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Biochemical Pharmacology 91 (2014) 287292

Contents lists available at ScienceDirect

Biochemical Pharmacology
journal homepage: www.elsevier.com/locate/biochempharm

Commentary

SmileIts in your blood!


Fulvio DAcquisto *, Lorenza Rattazzi, Giuseppa Piras
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square,
London EC1M 6BQ, UK

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 23 June 2014
Accepted 17 July 2014
Available online 12 August 2014

Emotions and feelings are the bricks of our social life and yet we often forget that they have a signicant
impact on our physical wellbeing. Indeed, a growing number of studies have shown that both an
imbalanced or improved emotional state can signicantly inuence the way our immune system
responds. In this commentary, we have summarized the most recent studies on the effects of different
types of emotional states on the immune system and we have also explored the effects of mood
modulator approaches on the immune response. We hope this commentary will prompt scientists and
clinicians to think about the therapeutic value and potential of emotions and feelings in immune-related
diseases. At the same time, we think that this commentary will shed some light on the scientic truth
behind the very famous expression Its in my blood when we talk about feelings and personality.
2014 Elsevier Inc. All rights reserved.

Keywords:
Emotions
Immunomodulation
Inammation
Autoimmunity
Mental health

1. Introduction
The progress we have made since the birth of our ancestor
homo sapiens has given the word wellbeing a completely new
meaning [1,2]. Looking back to the time of the dinosaurs, our main
preoccupation was to ght with other species and survive at their
expense. Nowadays, physical survival is not an impending issue
anymore (unfortunately, not the case in all the countries) while
emotional and psychological integrity has taken the center stage.
What is even more important, the effects of emotional distress
seem to have spilled over from the realm of our social interaction to
the physicality of our living.
How do emotions inuence our physical wellbeing? Stressors
and dangers of mental health often populate the front pages of the
daily news and include a wide range of settings and situations
including working long hours, social pressure, relationship
problems or constant reminders of what one should be eating
or doing to be well. Interestingly, stressors and dangers are also
buzzwords in the immunology eld and now more than ever on the
front pages of scientic news [36]. What seems to be just a mere
coincidence might instead hide an interesting link. Indeed, we have
now come to realize that often stressors for the immune system are

* Corresponding author. Tel.: +44 207 882 6081; fax: +44 207 882 6076.
E-mail address: F.Dacquisto@qmul.ac.uk (F. DAcquisto).
http://dx.doi.org/10.1016/j.bcp.2014.07.016
0006-2952/ 2014 Elsevier Inc. All rights reserved.

also stressors of our emotional wellbeing and vice versa [79].


Thus, infections and inammatory diseases inuence our mood
and behavior in the same way that psychological problems and
mental disorders seem to pose a threat to the proper functioning of
the immune system.
This commentary will explore the most recent ndings in the
eld of body and mind crosstalk with specic focus on how
emotions inuence the immune and inammatory response. In
doing so, we will rst summarize the most recent discoveries on
the events that trigger the release of inammatory mediators and
other immunomodulators that are known to modulate mood and
emotions. For the reverse, e.g. how inammation inuences
emotions, we redirect the readers to a number of excellent
reviews on the topic [1015]. In the second part, we will discuss
whether drug-free therapies modulating the emotional response
should be considered as a new avenue for therapeutic strategies
targeting inammatory and immune-mediated diseases.
2. Performance-management by the immune system
Remembering the last time we had a fever or an infection, we
immediately recall the time spent in bed or stranded in the house,
the nauseating feelings and the overall sense of hopelessness
(man u for the males!) that came with it. What seems to be an
unnecessary extra that adds to the already difcult-to-manage
signs of inammation (redness, swelling, heat, loss of function) is a

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F. DAcquisto et al. / Biochemical Pharmacology 91 (2014) 287292

blessing rather than a nuisance. Indeed, the low mood that


comes with inammation, also known as sickness behavior
[14,16,17], should be considered as an evolutionary-conserved
protective response that prevents us from engaging in the routine
of life (this being hunting dinosaurs or shopping for groceries) in
order to facilitate the reparative response that we now call
inammation [1820].
If inammation controls our emotional state through sickness
behavior, one would expect that the opposite is also true i.e. that
emotions exert some degree of control over the immune system.
Several lines of evidence seem to support this hypothesis although
it is still not clear whether and how emotions and feelings can
differentially (i.e. positively or negatively) affect our immune
system (Fig. 1). This is indeed one of the most challenging
questions that hunt many scientists in the eld of psychoneuroimmunology.
The answers to these questions are far from being conclusive.
For instance, common knowledge and wisdom suggest stress is
very bad for you. And yet, such a simple statement clearly does not
reect the complexity of stress and its function, this would indeed
be the same as saying that inammation is bad for you. Is this the
case? Is inammation always detrimental? What about the
inammation that sustains the host response? Protective inammation is what helps us to ght pathogens and similarly, one might
argue that protective stress is what makes us thrive in daily life.
How would one know if stress is good or bad for the immune
system? What would be the best experimental system or model?
Looking through the literature, one can immediately appreciate the
experimental difculties in working in this area. A recent very
interesting study from a group of scientists in Vienna has shown
how the same stressful task, public performance, can provide
different outcomes depending on the context [21]. Members of a
symphony orchestra were tested on the day of rehearsal (the
control situation) and on the following day of the premiere concert
(the test situation) for their level of classical stress biomarkers such
as salivary cortisol, plasma myeloperoxidase (MPO) and interleukin (IL)-6, serum C reactive protein (CRP), and homocysteine. The
results showed a signicant increase in the levels of these
biomarkers when the musicians performed in the presence of a
real audience (e.g. 20% MPO, 26% IL-6 and 44% salivary cortisol) and
a correlation between unpleasant feelings and high levels of MPO
in these subjects [21] (Fig. 1). In a similar study conducted on
medical students, another group measured the levels of salivary
cortisol and other circulating immune mediators 7 weeks before, 1

day before, immediately after, and 1 week after an examination.


The results showed that of the 50 mediators measured, proinammatory cytokines such as granulocyte colony-stimulating
factor (G-CSF), interferon-g (IFN-g), IL-1b, and tumor necrosis
factor-a as well as Th2 cytokines such as IL-4, IL-5, and IL-13
showed a signicant increase up until the day of the exam and then
drop to normal levels soon afterwards [22]. This interesting pattern
of cytokine secretion seems to suggest a dual effect on the immune
system: on one side we have G-CSF that promotes neutrophil
survival/proliferation and IFN-g that primes macrophages for
activation; on the other side, the anti-inammatory and immunosuppressive effect of Th2-polarising cytokines such as IL-4 and IL13 (Fig. 1). This immunological scenario clearly reects an
ancestral response of our body that needs to be activated to
respond to the attack of the enemy (with more neutrophils and
macrophages) while making itself ready to heal the trauma
(favoring the Th2 anti-inammatory state).
Thus, if we just consider the example above of performanceinduced stress, one can appreciate that the context of the
challenge as well as the timing are two important components
that inuence the immune response to the stressor. The scenario
becomes even more complex when we take into consideration
more intrinsic i.e. subject-specic elements such as ones
attitude and personality. In a number of very interesting studies
Steptoe and colleagues have indeed shown that optimism
promotes health, by counteracting stress-induced increases in
inammation and boosting the adjuvant effects of acute stress
[2325]. Consistent with this, other studies have shown that
pessimism correlates to higher levels of inammation while
inuencing other important factors such as body/mass index,
blood pressure and glucose levels [26,27] (Fig. 1).
2.1. You are stressing me out!
Life events (positive or negative) are amongst the most
common causes of emotional and physical distress. In line with
the idea brought forward of the immune system as mirror of
emotional wellbeing, a great deal of studies have reported changes
in the immune response upon changes in psychosocial settings. In
a study carried out on bereaved spouses or parents it was shown
that within 2 weeks of bereavement participants had higher
neutrophil counts and platelet/granulocyte aggregates compared
to non-bereaved subjects [28]. The pro-inammatory prole
caused by bereavement has been conrmed in a large clinical

Stressful task
EMOTIONS

Corsol, IL-6, IL-1, TNF-,


CRP, MPO and G-CSF
Th1 and Th2 mediators

Opmism
Pessimism

Traumac stress

Aachment
Anxiety

Corsol and inammaon


Inammaon

CD4+ and CD8+ T cells


CRP (lasng even 20 year
aer the trauma)

Corsol
CD4+ and CD8+ T cells

Fig. 1. Emotional control of the immune response. The scheme summarizes a few examples of different types of emotions and their impact on the immune response.

F. DAcquisto et al. / Biochemical Pharmacology 91 (2014) 287292

trial performed on 529 participants (age 3484 years) where the


results have shown signicantly higher levels of IL-6 and soluble Eselectin, but not CRP, in bereaved subjects compared to nonbereaved controls [29].
A number of remarkable studies have highlighted the deleterious effect of maltreatment on childrens immune responses.
Physical abuse and traumatic stress have been reported to cause
profound changes in the immune repertoire with clear increases in
the percentages and absolute numbers of activated (HLA-DR+) CD4
and CD8T cells [30]. Looking at the long-term consequences of
these traumatic events, another group of scientists has shown that
the percentage of T cells expressing the early activation marker
CD45RA was higher in women with a history of sexual trauma
during childhood and with clinical signs of posttraumatic stress
disorder [31]. Similarly another study has shown that maltreated
children showed a signicant and graded increase in the risk for
clinically relevant CRP levels 20 years after the trauma and in more
than 10% of the cases the presence of a low-grade inammatory
state [32] (Fig. 1). In contrast to bereavement, and for reasons that
are not fully understood, the psychosocial stress exerted on
children seems to have a more marked and long-lasting effect.
More specically, these examples point towards the existence of a
critical time-frame when the plasticity of the neuronal and
immune systems is very high and hence the impact of long-term
epigenetic changes are highly probable. The time-dependent
changes in plasticity and the subsequent consequences for the
immune system have recently been explored by Brignolio et al.
who have proposed the existence of a Liquid Self [33]. Whatever
the mechanisms behind these changes, there is emerging and very
alarming evidence that the disastrous impact of these events might
last even longer than the lifespan of the victim [34,35]. A very
elegant study by Sandi and co-authors has indeed shown that male
rats experimentally induced to become highly aggressive
towards their female partners can pass this maladaptive behavior
to their offspring [36]. Whether this transgenerational transmission of behavioral traits are limited to the neuronal system is still to
be determined and in this context, an equal contribution of a
perturbed immune system should not be completely discarded.
3. The bright side of the immune response
Whether one is young or old, happiness and good mood seem
to always exert a consistent positive effect on the immune
system. As an example of this, children exposed to tale tellers,
puppeteers and handicraft artists showed changes in lymphocyte
counts and IFN-g levels in blood samples compared to control
unexposed children [37]. Similarly, aging women with higher
levels of eudaimonic (e.g. sense of meaning and self-realization)
wellbeing had lower levels of daily salivary cortisol and proinammatory cytokines, compared with those showing lower
levels of eudaimonic wellbeing while subjects pursuing hedonic
(e.g. pleasure attainment and pain avoidance) wellbeing showed
no correlation with any biomarker [38].
This last study poses the question of whether eudaimonic
wellbeing is attainable for anyone and if there are other means by
which one can elicit a sense of satisfaction and self-realization. In
a recent study conducted on enthusiastic male ice hockey
spectators attending the Finnish national ice hockey matches,
Tulppo et al. found that plasma catecholamines, endothelin-1 (ET1) and IL-6, showed a signicant increase compared to baseline
[39]. It goes without saying that it would be interesting at this
point to investigate whether after a given sporting occasion
(football, hockey match or anything similar), the immune response
would concordantly change in the winners as well as the losers. It
would be even more interesting to perform the same analysis in
the players rather than just in the spectators.

289

These considerations take us to the previous point on the


importance of the context. Happiness (as well as stress) is
intrinsically linked to our social conditions and quality of our
relationships with others. This might be at the core of the popular
saying money dont make you happyit might be that people do!
Ground breaking research by Steve Cole and colleagues have
indeed tried to assess the impact of social living on the immune
system and have shown that at the level of gene expression more
than 200 genes were differentially expressed in circulating
leukocytes from 14 high- versus low-lonely individuals. The
upregulated genes were largely those involved in the inammatory response, whereas many of the downregulated genes had
antiviral roles [40]. Further studies in collaboration with Barbara
Fredrickson expanded and conrmed these very intriguing
ndings [41] and prompted other scientists to investigate this
area of research. One such example is a study that takes as starting
point the very popular theories originally developed by Melanie
Klein and John Bowlby on attachment styles [42,43]. According to
these theories, people differ in the extent to which they believe
close others will be supportive and available during times of need.
The study conducted on 85 married couples showed that
participants with higher attachment anxiety produced more
cortisol and had fewer numbers of CD3+ T-cells, CD45+ T-cells,
CD3+CD4+ helper T-cells, and CD3+CD8+ cytotoxic T-cells than
those with lower attachment anxiety [44,45] (Fig. 1).
4. Feelings and emotions as therapeutic targets for immune
disorders?
Having summarized some of the latest ndings on how
different emotional settings and environmental (mainly social)
factors inuence the immune system, we will now explore
whether the results of this research has any therapeutic value
for the treatment of immune and inammatory diseases. Not
surprisingly, the literature in this area of research is populated by
studies investigating the effect of so-called mind-body or
psychological therapies on immune and inammatory conditions.
If one just considers three types of mind-body therapies such as
yoga, meditation and music, it is easy to see why there are so many
people now that would consider emotional wellbeing as a
therapeutic target.
Yoga treatments as short as 10 days have been reported to
provide a signicant reduction in the levels of cortisol, IL-6 and
TNF-a in patients suffering from chronic inammatory diseases
while improving the risk of cardiovascular disorders in obese/
overweight subjects [46,47]. Several recent studies have also
highlighted the therapeutic benet of meditation and related
techniques for the immune system; it has been shown that
volunteers trained for 10 days in meditation, breathing techniques
and exposure to cold showed a faster release of the antiinammatory cytokine IL-10 and lower levels of TNF-a, IL-6,
and IL-8 compared to control subjects when challenged with E. Coli
endotoxin [48] (Fig. 2).
Music as medicine is another hot topic in this eld [49]. Either in
the form of passive listening or in the form of active singing music
has been reported to exert a wide range of immunomodulatory
effects including: to inuence 16 distinct molecular pathways that
control the immune response [50]; to increase the survival of
fully allogeneic cardiac allografts stimulating the production of
CD4+CD25+Foxp3+ regulatory cells [51,52]; and to reduce the
level of IL-4 and corticosterone in experimental asthma [53]
(Fig. 2).
A possible molecular mechanism responsible for the therapeutic effect of these different approaches could be a physiological
phenomenon known as the relaxation response [5456]. According
to a study performed at Harvard University, the relaxation

F. DAcquisto et al. / Biochemical Pharmacology 91 (2014) 287292

290

Yoga

10 days

Music therapy

Meditaon

Acve
(singing)

10 days

Passive
(listening)

Corsol levels

IL-10

Corcosterone levels

IL-6 and TNF- in chronic


inammatory diseases

IL-6, IL-8, TNF-


aer challenge
with E. Coli
endotoxin

IL-4 in experimental asthma

Risk of cardiovascular
events in obese subjects

Producon of
CD4+CD25+Foxp3+ regulatory
cells in allogeneic cardiac
allogras

Fig. 2. Modulation of the immune response by mind-body therapies. The gure shows a few selected examples of psychological therapies with immuno-modulatory effects and
their relative mechanisms of action.

response signicantly affects multiple pathways through mitochondrial signaling that may promote cellular and systemic
adaptive plasticity responses [57,58]. More specically, the
increased production of energy in the form of ATP, through the
ATP synthase electron transport complex, results in an enhanced
mitochondrial reserve. This saved energy is then used to meet
the metabolic demand that emerges in many stress-related
diseases. This is a rather interesting idea since it links with what
we have discussed before regarding the plasticity of the neuronal
and immune system at the early stages of life. It is indeed well
known that mitochondrial respiratory malfunction is associated
with aging-related complex diseases [59,60]. It is thus possible to
hypothesize that these therapies might indeed work better when
administered during the rst half of life as a preventive measure for
the development of autoimmune and chronic inammatory
diseases that classically are up in adult age.
5. Conclusions and perspectives
The studies we have summarized so far clearly support the idea
that our emotional state changes the way our immune system
functions. Most importantly, we have provided evidence that
therapies targeting mood and emotions can have a measurable
(and hence translational) impact on the immune response. Thus, in
our opinion, the most obvious next step should be to bring the
best of both and test the effect of classical drug-based therapies
in conjunction with alternative ones to achieve better and more
personalized therapeutic programs. We think that this would be an
important stepping-stone towards the most longed for personalized medicinethis being personalized not on the basis of your
genomic imprinting but rather on what makes you feel better.
The success of this proposed approach seems to be far from
becoming reality because of skepticisms and territorial attitudes
in clinical and experimental research. Reading one of the latest
Nature news feature articles, Immunology: the pursuit of happiness [61], it is clear that there is a split in the scientic community
between those that are open to the idea that the context (social,
emotional, physical, etc.) has a great deal of inuence on our
immune response and those that will not be satised and
convinced by this research until a proper mechanism of action
for these effects has been identied. And yet, we seem to forget
that most current medical challenges are not around the

identication of the right molecular targets or better drugs


but about the ever-increasing therapeutic non-compliance and
lack of trust in the medical sector [62,63]. We think that the poor
appreciation of the context is one of the main reasons for the
distance between the medical sector and patients as well as for the
failing of therapies that have been extensively studied and
accurately thought through in test tubes and experimental labs.
We think that times are ripe for lling this emotional gap in the
treatment of immune and inammatory disorders with new types
of therapies that tackle at the same time our emotional and
physical imbalance. In a similar way, we think that more research
is needed in the area of treatment of mental disorders with
immunotherapy.
We, as many others, think that the immune and emotional
systems are tightly interlinked and connected [14,6467]. In two of
our recent studies we have shown how T cells can signicantly
change the pattern of gene expression in mouse brain [68] and we
have been also able to correlate T cell movement in and out of the
circulation with changes in the emotional response [69]. This latter
study was performed in a mouse model of multiple sclerosis, one of
the autoimmune diseases that is known to be linked to emotional
imbalance [70]. Both studies suggest that modulating the immune
repertoire might provide a benet for mood disorders (evaluated
as animal behavior), however we would be the rst to admit that a
great deal of work is needed to support this hypothesis.
Nevertheless, we feel condent that the scientic community is
now more open to this type of interdisciplinary research and hence
we might be very close to the time where mood disorders such as
anxiety and depression could be cured with a wide range of
immune-based approaches including vaccination as some scientists have already proposed [71] or, even better, a relaxation
response approach together with an immunomodulator. Until that
time is here, we would like to invite readers to test the ideas
reported in this commentary themselves by practicing smiling on a
daily basis. Such an experiment would not require any extra
reagents and might surprise you with the signicance of its
effects! We look forward to hearing the results!
Acknowledgements
We would like to thank Dr Dianne Cooper for her suggestions
and guidance.

F. DAcquisto et al. / Biochemical Pharmacology 91 (2014) 287292

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