Scandinavian Journal of Psychology, 2009, 50, 645–651 DOI: 10.1111/j.1467-9450.2009.00779.

Health and Disability

Psychoneuroimmunology: A bio-psycho-social approach to health
and disease
ROBERT ZACHARIAE
Psychooncology Research Unit, Aarhus University Hospital and Department of Psychology, University of Aarhus, Denmark

Zachariae, R. (2009). Psychoneuroimmunology: A bio-psycho-social approach to health and disease. Scandinavian Journal of Psychology, 50, 645–651.
Since the early 1980s, the interdisciplinary field of psychoneuroimmunology has explored the complex bi-directional interactions between brain, behav-
ior, and the immune system. Taken together, this research has expanded the limits of the questions we can ask about the organism by challenging the
biomedical paradigm of the immune system as predominantly ‘‘autonomous’’. Psychoneuroimmunology has played a key role in establishing a biolog-
ical basis for the ancient idea that the mind can play a role in health and disease. This article describes the development of psychoneuroimmunology
and reviews a number of key findings concerning psychological phenomena of potential relevance to understanding brain-behavior-immune interac-
tions, including learning, emotions, stress, and the role of sensory processes.
Key words: Psychoneuroimmunology, immunology, systems theory, health, stress, learning, emotions, sensory processes.
Professor Robert Zachariae, MDSci, Psychooncology Research Unit, Jens Chr. Skous Vej 4, DK-8000 Århus C, Århus, Denmark. E-mail: bzach@
aarhus.rm.dk

INTRODUCTION historically, the predominant focus of immunological research

Over the past decades there has been increased scientific as well
as public interest in the possible influence of psychological and
social factors on human physiology, and a growing body
of research has provided evidence for psychosocial influences
on both the development and the course of a number of medical
illnesses. Psychoneuroimmunology, the interdisciplinary area of
research examining interactions between brain, behavior, and
the immune system, has played a key role in the exploration of
behavioral and biological mechanisms linking psychosocial fac-
tors, health, and disease (Zachariae, 1996). By challenging the
biomedical concept of the immune system as an ‘‘autonomous’’
defense system, psychoneuroimmunology represents a shift
from a predominantly biomedical paradigm of health and dis-
ease towards an interdisciplinary bio-psycho-social approach
(Engel, 1977). In the following, the development of psychoneu-
roimmunology and some key findings within this field will be
described.
THE EARLY HISTORY OF
PSYCHONEUROIMMUNOLOGY
The behavior of the immune system, e.g. interactions between
antibodies and antigens, can be investigated intelligibly through
cloned cells in vitro, i.e. in test tubes outside the living organ-
ism, and this has no doubt contributed to the fact that for many
decades the dominant ‘‘normal’’ scientific view of the immune
system has been one of an ‘‘autonomous’’ defense against exter-
nal and internal threats to the organism, which is essentially
unrelated to other systems and processes of the organism. While
has been on interactions between the immune system and for-
eign antigen and between the various components of the
immune system itself, a small number of ‘‘deviant’’ studies have
appeared over the years. The first study, which reasonably can
be termed as ‘‘psycho-immunologic’’, was published in 1919
and suggested that negative emotions could influence the
immune system of patients with tuberculosis (Ishigami, 1919).
In the 1920s, a series of animal studies of interactions between
the brain and the immune system were conducted in the Soviet
Union by pupils of Pavlov (1849–1936), indicating that immune
responses could be influenced by classical conditioning.
Repeated pairings of a neutral stimulus (e.g. heat) with an
immune-stimulating antigen (e.g. inactivated bacteria) were
found to result in activation of the immune response when the
neutral stimulus was presented alone (Metal’nikov & Chorine,
1926). In the 1950s and 1960s, results from a small number
of studies suggested that psychological stress could increase
susceptibility to infection (Rasmussen, Marsh & Brill, 1957)
and exacerbate autoimmune diseases such as lupus (Fessel &
Solomon, 1960) and rheumatoid arthritis (Solomon, Amkraut &
Kasper, 1964). The term ‘‘psychoneuroimmunology’’ itself,
however, was not coined until 1981, when it appeared as the
title of an anthology reviewing the evidence available at the
time for associations between behavioral, neural, endocrine, and
immune system processes (Ader, 1981). The first official psy-
choneuroimmunology meeting held in 1986 proposed a number
of key questions: (1) Are there interactions between the brain
and the immune system? (2) If so, how are they mediated? (3)
Are they bi-directional? and (4) are they trivial or important to
understanding health and disease? (Cohen, 1987).

 2009 The Author. Journal compilation  2009 The Scandinavian Psychological Associations. Published by Blackwell Publishing Ltd., 9600
Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA. ISSN 0036-5564.
646 R. Zachariae
THE IMMUNE SYSTEM IN THE LIVING ORGANISM:
A SYSTEMIC APPROACH
Posing the first question: is there evidence of interaction
between the brain and the immune system, is not possible
within the framework of the conventional ‘‘autonomous’’ view
of immunology. This requires a broader framework, as provided
by a general systems perspective of the organism (von Berta-
lanffy, 1969). From this perspective, we should expect that the
various systems of the organism have developed the ability to
interact in a coherent way with the self-regulatory purpose of
maintaining a dynamic internal equilibrium while adapting to
the challenges posed by changes in the external and internal
environment (Zachariae, 1996). While conventional immunol-
ogy may be able to describe a number of important immunolog-
ical phenomena independently of other processes, the full
understanding of the behavior of the immune system in the liv-
ing organism requires investigation of both the cooperation
between the elements of the immune system itself as well as of
their interdependencies with other elements of the system as a
whole.
While regarded as rather heretical at the time, the immunolo-
gist Niels Jerne (1911–1994), in his controversial Network The-
ory of the immune system (Jerne, 1974), pointed to the apparent
functional similarities between the immune system and the brain.
Both the brain and the immune system are self-referential, i.e.
are involved in the recognition of ‘‘self’’ versus ‘‘non-self’’, and,
according to Jerne, the immune network constitutes the identity
of the organism at the molecular level. Similarly, as suggested
by more recent developments in neuroscience, neural networks
of the brain can be viewed as constituting a neuromatrix, repre-
senting the physiological ‘‘self’’ of the organism (Melzack,
1993). Furthermore, both systems involve innate responses as
well as characteristics acquired through interactions with the
environment, i.e. ‘‘learning’’ and ‘‘memory’’. Finally, both the
brain and the immune system can be described as ‘‘sensory
organs’’. While the five ‘‘classical’’ senses enable us to be cogni-
zant of what we can see, hear, touch, taste, and smell, the
immune system can be viewed as a ‘‘sixth sense’’ that enables
the organism to recognize bacteria, viruses, cancer cells, and
other entities too small to see, touch, taste or smell (Blalock,
1984). While this challenge to the ‘‘autonomous’’ view of the
immune system is clearly ‘‘meta-theoretical’’, it has inspired
researchers to pose a number of questions that cannot be asked
within conventional immunology. These questions and their
answers form the basis of psychoneuroimmunology.
BRAIN-IMMUNE INTERACTIONS
Over the last three decades, psychoneuroimmunology research
has provided evidence for extensive bidirectional communica-
tion between the brain and the immune system. The evidence
stems from several sources. First, early animal studies indicated
that left- and right-brain lesions produce different patterns of
suppression and activation of various immune measures (Biziere,
 2009 The Author. Journal compilation  2009 The Scandinavian Psychological Associations.
Scand J Psychol 50 (2009)
Guillaumin, Degenne, Bardos & Renoux, 1985). Second, a
large body of research has identified ‘‘hard-wired’’ neural con-
nections between the brain and immune system. For example,
there is evidence for both sympathetic and parasympathetic
innervation of organs and tissues associated with the immune
system, including the lymph nodes, thymus, spleen, and bone
marrow, and other neural-immune cell associations are found in
cutaneous, gastro-intestinal, and mucosal tissue (Bellinger,
Lorton, Lubahn & Felten, 2001). Finally, it is now recognized
that the nervous and immune systems communicate through a
common biochemical language that involves shared neuroendo-
crine hormones, neurotransmitters, cytokines, and their respec-
tive receptors (Carr & Blalock, 1991). Taken together, the
available evidence has confirmed the existence of a complex
bidirectional brain-immune network, providing a biological
basis for the ancient anecdotal notion that the mind can play a
role in health and disease by its ability to influence relevant
biological processes. Figure 1 summarizes the verified commu-
nication pathways between brain and immune system.
ENVIRONMENT-BRAIN-BEHAVIOR-IMMUNE EFFECTS
The existence of an extensive brain-immune network suggests
that the immune system should be under at least partial influ-
ence by psychological processes. Examples of psychological
phenomena of potential relevance to understanding the brain-
behavior-immune connection include learning, psychological
stress, emotions, and sensory processes.
Learned immune responses
Learning is a primary function of the brain by which the organ-
ism adapts to the environment. One example of the role of the
brain in modulating the immune system is provided by studies
showing that the immune response can be modified by classical
conditioning. The early studies by Soviet researchers described
above went largely unnoticed at the time, and the first modern
psychoneuroimmunology conditioning experiment was a result
of a serendipitous finding by the psychologist Robert Ader.
A taste-aversion experiment using a saccharine-flavored drink-
ing solution as the conditioned stimulus (CS) paired with an
unconditioned stimulus (UCS) in the form of a tasteless nausea-
inducing (and immunosuppressive) agent (cyclophosphamide)
revealed that some of the animals died when subsequently pre-
sented with the CS alone. This led to the hypothesis that a con-
ditioned immunosuppressive effect of the nausea-inducing agent
had taken place, which was confirmed in a subsequent experi-
ment (Ader & Cohen, 1975). In the following years, animal as
well as human studies confirmed that a large number of immune
parameters can be both suppressed and enhanced using various
types of pharmacological and environmental stimuli as UCS
(Ader & Cohen, 2001). Cancer patients treated with cytotoxic
agents usually experience side-effects in the form of nausea,
vomiting, and fatigue as well as immunosuppressive effects
Scand J Psychol 50 (2009)
Symbolic
stimuli from the
environment
Neuropeptides
Sensory
Nervous system
Endocrine Vascular system
system
”Hormonal”
peptides
Fig. 1. The bi-directional brain-immune network.
(Zachariae, Paulsen, Mehlsen, Jensen, Johansson & von der
Maase 2007b). Some patients display anticipatory or condi-
tioned side-effects, with the hospital environment and tastes and
odors associated with the treatment serving as CS (Zachariae,
Paulsen, Mehlsen, Jensen, Johansson & von der Maase 2007a),
and studies using cancer treatment as a natural experiment have
shown results suggestive of conditioned immunity (e.g.
Bovbjerg, Redd, Maier et al., 1990).
The strength of learned associations depends on several fac-
tors. Certain personality traits related to sensory perception and
imaginative involvement such as hypnotizability and absorption
(Zachariae, Jorgensen & Christensen, 2000b) have been associ-
ated with both increased conditionability (Zachariae et al.,
2007a) and increased reactivity of the autonomic nervous and
immune systems (Ehrnrooth, Zachariae, Svensen et al., 2002;
Zachariae, Jorgensen, Bjerring & Svendsen, 2000a; Zachariae,
Jorgensen, Christensen & Bjerring, 1997). The term state-
dependent learning (SDL) describes the phenomenon that
behavior learned in one physiological state is better remembered
when retention is tested in the same state (Overton, 1991).
Although the concept of SDL generally applies to human mem-
ory and behavior, the hypothesis that SDL also applies to the
memory and behavior of the immune system has been con-
firmed in an experiment showing that the so-called delayed-type
hypersensitivity (allergic) response (DTH) was stronger when
the individual had been sensitized to an experimental allergen
 2009 The Author. Journal compilation  2009 The Scandinavian Psychological Associations.
Psychoneuroimmunology 647
Autonomic
Nervous system
Cytokines
Immune Immuno-
system genic
stimuli
and later exposed to a challenge with the same allergen under
similar psychophysiological conditions of either relaxation or
no-relaxation (Zachariae et al., 1997).
Stress and immunity
The available evidence shows that acute stressors generally are
associated with enhanced immunity and long-term or chronic
stressors with suppressed immune function (Dhabhar & Mc-
Ewen, 1997). While it makes sense from an evolutionary per-
spective that stress is associated with enhanced immunity
thereby preparing the organism to deal more effectively with
potential infections, it seems more puzzling that under long-term
stress, the same brain-immune mechanisms are associated with
suppression of some immune parameters, e.g. antibody produc-
tion, and enhancement of others, e.g. allergic and inflammatory
responses (Dhabhar & McEwen, 2001). The currently best
explanation seems to be that the immune system has developed
the ability to selectively up- and down-regulate its responses
under different conditions, e.g. up-regulate during infection and
down-regulate to avoid autoimmune reactions when the upregu-
lated immune response is no longer needed. The concept of
‘‘allostasis’’ represents the processes involved in the adaptive
responses to stressful situations, e.g. increased number of circu-
lating immune cells and enhanced cell-mediated immunity,
while ‘‘allostatic load’’ represents the physiological costs to the
648 R. Zachariae
organism, e.g. in terms of suppressed immunity to antigens or
chronic inflammation, when these mechanisms are activated fre-
quently over longer periods of time. The different immune
response patterns depend on the timing and duration of the
stressor and are modulated by stress-hormones such as gluco-
corticoids and catecholamines.
While the research demonstrating effects of various types of
stressors on immune and inflammatory processes (Herbert & Co-
hen, 1993b) has provided evidence for potential mechanisms link-
ing stress with increased risk of a number of diseases, including
infections, allergies, autoimmune diseases, and even cardiovascu-
lar diseases, the current evidence for a link between stress and
cancer is less convincing. One reason could be the limited focus
of the research so far. The prognosis of many cancer patients is
not only related to the cancer itself, but also to complications
related to the cancer and its treatment, such as infections and post-
ponement of treatment due to immunosuppression (Bovbjerg,
Valdimarsdottir & Zachariae, 1999). Stress has been shown to
increase susceptibility to infection (Pedersen, Bovbjerg & Zacha-
riae, 2009b), and to influence immuno-competence, e.g. mea-
sured as the strength of the immune response to vaccination
(Pedersen, Zachariae & Bovbjerg, 2009c). The role of stress for
the risk of infection in cancer patients, however, has so far only
been explored in one study, which showed that stress measured
prior to treatment was associated with increased risk of being hos-
pitalized with infection during treatment (Pedersen, Zachariae,
Jensen, Bovbjerg, Andersen & von der Maase, 2009d).
Immune modulation by emotions
Systematic reviews of the literature generally conclude that neg-
ative emotions such as depression are associated with increased
mortality (Cuijpers & Smit, 2002), and – conversely – that posi-
tive well-being may be associated with reduced mortality (Chida
& Steptoe, 2008). While there is good evidence of a link
between depression and immunity (Herbert & Cohen, 1993a), it
is not clear to what extent this link can explain the association
between depression and mortality. However, as positive and
negative emotions are essential psychological mechanisms,
which serve adaptive purposes in the regulation of behavior, we
should expect that changes in emotional state be reflected in
changes in the immune system. This hypothesis is supported by
results from studies showing that experimentally induced emo-
tional states can affect immunological and inflammatory param-
eters. In one study, experimentally induced negative mood was
found associated with suppression and positive mood with
enhancement of chemotaxis, a measure of immune function
(Zachariae, Bjerring, Zachariae et al., 1991). In another, the
inflammatory skin response to histamine, a model of relevance
to immediate-type allergic reactions, was found increased after
negative mood and suppressed after positive mood (Zachariae,
Jorgensen, Egekvist & Bjerring, 2001). It is worth noting that
the association between mood valence and the direction of the
immune or inflammatory response is not a simple question of
positive moods being associated with increase and negative with
 2009 The Author. Journal compilation  2009 The Scandinavian Psychological Associations.
Scand J Psychol 50 (2009)
suppression, but is in concordance with the clinical implications,
i.e. that both suppressed chemotaxis and enhanced inflammatory
reaction are associated with negative clinical outcomes. Under
natural conditions, the associations between immunity and emo-
tions might be mediated by other behavioral factors. Negative
affect is thus associated with impaired sleep quality (Thomsen,
Mehlsen, Christensen & Zachariae, 2003), which in turn is
known to affect immune function (Born, 1999), and other stud-
ies have confirmed that the associations found between depres-
sion and immune function found in clinical populations, e.g.
HIV-infected, are partly mediated by impaired sleep quality
(Cruess, Antoni, Gonzalez et al., 2003).
Theories that various types of emotional inhibition, e.g. alexi-
thymia (Jorgensen, Zachariae, Skytthe & Kyvik, 2007) and
emotional repression (Jorgensen & Zachariae, 2006) are associ-
ated with increased risk of somatic symptoms, have led to the
hypothesis that emotional inhibition may be a risk factor for
development of cancer (LeShan, 1959). Later findings, however,
suggest that the increased level of repression often found in can-
cer patients may be a coping response to the cancer diagnosis,
rather than a premorbid personality trait (Zachariae, Jensen,
Pedersen et al., 2004). This does not exclude the possibility that
repressive coping could be associated with poorer cancer prog-
nosis. The plausibility of this theory would however be
strengthened, if clear associations between emotional inhibition
and cancer-relevant immune-measures could be identified. Only
few studies have so far addressed this issue with mixed results
(e.g. Esterling, Antoni, Kumar & Schneiderman, 1993; Jamner,
Schwartz & Leigh, 1988).
Voluntary modulation of the immune system through sensory
imagery
While the psychoneuroimmunologic phenomena described
above can still be understood as ‘‘autonomous’’ – i.e. non-vol-
untary – responses to various types of external stimuli (e.g.
stressors) and psychological states (e.g. emotions), the idea that
the immune system can be influenced by voluntary, conscious
processes is more controversial from a conventional biomedical
view. Nevertheless, there is growing evidence that this may
indeed be possible by altering sensory perception through vari-
ous psychological techniques such as guided imagery or hypno-
sis (Zachariae, 2001). The response of the organism to
potentially damaging external stimuli is regulated by a number
of highly integrated mechanisms, involving both the central and
peripheral nervous systems. The two systems interact with the
aim of producing those responses of the cardiovascular, endo-
crine, immune, and sensory nervous (SNS) systems that pro-
mote the most adaptive physiological and behavioral reactions
under different conditions.
For instance, inflammatory reactions of the skin have been
shown to be partly regulated by ascending and descending path-
ways between the brain and the SNS (Zachariae, 1996).
For example, animal studies have shown that lesioning of the
sensory nerves suppresses the inflammatory skin reaction to
Scand J Psychol 50 (2009)
histamine, and, in humans, inflammatory skin reactions can be
suppressed by local anesthetics. This suggests that the intensity
of a local inflammatory reaction, e.g. to a burn, partly depends
on sensory feedback to the brain from the affected area. It is
well documented that hypnotic suggestions can alter both the
self-reported perception of sensory stimuli such as pain as well
as sensory-related brain-correlates (Zachariae & Bjerring, 1994;
Zachariae, Andersen, Bjerring, Jorgensen & Arendt-Nielsen,
1998; Zachariae, Bjerring, Arendt-Nielsen, Nielsen & Gotlieb-
sen, 1991a), and in an integrated bio-psycho-social system we
should therefore expect that psychologically induced altered
perception can reduce local inflammatory reactions. This
hypothesis was confirmed in a study showing reduced inflam-
matory reactions to histamine under a hypnotic analgesia condi-
tion, compared to reactions in a control condition, with
reductions in pain-evoked brain potentials confirming reduced
sensation during hypnotic analgesia (Zachariae & Bjerring,
1990).
Other studies have confirmed that hypnotic suggestions to
suppress or enhance reactions of the skin can alter both inflam-
matory skin reactions associated with immediate-type allergic
reactions and delayed-type immune reactions of relevance to
eczemas, psoriasis and other skin diseases (Zachariae, Bjerring
& Arendt-Nielsen, 1989). Further results indicate that the
immune system is susceptible to psychological influences both
during the sensitization or ‘‘learning’’ phase of the immune
response and during the later challenge or ‘‘retention’’ (Zacha-
riae & Bjerring, 1993; Zachariae et al., 1997). The available
results suggest that voluntary changes of local immune reactions
require sufficiently strong sensory pathways (Locke, Ransil,
Zachariae et al., 1994b), and that effects on specific immune
components of skin and mucosa are likely to be mediated
through neural influences on local vascular processes, rather
than through direct differential effects on specific types of
immune cells (Zachariae, Oster & Bjerring, 1994). This was
supported by results of a study comparing effects of non-spe-
cific instructions to relax and guided imagery instructions to
imagine enhancement of specific immune cells (Zachariae, Han-
sen, Andersen et al., 1994). While both interventions may influ-
ence the function of various immune cells in the blood stream
when compared to no intervention, the results of this study
showed no difference between the effects of relaxation and
guided imagery, suggesting that effects on cells in the peripheral
blood stream are probably due to more general non-specific
effects of relaxation and stress-reduction through altered auto-
nomic nervous system activity. Few studies have explored the
clinical applicability of these findings, but preliminary results
indicate that patients with immune-related skin diseases such as
psoriasis may benefit from psychological intervention (Zacha-
riae, Oster, Bjerring & Kragballe, 1996).
IMMUNE-BRAIN-BEHAVIOR EFFECTS
As expected from theories of living systems, the pathways
between the brain and the immune system are unlikely to be
 2009 The Author. Journal compilation  2009 The Scandinavian Psychological Associations.
Psychoneuroimmunology 649
unidirectional, and there should be at least some form of ‘‘feed-
back-loop’’ from the immune system to the brain (Zachariae,
1996). This has been demonstrated most clearly by studies of
so-called cytokine-induced sickness behavior during infection
(Dantzer, 2001). At the behavioral level, infected individuals
show depressed activity, loss of interest in the environment, and
reduced food intake, and, subjectively, infection is associated
with fatigue, depressed mood, and increased pain sensation.
These changes can be experimentally induced in healthy ani-
mals and humans by injections of proinflammatory cytokines
(e.g. interleukin-1) that are normally released by activated
immune cells during the response to bacterial or viral infections.
It could be argued that the sickness behavior pattern induced by
the immune system is the expression of a motivational state,
rather than the consequence of physiological weakness, and that
it represents a response that promotes behaviors that support the
adaptive physiological changes that occur during infection. For
instance, the increase in body temperature that is needed to pro-
duce fever leaves little room for costly activities that are of no
use in fighting the infectious pathogens, and the reduced level
of activity characteristic of sickness behavior can thus be seen
as a highly organized strategy that is critical to the survival of
the organism (Dantzer, 2001).
This perspective on cytokine-induced sickness behavior could
potentially lead to new psychoneuroimmunologic perspectives
on cancer. Cancers are often associated with increased inflam-
mation, and the high prevalence of depression found among
cancer patients (Christensen, Zachariae, Jensen et al., 2009)
could, at least partly, represent a cytokine-induced sickness syn-
drome (Raison & Miller, 2003). As increased inflammation has
been associated with poorer prognosis, this could theoretically
explain the links found between depression and increased cancer
mortality. Another area of potential interest is the common com-
plaint of impaired cognitive function following cancer treat-
ment, often referred to by patients as ‘‘chemo brain’’. As such
cognitive complaints are less likely to be due to the chemother-
apy itself (Mehlsen, Pedersen, Jensen & Zachariae, 2009; Peder-
sen, Rossen, Mehlsen, Pedersen, Zachariae & von der Maase,
2009a), they could perhaps be due to cancer-induced immune-
influences on the brain.
CONCLUSION
As reviewed above, psychoneuroimmunologic research over the
last three decades has confirmed the existence of bi-directional
interactions between the brain and the immune system, and
results from a growing number of studies indicate that negative
psychosocial factors such as depression and stress are associated
with increased morbidity and mortality. Still lacking, however,
is sufficiently convincing evidence that the links between psy-
chosocial factors and health and disease are mediated by the
identified brain-immune pathways, and further research is
needed. Psychoneuroimmunologic research has revealed the
high degree of complexity of the brain-immune interactions,
and the adaptive function of many of these interactions is as yet
650 R. Zachariae
far from fully understood. This makes it difficult to interpret
various immune outcomes in studies of psychosocial factors and
immunity and also underscores that the promises of a ‘‘strength-
ened immune system’’ frequently promoted by proponents of
complementary and alternative treatments are only metaphors
that make little sense from a scientific perspective (Zachariae,
1996). Although the field of psychoneuroimmunology has pro-
vided promising results, the critical question of whether behav-
ioral manipulation, e.g. stressors or intervention, can affect
immunity so as to influence health and survival, still remains to
be answered.
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Received 27 July 2009, accepted 29 July 2009