Psychoneuroimmunology: interactions
system and the immune system
Introduction
Over the past 15 years, the functional autonomy of the
immune system has been successfully challenged.
Certainly, the immune system has idiosyncratic, self-
regulatory properties and functions-as does the nervous
system and the endocrine system. Each has evolved to
respond to specific stimuli originating from the internal or
external environment; in this sense, the immune system
has been likened to an additional sensory organ. Yet,
research suggests that immunoregulatory processes are
part of an integrated system of defence. Integration is
reflected in the development of psychoneuroimmunology,
the study of behavioural-neural-endocrine-immune
system interactions. Currently, pieces of this puzzle are
only now being identified. Therefore, we have adopted
the customary and somewhat arbitrary strategy of
reviewing the reciprocal relations between neural and
immune function, endocrine and immune function, and
behaviour and immune function.
Neural-immune interactions
Two pathways link the brain and the immune system: the
autonomic nervous system and neuroendocrine outflow
via the pituitary. Both routes provide biologically active
molecules capable of interacting with cells of the immune
system. 2,3 Primary and secondary lymphoid organs are
innervated with noradrenergic postganglionic sympathetic
nerve fibres.4 Peptidergic nerve fibres are also present in
bone marrow, thymus, spleen, lymph nodes, and
mucosal-associated lymphoid tissue.4 These nerve fibres
form close neuroeffector junctions with lymphocytes and
macrophages. Neurotransmitters released from these
nerves diffuse to act at distant sites, further extending the
potential for neural-immune interactions. Moreover,
lymphocytes, monocytes/macrophages, and granulocytes
possess receptors for these neurotransmitters.
5 inflammatory diseases. Other neurotransmitters inhibit or
The presence of chemically specific nerve fibres
associated with primary and secondary lymphoid tissues,
the release and availability of neurally derived substances
for interaction with immune cells, and identification
of immunoregulatory effects are criteria for
neurotransmission which have been satisfied for several
transmitters, such as noradrenaline and substance P.6,7 For
instance, noradrenaline interacts with (3-adrenoceptors on
thymic lymphocytes to inhibit thymocyte mitogenesis and
enhance
expression of cell-surface differentiation
In
antigens.8 secondary lymphoid organs, noradrenaline,
Center for Psychoneuroimmunology Research and Departments of
Psychiatry, Microbiology and Immunology, and Neurobiology and
Anatomy, University of Rochester School of Medicine and Dentistry,
Rochester, NY 14642 (R Ader PhD, N Cohen PhD, D Felten MD)
Correspondence to: Dr Robert Ader, Department of Psychiatry,
University of Rochester Medical Center, Rochester, NY 14642, USA
between the nervous
at physiological concentrations, potentiates primary in-
vitro IgM antibody responses that can be prevented by p
blockers.9 Also, noradrenaline is reported to inhibit
complement activation and macrophage-mediated lysis of
tumour or herpes simplex virus infected cells.° In
rodents, chemical sympathectomy attenuates primary
splenic antibody responses to systemic immunisation and
lymph-node antibody responses to footpad challenge,
suppresses cytotoxic T-cell responses to allogeneic cells,
and reduces delayed-type hypersensitivity reactions; it is
also associated with an enhancement of in-vivo
lymphoproliferation in some lymph nodes and an increase
in natural killer (NK) cell activity. 11,12 Chemical
sympathectomy also increases the severity of experimental
allergic encephalomyelitis 13 and adjuvant-induced arthritis
in susceptible strains of rats. 1-1
Lymphocytes and macrophages bear receptors for
substance P, somatostatin, and vasoactive intestinal
peptide.5 Substance P facilitates lymphocyte migration to
inflammatory sites, enhances lymphoproliferative
responses to mitogenic stimulation and lymphocyte
production of IgA, and promotes phagocytosis and
chemotaxis. 15 The denervation of subtance P nerve fibres
reduces the inflammation associated with herpes zoster
infection (shingles) and rheumatoid arthritis,.6 In arthritis,
the greater involvement of distal joints is correlated with
the density of substance P-containing afferent nerve fibres
to these areas. Focal neural lesions alter the bilateral
symmetry of rheumatoid arthritis in humans and in rats.
Patients with paralysing central or peripheral lesions, who
later develop arthritis, do not develop joint inflammation
in the paralysed limb.16 Thus, neurotransmitter release in
joints may be an additional pathway, besides the
secondary lymphoid organs, through which the nervous
system contributes to the pathogenesis and severity of
counteract the effects of substance P.S
Even before sympathetic innervation of lymphoid
tissues was recognised, it was known that lesions of the
brain, especially the hypothalamus and limbic system,
had immunological consequences. 17 Preoptic/anterior
hypothalamic lesions suppress splenocyte and thymocyte
numbers, proliferative responses to T-cell mitogens, NK-
cell cytotoxicity, antibody production, and lethal
anaphylactic responses. Many of these effects are
mediated by neuroendocrine changes since
hypophysectomy of lesioned animals obviates these
immune changes. Medial or posterior hypothalamic
lesions are associated with reduced numbers of T and B
cells and enhanced allograft rejection.
There is also laterality in the immunomodulatory
effects of the cerebral cortex.18 Large lesions of the left
hemisphere of mice suppress T-cell function but do not
influence B-cell activities or macrophage function. By
contrast, lesions of the right cerebral hemisphere enhance
99
T-cell function. These data yield interesting correlations
with handedness and the increased incidence of early
dyslexia, together with the development of autoimmune
disease in lefhanded individuals. In view of the central
role of the neocortex in the perception and interpretation
of environmental circumstances, including stressful life
experiences, the immunomodulatory effects of the
cerebral cortex could be an important link between
psychosocial factors and alterations in
immunocompetence.
Pathways between the brain and the immune system are
bidirectional. For example, Besedovsky and colleagues9
observed that activation of the immune system is
accompanied by changes in hypothalamic, autonomic,
and endocrine processes. Immune system activation
increases the firing rate of neurons in the ventromedial
nucleus of the hypothalamus at the time of peak antibody
production; sympathetic activity, indexed by
noradrenaline turnover, is increased in the spleen and the
hypothalamus; and some immune responses, including
those initiated by viral infections, are associated with
dramatic increases in blood levels of adrenocorticotropic
hormone (ACTH) and corticosterone. Such data indicate
that signals generated by an activated immune system are
being received and acted upon by the CNS.
Cytokines released by activated immune cells, in
addition to their role in regulating cellular interactions,
are one means by which the immune system
communicates with the CNS and thereby influences
behaviour. Interleukin (IL)-I, IL-2, IL-6, interferon-),
and tumour necrosis factor influence activation of the
hypothalamic-pituitary-adrenal (HPA) axis and are, in
turn, influenced by glucocorticoid secretion.2O The
precise sites at which cytokines act within the brain
has not been fully worked out. It is known that
cytokines are endocrinologically, electrophysiologically,
and behaviourally active. Central and peripheral
administration of cytokines influence fever, sleep and
eating behaviours, locomotor and exploratory behaviour,
and mood states; the recent therapeutic use of interferons
in human disease has been associated with neurological
and psychiatric side effects.21
Endocrine-immune interactions
In addition to autonomic nervous system activity, the
immune system is influenced by neuroendocrine outflow
from the pituitary. All immunoregulatory processes take
place within a neuroendocrine environment that is
sensitive to the influence of the individuals perception of
and response to events in the external world. Because
lymphocytes bear receptors for various hormones and
neuropeptides, the cellular interactions that mediate
humoral and cellular immune responses can be
modulated by the neuroendocrine environment in which
these immune responses occur.
In rodents, deficiencies of growth hormone are
associated with abnormal cellularity of the bone marrow
and thymus, together with diminished antibody
production, T-cell function, and NK-cell activity. These
effects are, to a large extent, overcome by administration
of exogenous growth hormone.== Prolactin exerts a
stimulatory effect on immune functions.23 Inhibition of
pituitary prolactin secretion suppresses antibody and cell
mediated immune funtions and increases susceptibility to
infections such as Listeria monocytogenes. These defects in
immune function can be reversed by exogenous treatment
100
with prolactin or dopamine antagonists given to stimulate
endogenous release of prolactin. Prolactin released in
response to stressful experiences counters many of the
immunosuppressive effects of corticosteroids.
Lymphocytes bear receptors for corticotropin-releasing
factor (CRF), ACTH, and endogenous opioids.
Endorphins (and enkephalins) directly influence antigen-
specific and non-specific in-vivo and in-vitro responses,
the direction and magnitude of the effects being
determined by several factors including the nature and
quality of the peptides, their binding sites, and the timing
of administration in relation to dose and route of
antigenic stimulation.24 Although there are direct
immunomodulatory effects of CRF and ACTH, their
major in-vivo effects are exerted through interactions with
other hormones and immune system products.3,25
The most conspicuous hormonal influences on immune
function are achieved through ACTH-induced release
of adrenocortical steroids. The administration of
glucocorticoids to reduce inflammatory responses and to
prevent rejection of transplanted tissues is based on their
immunosuppressive effects. However, many immuno-
suppressive properties of corticosteroids were observed
after pharmacological rather than physiological doses of
the hormone. In physiological doses, glucocorticoids are
essential for normal immune function (compromised
adrenal function increases susceptibility to infections)
and, in some circumstances, corticosteroids can be
immunoenhancing.26
The generally immunosuppressive effects of
glucocorticoid release may protect the organism against
an overreaction of the immune system that could lead to
autoimmune disease.19,27 In the case of experimental
allergic encephalomyelitis, a central demyelinating
autoimmune disease, the anti-inflammatory effects of
corticosterone attenuate the time-limited course of the
paralysis.28 However, adrenalectomised animals do not
recover from this condition unless treated with
glucocorticoids. An apparent defect in the release of CRF
and the diminished adrenocortical activity in Lewis
compared with Fisher strain rats makes the former more
susceptible to the induction of rheumatoid arthritis.29
These findings show the pathophysiological consequences
of neuroendocrine-immune system interactions.
Pathways between the endocrine system and the
immune system are also bidirectional. Neural or
lymphocyte-derived cytokines contribute to the
interacting feedback mechanisms regulating the HPA axis
and its target organs by triggering CRF release or
stimulating (eg, growth hormone) and inhibiting (eg,
prolactin) production of pituitary hormones.3o-32 The
potential interaction between neuroendocrine and
immune processes is further shown by observations that
immune cells activated by immunogenic stimuli are
capable of producing neuropeptides.33
Behavioural-immune interactions
Changes in behavioural and emotional states that
accompany the perception of, and the effort to adapt to,
environmental circumstances are accompanied by
complex patterns of neuroendocrine changes. Animal and
human studies implicate psychosocial factors in the
predisposition to and initiation and progression of various
pathophysiological processes, including infectious,
bacterial, allergic, autoimmune, and neoplastic diseases
that involve alterations in immunological defence
 mechanisms.2 The chain of psychophysiological events has
not yet been firmly established, but changes in several
components of antibody and cell mediated immunity have
been associated with naturally occurring and
experimentally induced behavioural and emotional states.
The death of a family member is an especially stressful
experience and can be associated with depression and an
increased morbidity and mortality.34 Several reports
describe immune alterations in the setting of bereavement
and depression, especially in severe depressive states and
in older men. A meta-analysis (up to 1991)35 revealed
reliable effects for both enumerative and functional
measures of immunity. Clinical depression is associated
with an increased number of circulating neutrophils and a
decreased number of NK cells, T and B lymphocytes, and
helper and suppressor/cytotoxic T cells. Depression is also
associated with a reduction in NK cell activity and
lympho-proliferative responses to mitogen stimulation.
B-cell function is also affected. Depressed patients have
increased antibody titres to herpes simplex virus (HSV-1)
and cytomegalovirus compared with other hospitalised or
healthy groups.36 As in patients with recurrent HSV
infections, a greater number of depressed patients
respond to in-vitro stimulation with HSV during the acute
phase of depression than when they are in remission. The
possibility that reactivation of latent herpes infection
occurs shortly before onset of depression has prompted
speculation that a chronic, subclinical infection or
reactivation of latent virus in the brain could influence
neurotransmitter function and be implicated in the
pathogenesis of some mental disorders.36 There seems to
be no relation between hypercortisolaemia and immune
function in depressed patients, but any of several other
endocrine abnormalities in depression might be involved
in the associated changes in immune function.
Of related interest are the immunomodulating effects of
psychotropic drugs37-drugs of misuse and those given for
therapeutic purposes. The immunological effects of
psychotropic agents depend on the species, the in-vitro or
in-vivo immune response studied, the dose and duration
of drug treatment, and the timing of drug administration
in relation to antigenic stimulation. Psychotropic drug
action, like the effects of other experimental interventions,
also depends on the psychophysiological state of the
organism upon which it is superimposed.
Changes in humoral and cell-mediated immunity are
associated with the affective responses to other losses,
such as marital separation and divorce in humans3$and
with separation experiences in non-human primate .31
Changes in immune function also accompany less severe,
naturally occurring stressful experiences. For instance, the
level of distress in medical students during examination
periods is greater than during control periods and there
are transient impairments in several parameters of
immune function at such times.36 Examination periods are
associated with a decrease in mitogen responsiveness,
NK-cell activity, proportion of helper T-lymphocytes, and
interferon production. In students seropositive for
Epstein-Barr virus (EBV), there are increased EBV
antibody titres, interpreted as a poorer cellular immune
response during examination periods. The incidence of
self-reported symptoms of infectious illness is also
increased during examination periods. Increased antibody
titres to latent herpes viruses (EBV, HSV,
cytomegalovirus) can occur in the context of marital
discord, chronic caregiving behaviours, and the distress
Quality and quantity of stressful stimulation
Ability of an individual to cope effectively with stressful events
Quality and quantity of immunogenic stimulation
Temporal relation between stress and immunogenic stimulation
Sampfe time and component of immune system studied
Environmental background
Host factors (age, sex, nutritional state)
Table: Factors influencing stress-induced alterations of
immunity
associated with environmental disasters such as the Three
Mile Island nuclear accident, -10 suggesting that cell-
mediated immunity may mediate between stressful
experiences and reactivation of latent viruses. Stressful life
events also increase the rate of infectivity in response to
experimental inoculation with rhinoviruses, although
there is no increase in the incidence of common colds.4
In laboratory animals and in human beings, various
stressful behavioural manipulations influence immune
responses. Depending on the environmental demands and
the nature of the pathophysiological process, stress can
also alter host defence mechanisms, thereby altering
susceptibility to bacterial and viral infections, modifying
the neuroinvasiveness of normally non-neurovirulent
strains of virus, or allowing an otherwise inconsequential
exposure to a pathogen to develop into clinical disease .40-2
Stress activates the HPA axis, increases circulating
glucocorticoids, and is associated with alterations of
immune function and susceptibility to infection and
neoplastic disease. However, it is not possible to attribute
all immunological can sequences of altered behavioural
states to increased adrenocortical steroids. There are
numerous exmaples of stress-induced, adrenocortically
mediated changes in immunity, but there are many other
observations of behavioural and stress-induced changes in
immunity that are independent of adrenocortical
activation.43 Also, stress-induced immunosuppression is
seen in adrenalectomised animals and hypophysectomy
obviates the effect of some stressful events on some
measures of immunity while potentiating effects on
others.44
Opioid peptides and catecholamines, subject to
hypothalamic-pituitary influences, are also part of the
response to stressful experiences and exert
immunomodulatory effects. For example, intermittent
electric footshock results in opioid-mediated analgesia
whereas continuous footshock produces naloxone-
insensitive analgesia. Only intermittent footshock reduced
NK cytotoxicity, and only the intermittent stressor
enhanced growth of an experimentally induced NK-
sensitive tumour In sum, the direction, magnitude, and
duration of stress-induced alterations of immunity (and
susceptibility to disease) are influenced by several
interacting factors (table)}6
A striking example of CNS involvement in the
modulation of immunity is the classical (Pavlovian)
conditioning of antibody and cell mediated immune
responses .47 When a distinctively flavoured drinking
solution, the conditioned stimulus, is paired with the
injection of an immunosuppressive drug, eg,
cyclophosphamide, the unconditioned stimulus, the
subsequent antibody response to sheep red blood cells is
attenuated in conditioned animals re-exposed to the
conditioned stimulus. Similarly, the immunological effects
of stress have been conditioned}8 Other studies-l9 have
shown conditioning effects using antigen as the
unconditioned stimulus. Mediation of conditioned
101
immunopharmacological effects, stress effects, and of the
direct conditioning of immune responses are not yet
known but probably involve sympathetic and/or
neuroendocrine mechanisms, including feedback
regulation by the immune system. The hypothesis that
conditioned alterations of immunity are merely a
reflection of stress responses, notably adrenocortical
secretions, is not supported by the evidence.43
The biological impact of conditioned alterations of
immunity is shown by the application of conditioning
operations in the pharmacotherapy of spontaneously
developing systemic lupus erythematosus in New Zealand
mice. Substituting conditioned stimuli for active drug on
some of the scheduled treatment days delays onset of
autoimmune disease using a cumulative amount of
immunosuppressive drug that is ineffective by itself in
altering progression of disease.,30 Similarly, re-exposure to
a conditioned stimulus previously paired with
immunosuppressive drug treatment prolongs survival of
foreign tissue grafted onto mice." These results point to
further clinical implications of research in
psychoneuroimmunology, but they have yet to be verified
in patients. One case study describes the successful use of
conditioning in reducing the amount by cytoxan therapy
received by a child with lupus. 52
In keeping with the reciprocal nature of the relationship
between neural and endocrine and immune responses, the
interactions between behaviour and immune function are
bidirectional. In the same way that behavioural
conditioning can modulate immune responses, the
physiological effects of IL-1 can be conditioned. 53 Also,
the behavioural effects of (early) viral infections, the
behavioural differences between normal mice and those
with a genetic susceptibility to autoimmune disease, and
the cognitive and emotional sequelae of autoimmune
disease are cases in point. S4
Consistent with an extensive literature on the
behavioural regulation of physiological states, behavioural
changes associated with immunological dysfunction may
act to maintain or restore immune homoeostasis. In
failing to acquire avoidance responses to cyclo-
phosphamide or in voluntarily consuming drinking
solutions containing cyclophosphamide, lupus-prone mice
behave in a manner suggesting a recognition of their
immunological dysregulation and an attempt to restore
health.55 The animal may be responding to non-specific,
immunologically induced pathophysiological changes in
one or another target organ. It is also possible, though,
the brain is receiving information from the (dysregulated)
immune system directly.
Conclusion
There is of the interactions between
a new appreciaton
behavioural, neural, endocrine, and immune processes.
Indeed, there has been a paradigm shift in the attempt to
understand immunoregulatory function. The innervation
of lymphoid organs and the availability of
neurotransmitters for interactions with cells of the
immune system add a new dimension to our
understanding of the microenvironment in which immune
responses occur. Similarly, the interaction between
pituitary, endocrine, and lymphocyte derived hormones,
which define the neuroendocrine environment in which
immune responses take place, adds another level of
complexity to the analysis of cellular interactions that
drive immune responses. Collectively, these observations
102
provide the basis for behaviourally induced alterations in
immune function and immunologically based changes in
behaviour. They may also provide the means by which
psychosocial factors and emotional states influence
development and progression of infectious autoimmune,
and neoplastic disease. Neurotransmitters and cytokines,
the signal molecules of the nervous and immune systems,
are expressed and perceived by both systems and, as such,
are misnomers. What have been considered separate
"systems" can be considered components of a single,
integrated defence mechanism in which the interaction
between systems is as important to an understanding of
adaptation as the interactions within a system.
The association between stressful life experiences and
changes in immune function do not establish a causal link
between stress, immune function, and disease. This chain
of events has not yet been definitively established.
However, major links between these "systems" have been
described and a new understanding of interactive
biological signalling has begun. Psychoneuroimmunology
is developing the means to explore these relations and
their clinical and therapeutic implications.
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