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Molecular Psychiatry (2009) 14, 532–536
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ORIGINAL ARTICLE
Behavioral immunization: immunity to self-antigens
contributes to psychological stress resilience
GM Lewitus and M Schwartz
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
The psychobiological mechanisms that contribute to the development of stress resilience are
not fully elucidated. One potential approach for enhancing resilience is the exposure to mild
challenges. According to this approach, a mildly stressful episode may immunize the
individual, thereby strengthening resistance to subsequent stressors. This phenomenon is
often viewed as a form of behavioral immunization. Although, the term ‘behavioral
immunization’ was borrowed from the field of immunology, the involvement of the adaptive
immune system in stress resilience was never investigated. However, based on accumulated
new data, we suggest that the immunological memory does have a significant role in
developing coping responses to stress. Although, immune deficiency results in an impaired
ability to cope with stress, boosting immunological memory can increase stress resilience.
Therefore, we propose that defense against mental challenge, similarly to defense against
intruders, involves an immunological mechanism, which establishes stress resilience to a later
challenge. Here, we review the involvement of the adaptive immune system in coping
mechanisms in response to psychological stress, and discuss the connection between
cognitive memory and immunological memory in establishing ability to efficiently cope with
stressful episodes.
Molecular Psychiatry (2009) 14, 532–536; doi:10.1038/mp.2008.103; published online 9 September 2008
Keywords: stress; immune; behavioral immunization; memory T cells; resilience; BDNF
Introduction
‘Behavioral immunization’ refers to the ability of
earlier mildly stressful experience to strengthen the
resilience to a subsequent stressor. Seligman and
Maier1 were the first to use this term when they
observed that dogs that were subjected to an inescapable mild electric shock, showed no deficit in their
escape response to subsequent shocks, if they had
been previously trained in escape maneuvers.1 This
phenomenon has long been recognized in humans; for
example, in children, previous mildly stressful life
events attenuate fearfulness in a daycare setting.2
Furthermore, experienced survivors of floods exhibit
lower anxiety after encounters with the same disaster
compared with inexperienced survivors3 (for review
see4). Thus, memory of a past experience is clearly a
factor in developing this experience-based resilience,
but the nature of such a memory is not fully understood. Is it only the cognitive memory of overcoming
past experience that contributes to increased resilience, or does the development of resilience involve
components of the immune system, with its unique
capacity for immune memory, which is reactivated
Correspondence: Dr M Schwartz, Department of Neurobiology,
Weizmann Institute of Science, Rehovot 76100, Israel.
E-mail: [email protected]
Received 4 August 2008; revised 8 August 2008; accepted 12
August 2008; published online 9 September 2008
upon need? Although Seligman and Maier borrowed a
term from the field of immunology when they named
the resilience phenomenon ‘behavioral immunization’, the involvement of the adaptive immune system
(immunological memory) in stress resilience was
never investigated. Is it possible that a stressful
episode induces immune changes that build resilience to future stress? In other words, is the increased
resilience encountered following the survival of a
mildly stressful experience an outcome of stressinduced immunological memory?
The immune system beyond host defense
The main arm of the immune system responsible for
immunological memory is the adaptive immune
system. The adaptive immune response has the
ability to recognize and remember a wide range of
antigens, and to mount a more intense immune
response following each subsequent antigen encounter. It was generally accepted that the primary
function of the immune system is in host defense,
and thus it was believed for decades that the major
task of the adaptive immune system in host defense is
to discriminate between self and nonself. A decade
ago, our laboratory discovered the importance of the
self-reactive T cells in the repair of central nervous
system (CNS) injury.5 The protective capacity of
autoimmune cells was further shown in several
Immunity to self for stress resilience
GM Lewitus and M Schwartz
models of CNS pathology including mechanical
injury,5,6 Alzheimer’s disease,7 Parkinson’s disease8
and imbalances in neurotransmitter levels,9 as well as
non-CNS processes such as skin wound healing.10
The neuroprotective immune response is a physiological response that is spontaneously evoked after
trauma.11 Furthermore, immune neuroprotection is
antigen-specific, and aimed at antigens expressed at
the site of insult.6,12,13 In addition to the role of CNSspecific T cells in CNS repair, our group has found
that adaptive immune cells are key players in CNS
maintenance under nonpathological conditions, especially in hippocampal plasticity.9,14 We showed that
autoreactive T cells are needed to support hippocampal-dependent learning and memory tasks, as well as
for the regulation of adult hippocampal neurogenesis
and neurotrophic factor production,14 possibly by
regulating microglial phenotype.15
Adaptive immunity in coping with mental stress
Recently, we found an association between T cells and
adaptation to psychological stress.16 In these studies,
we used the predator odor model as the psychological
stressor. This stress model was shown to result in a
long-term effect on both behavioral (reflecting
psychological) and physiological functioning, remi-
niscent of posttraumatic stress disorder (PTSD) in
humans.17,18 In these experiments, T-cell-deficient
mice showed poor ability to adapt to mental stress.
However, transgenic mice overexpressing autoreactive T-cells reactive to the CNS-related self-antigen,
myelin basic protein (MBP), exhibited reduced
incidence of PTSD-like symptoms in response to
predator odor relative to their matched controls.16
These results led us to ask whether T-cells traffic to
the CNS after intense experiences, and whether these
T cells can become memory T cells and better protect
the CNS after a second stress episode.
Dhabhar and McEwen19 were the first to show that
acute stress increases immune surveillance and
immune responses in organs that can be affected by
stress, such as the skin. This effect is mediated by the
stress hormones such as the glucocorticoids and
catecholamine.20,21 They suggested that the ability of
stress to enhance the immune response is a defensive
response that is aimed at protecting the organism
from a possible infection or injury caused by the
stressful situation (such as possible injury by a
predator). As the brain is the first organ to be affected
by psychological stress, as well as the main organ that
is responsible for orchestrating the complex response
to stress, we suggested that stress may enhance
lymphocyte surveillance of the brain as a protective
mechanism. To test this hypothesis, we evaluated the
533
Figure 1 A proposed model of the bidirectional interaction between the brain and the immune system following
psychological stress. (a) Psychological stress activates the sympathetic nervous system and the hypothalamic–pituitary–
adrenal (HPA) axis leading to the immediate flight or fight response. The elevation of stress hormone levels changes brain
homeostasis (such as reduction of brain-derived neurotrophic factor (BDNF)). (b) The stress hormones induce the increased
expression of ICAM-1 in the choroid plexus and the expression of LFA-1 (ICAM-1 ligand) on lymphocytes, thereby
increasing lymphocyte surveillance of the brain. The infiltrating lymphocytes restore BDNF levels, through interaction with
the local antigen presenting cells.
Molecular Psychiatry
Immunity to self for stress resilience
GM Lewitus and M Schwartz
534
immune response in mice subjected to the predator
odor model of stress. We found that acute exposure
to predator odor enhances lymphocyte trafficking
to the brain through a mechanism similar to
stress-induced lymphocyte trafficking to the skin.22
Furthermore, we found an association between
lymphocyte recruitment to the brain and stress
resilience. Mouse strains in which stress-induced
lymphocyte trafficking is enhanced, exhibit improved
ability to cope with the stress, and hippocampal
brain-derived neurotrophic factor (BDNF) was
restored to prestress levels.22 These results supported
our hypothesis that a stressful experience enhances
lymphocyte trafficking to the CNS as physiological mechanism for maintenance of homeostasis
(Figure 1).
It was shown that the action of several psychotropic
drugs involves neurogenesis and BDNF induction,23
both of which must be restored following stress to
prevent stress-induced pathologies such as depression. It is therefore not surprising that boosting
immunity as a therapy actually results in physiological adaptations to meet the increased need. Taking
together, we propose to view adaptive immunity, in
the context of mental stress, as a physiological
psychotropic self-therapy.
Immune memory to self-antigens underlies physiological mechanism of resilience to mental stress
The successful resolution of a stressful experience
elicits cognitive processing as well as immunological
memory, which make subsequent coping efforts more
efficient. To distinguish between the cognitive memories of an experience and the stress-induced immunological memory, we therapeutically induced
immune memory by vaccination with a self-antigen.
One week before the exposure of mice to predator
odor, we inoculated them with a CNS-derived peptide
emulsified in adjuvant; control animals were injected
with the adjuvant alone. Mice that were vaccinated
with the CNS-related peptide showed reduced anxiety levels and a reduced acoustic startle response, as
well as enhanced recovery of hippocampal BDNF.22
Other experiments also support the involvement
of immunological memory in CNS recovery from
Figure 2 Schematic model of the induction of immunological memory. (a) Time course of induction of immunological
memory following pathogen exposure and clearance of infection. Entry of an infectious agent activates an innate response
and antigen presentation. Once antigen levels exceed the threshold dose, the adaptive immune system is activated. Activated
T cells secrete effector molecules that orchestrate the clearance of the infectious agent. At this stage, immunological memory
also starts to form. (b) Time course of a protective immune response following exposure to mental stress. The stressful
experience activates the hypothalamic–pituitary–adrenal (HPA) axis, the sympathetic autonomous system, as well as other
cognitive processes that orchestrate the immediate response to stress (fight or flight). The stress hormones induce the
mobilization of immune cells to the central nervous system (CNS), where they are activated by local antigen presenting cells.
In the CNS, the activated cells secrete and regulate neurotrophic factors that maintain homeostasis, while building the
immunological repertoire.
Molecular Psychiatry
Immunity to self for stress resilience
GM Lewitus and M Schwartz
physical injury. We observed significantly improved
locomotor activity in rats that were passively transferred with MBP-activated splenocytes derived from
CNS-injured rats, compared to injured rats that
received splenocytes from an uninjured, naive animal.11 Furthermore, there is a greater survival of
retinal ganglion cells when the optic nerve injury was
preceded by an unrelated CNS (spinal cord) injury.
As both types of CNS insult (mechanical and psychological) increase trafficking to the CNS, as well as
increasing expression of MHC II on the resident
antigen-presenting cells,24–26 we suggest that a psychologically stressful experience can activate CNSspecific cells, leading to the development of memory
cells, thereby enhancing resilience to subsequent
stressful experiences.
Another aspect of the involvement of the adaptive
immune system in stress resilience is an immunespecific tolerance mechanism that can lead to reduced coping ability. The magnitude of the immune
response depends on the antigen dose. Below a
certain antigen dose, a suboptimal immune response
is elicited; above the threshold dose, there is a gradual
increase in the response, until an optimal dosage is
reached at which the immune response is at its peak.
At higher doses, the immune response again declines,
whereas extremely high antigen doses can induce
tolerance. As psychological stress elicits an immune
response, a similar dose–response relationship is
likely to apply. Living in a psychologically sterile
environment will result in reduced immune activation and thus in reduced immunological memory;
such an individual is likely to cope poorly upon
exposure to even moderate stress levels. On the other
hand, an overwhelmingly stressful experience, as
well as chronic stress, could overwhelm the immune
response to CNS antigens, leading to immune tolerance. These extreme effects will result in reduced
resilience to future stressful episodes. For example,
chronic mild stress was shown to induce depressivelike behavior as well as suppression of the immune
system.27 Recently we have shown that immunization
with a CNS-related antigen ameliorates depressive
behavior by regulating hippocampal BDNF levels and
neurogenesis.28
In conclusion, we propose that a mildly stressful
experience stimulates CNS-specific lymphocytes in a
manner similar to inoculation with an antigen, thereby inducing immunological memory. As a result, the
secondary response to the same challenge (psychological or immunological) is more efficient and effective
(Figure 2). Thus, we suggest that it may be possible to
therapeutically enhance the immunological repertoire
needed for mental resilience, thereby offering protection from stress-induced pathologies.
Acknowledgments
We thank R Halper and S Schwarzbaum for editing
the paper and to S Ovadia for animal maintenance.
MS is the incumbent of the Maurice and Ilse Katz
Professorial Chair in Neuroimmunology. This study
was supported by a grant from the National Alliance
for Research on Schizophrenia and Depression
(NARSAD).
535
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