thyroid hormones T3 and T4 (thyroxine), which regulate many aspects of cellular metabolism.
Growth hormone (GH) regulates the size of bones and soft tissues.
Gonads Two anterior pituitary hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), regulate the development of testes and ovaries, puberty and the release of sex hormones. These changes are especially subject to hypothalamic influence, e.g. psychological or, in animals, seasonal. Breast Prolactin (PL) stimulates breast development and milk secretion.
Posterior pituitary Here the main product is antidiuretic hormone (ADH), which retains water via the kidneys in response to osmotic receptors in the hypothalamus.
The pancreas and parathyroids function more or less autonomously to regulate glucose and calcium levels, respectively, although the pancreas also responds to autonomic nervous signals.
(Note: the elements shown in the figure are all considered in detail elsewhere in this book. Here, attention is drawn only to the features linking them to the nervous and endocrine systems.)
Cytokines The most convincing immune–nervous system link is the induction of fever by TNF, IL-1 and IFNs; high doses of many cytokines also cause drowsiness and general malaise. Cytokines, especially IL-2 and IL-6, are found in the brain. TNF and IL-1 are thought to induce ACTH secretion from the pituitary, probably via the hypothalamus.
Lymphoid organs Neurones terminating in the thymus and lymph nodes can be traced via sympathetic nerves to the spinal cord. Neuropeptides released within lymph nodes may regulate inflammation and dendritic cell function.
Lymphocytes have been shown to bear receptors for endorphins, enkephalins and substance P, and also to secrete endorphins and hormones such as ACTH. Small numbers of T lymphocytes are found naturally within the CNS and some studies suggest they may interact with macrophages to regulate both neuronal development and repair.
Immune responses are inhibited by hydrocortisone and sex hormones, and under stressful conditions, particularly when stress is inescapable, as with bereavement, examinations, etc. Hypnosis has been shown to inhibit immediate and delayed skin reactions. Whether corticosteroids can explain all such cases is a hotly debated point.
Autoimmunity It is remarkable how many autoimmune diseases (see Fig. 38) affect endocrine organs. Especially striking is the thyroid, where autoantibodies can both mimic and block the stimulating effect of TSH. Autoreactive T lymphocytes specific for myelin components have a key role in multiple sclerosis. The progress of this disease can be slowed by treatment with interferon β, and by Copaxone, an immunomodulatory drug that is thought to inhibit antigen presentation.
Immunity and psychological illness
A number of psychological illnesses have been linked to malfunction of immunity and/or vaccination, although it must be stressed that the links remain at best inconclusive.
Autism is a complex developmental disability of unknown cause that results in a range of behavioural and psychological symptoms. The condition usually manifests between the ages of 2 and 3, leading to the suggestion that the disease was caused by the MMR (measles, mumps and rubella) vaccine (see Fig. 41). Although the research leading to this suggestion has been completely discredited, and extensive epidemiological studies have failed to find any evidence to support any link between vaccination and autism, the publicity sur- rounding the research has caused a significant drop in the number of children vaccinated, leading to fears of a measles epidemic.
Myalgic encephalomyelitis/encephalopathy (sometimes known as chronic fatigue syndrome). A poorly defined condition characterized by extreme tiredness and exhaustion, problems with memory and concentration, and muscle pain. It may be associated with infection with unidentified viruses (it is sometimes referred to as postviral fatigue syndrome), because similar symptoms are often reported after infection with known viruses such as Epstein–Barr virus (EBV) (glandular fever) and influenza.
Gulf War syndrome A heterogeneous collection of psychological and physical symptoms experienced by soldiers involved in the Gulf War (1990–1), which some claimed was linked to the large number of vaccines given to recruits.