The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.

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Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry

The brain and the immune system are the two major adaptive systems of the body During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome

The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System

Folk wisdom has long suggested that stressful events take a toll on health. The field of psychoneuroimmunology (PNI) is now providing key mechanistic evidence about the ways in which stressors--and the negative emotions that they generate--can be translated into physiological changes. PNI researchers have used animal and human models to learn how the immune system communicates bidirectionally with the central nervous and endocrine systems and how these interactions impact on health.

Stress-induced immune dysfunction: implications for health.

Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.

https://cancerres.aacrjournals.org/content/canres/72/4/917.full.pdf

Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.

Cytokines and major depression.

Psychoneuroimmunology: interactions between the nervous system and the immune system

Development of autoimmune disease in female New Zealand hybrid mice was dramatically modified by classical conditioning of immunosuppression. Groups of animals received each week a solution of sodium saccharin (conditioned stimulus). One group of conditioned animals received an injection of cyclophosphamide (the unconditioned stimulus) after half of the weekly occasions when they received the saccharin solution. The rate of development of proteinuria and mortality were significantly retarded in these conditioned mice relative to untreated controls and nonconditioned animals that received unpaired treatment with saccharin and cyclophosphamide.

https://science.sciencemag.org/content/sci/215/4539/1534.full.pdf

Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus

Converging data from different disciplines indicate that central nervous system processes are capable of influencing immune responses. This paper concentrates on recent studies documenting behaviorally conditioned suppression and enhancement of immunity. Exposing rats or mice to a conditioned stimulus previously paired with an immunomodulating agent results in alterations in humoral and cell-mediated immune responses to antigenic stimuli, and unreinforced reexposures to the conditioned stimuli result in extinction of the conditioned response. Although the magnitude of such conditioning effects has not been large, the phenomenon has been independently verified under a variety of experimental conditions. The biological impact of conditioned alterations in immune function is illustrated by studies in which conditioning operations were applied in the pharmacotherapy of autoimmune disease in New Zealand mice. In conditioned animals, substituting conditioned stimuli for active drugs delays the onset of autoimmune disease relative to nonconditioned animals using a dose of immunosuppressive drug that, by itself, is ineffective in modifying the progression of disease. The hypothesis that such conditioning effects are mediated by elevations in adrenocortical steroid levels receives no support from available data. Despite its capacity for self-regulation, it appears that the immune system is integrated with other psychophysiological processes and subject to modulation by the brain.

CNS–immune system interactions: Conditioning phenomena.

In this study, we searched for evidence for reactivation of three latent herpesviruses, Epstein-Barr virus (EBV), herpes simplex virus type-1 (HSV-1), and human herpesvirus 6 (HHV-6), in West Point cadets experiencing two different stressors. Blood samples were obtained from cadets before and after a 6-week training period known as "Cadet Basic Training" (CBT), at a baseline prior to final examinations, and then once again during the week of final examinations. Antibody titers to latent HSV-1, EBV, and HHV-6 were determined as a measure of the steady-state expression of latent virus. EBV virus capsid antigen (VCA) IgG antibody titers were unchanged in blood samples obtained prior to and immediately after CBT. However, EBV antibody titers were significantly higher in the blood sample obtained during examination week than in the baseline period before examination; they were also higher than antibody titers before/after CBT. None of the serum samples were positive for EBV VCA IgM antibodies, indicating that the changes in antibody titers to EBV were not associated with recent EBV infections in the class. No significant changes in antibody titers to HSV-1 or HSV-6 were found over the identical time periods, including examination week. Academic stress but not CBT modulated the steady-state expression of latent EBV, resulting in the reactivation of latent virus. The same stressors, however, did not affect the steady-state expression of latent HSV-1 or HSV-6, at least as measured by changes in antibody titers. The data provide additional evidence of the impact of different psychological stressors on the steady-state expression of latent herpesviruses.

The Differential Impact of Training Stress and Final Examination Stress on Herpesvirus Latency at the United States Military Academy at West Point

On Immunity and Its Phylogenesis. Adaptive Immune Responses in Insects. Insect Antibacterial Proteins. The Prophenoloxidase System and Its Role in Arthropod Immunity. The Multiple Biological Roles of Invertebrate Lectins: Their Participation in Non-Self Recognition Mechanisms. Historecognition in the Cnidaria. Biological Individuality and Disease: New Perspectives on Immunoevolution. The MHC Molecules of Ectothermic Vertebrates. The Major Histocompatibility Complex of the Chicken. Evolutionary Origins of Immunoglobulin Genes. Evolution of Lymphocyte Subpopulations, Their Interactions and Temperature Sensitivities. Phylogeny of Cytotoxic Cells. The Phylogenetic Conservation of Cytokines. Eicosanoids: Aspects of Their Structure, Function, and Evolution. Mechanisms of Molecular Evolution in the Immunoglobulin Superfamily.

Nicholas Cohen

Papers

Psychoneuroimmunology: interactions between the nervous system and the immune system

Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus

CNS–immune system interactions: Conditioning phenomena.

The Differential Impact of Training Stress and Final Examination Stress on Herpesvirus Latency at the United States Military Academy at West Point

Phylogenesis of Immune Functions