Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Vaccination wikipedia , lookup
Social immunity wikipedia , lookup
DNA vaccination wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Molecular mimicry wikipedia , lookup
Immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Adaptive immune system wikipedia , lookup
Innate immune system wikipedia , lookup
Molecular Psychiatry (2009) 14, 532–536 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp 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 References 1 Seligman ME, Maier SF. Failure to escape traumatic shock. J Exp Psychol 1967; 74: 1–9. 2 Jersild AT, Holmes FB. Experimental study of the fears of young children. Child Development Monographs 20. Teachers College: New York, 1935; 167–296. 3 Norris FH, Murrell SA. Prior experience as a moderator of disaster impact on anxiety symptoms in older adults. Am J Commun Psychol 1988; 16: 665–683. 4 Eysenck H. Stress, Disease, and Personality: The ‘Inoculation Effect’. John Wiley & Sons Inc.: New York, NY, 1983. 5 Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med 1999; 5: 49–55. 6 Hauben E, Butovsky O, Nevo U, Yoles E, Moalem G, Agranov E et al. Passive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. J Neurosci 2000; 20: 6421–6430. 7 Avidan H, Kipnis J, Butovsky O, Caspi RR, Schwartz M. Vaccination with autoantigen protects against aggregated betaamyloid and glutamate toxicity by controlling microglia: effect of CD4 þ CD25 þ T cells. Eur J Immunol 2004; 34: 3434–3445. 8 Mosley RL, Gordon PH, Hasiak CM, Van Wetering FJ, Mitsumoto H, Gendelman HE. Glatiramer acetate immunization induces specific antibody and cytokine responses in ALS patients. Amyotroph Lateral Scler 2007; 8: 235–242. 9 Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci USA 2004; 101: 8180–8185. 10 Park JE, Barbul A. Understanding the role of immune regulation in wound healing. Am J Surg 2004; 187: 11S–16S. 11 Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A et al. Protective autoimmunity is a physiological response to CNS trauma. J Neurosci 2001; 21: 3740–3748. 12 Mizrahi T, Hauben E, Schwartz M. The tissue-specific selfpathogen is the protective self-antigen: the case of uveitis. J Immunol 2002; 169: 5971–5977. 13 Schori H, Kipnis J, Yoles E, WoldeMussie E, Ruiz G, Wheeler LA et al. Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci USA 2001; 98: 3398–3403. 14 Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 2006; 9: 268–275. 15 Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/ progenitor cells. Mol Cell Neurosci 2006; 31: 149–160. 16 Cohen H, Ziv Y, Cardon M, Kaplan Z, Matar MA, Gidron Y et al. Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4 þ CD25 þ cells. J Neurobiol 2006; 66: 552–563. 17 Adamec R, Walling S, Burton P. Long-lasting, selective, anxiogenic effects of feline predator stress in mice. Physiol Behav 2004; 83: 401–410. 18 Adamec RE, Burton P, Shallow T, Budgell J. Unilateral block of NMDA receptors in the amygdala prevents predator stressinduced lasting increases in anxiety-like behavior and unconditioned startle—effective hemisphere depends on the behavior. Physiol Behav 1999; 65: 739–751. 19 Dhabhar FS, McEwen BS. Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. Brain Behav Immun 1997; 11: 286–306. Molecular Psychiatry Immunity to self for stress resilience GM Lewitus and M Schwartz 536 20 Dhabhar FS, McEwen BS. Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol 1996; 156: 2608–2615. 21 Kradin R, Rodberg G, Zhao LH, Leary C. Epinephrine yields translocation of lymphocytes to the lung. Exp Mol Pathol 2001; 70: 1–6. 22 Lewitus GM, Cohen A, Schwartz M. Reducing post-traumatic anxiety by Immunization. Brain Behav Immun 2008; 22: 1108–1114. 23 Xu H, Chen Z, He J, Haimanot S, Li X, Dyck L et al. Synergetic effects of quetiapine and venlafaxine in preventing the chronic restraint stress-induced decrease in cell proliferation and BDNF expression in rat hippocampus. Hippocampus 2006; 16: 551–559. 24 Butovsky O, Hauben E, Schwartz M. Morphological aspects of spinal cord autoimmune neuroprotection: colocalization of T cells with B7–2 (CD86) and prevention of cyst formation. FASEB J 2001; 15: 1065–1067. Molecular Psychiatry 25 Shaked I, Porat Z, Gersner R, Kipnis J, Schwartz M. Early activation of microglia as antigen-presenting cells correlates with T cell-mediated protection and repair of the injured central nervous system. J Neuroimmunol 2004; 146: 84–93. 26 Sugama S, Fujita M, Hashimoto M, Conti B. Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18. Neuroscience 2007; 146: 1388–1399. 27 Silberman DM, Ayelli-Edgar V, Zorrilla-Zubilete M, Zieher LM, Genaro AM. Impaired T-cell dependent humoral response and its relationship with T lymphocyte sensitivity to stress hormones in a chronic mild stress model of depression. Brain Behav Immun 2004; 18: 81–90. 28 Lewitus GM, Wilf-Yarkoni A, Ziv Y, Shabat-Simon M, Gersner R, Zangen Z et al. Vaccination as a novel approach for treating depressive behavior. Biological Psychiatry 2008; 21 August 2008 (e-pub ahead of print).