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.
Immune system
(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.
