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

Burns are one of the most common and devastating forms of trauma. Patients with serious thermal injury require immediate specialized care in order to minimize morbidity and mortality. Significant thermal injuries induce a state of immunosuppression that predisposes burn patients to infectious complications. A current summary of the classifications of burn wound infections, including their diagnosis, treatment, and prevention, is given. Early excision of the eschar has substantially decreased the incidence of invasive burn wound infection and secondary sepsis, but most deaths in severely burn-injured patients are still due to burn wound sepsis or complications due to inhalation injury. Burn patients are also at risk for developing sepsis secondary to pneumonia, catheter-related infections, and suppurative thrombophlebitis. The introduction of silver-impregnated devices (e.g., central lines and Foley urinary catheters) may reduce the incidence of nosocomial infections due to prolonged placement of these devices. Improved outcomes for severely burned patients have been attributed to medical advances in fluid resuscitation, nutritional support, pulmonary and burn wound care, and infection control practices.

Burn Wound Infections

Recent evidence indicates that glucocorticoids and catecholamines, the major stress hormones, inhibit the production of proinflammatory cytokines, such as interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, whereas they stimulate the production of antiinflammatory cytokines, such as IL-10, IL-4, and transforming growth factor (TGF)-beta. Thus, systemically, an excessive immune response, through activation of the stress system, stimulates an important negative feedback mechanism, which protects the organism from an "overshoot" of proinflammatory cytokines and other products of activated macrophages with tissue-damaging potential. Conversely, in certain local responses and under certain conditions, stress hormones actually may boost regional immune responses, through induction of TNF-alpha, IL-1, and IL-8, and by inhibiting TGF-beta production. Therefore, conditions that are associated with significant changes in stress system activity, such as acute or chronic stress, cessation of chronic stress, severe exercise, and pregnancy and the postpartum period, through modulation of the systemic or local pro/antiinflammatory cytokine balance, may suppress or potentiate autoimmune diseases activity and/or progression.

Stress Hormones, Proinflammatory and Antiinflammatory Cytokines, and Autoimmunity

T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-gamma, and lymphotoxin-alpha and stimulate type 1 immunity, which is characterized by intense phagocytic activity. Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody titers. Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation. Severe systemic stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a type 2 response to an infection normally controlled by type 1 immunity. In such cases, administration of antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful immune responses to clear the infection.

Type 1/Type 2 Immunity in Infectious Diseases

In general, stress has been regarded as immunosuppressive. Recent evidence, however, indicates that acute, subacute or chronic stress might suppress cellular immunity but boost humoral immunity. This is mediated by a differential effect of stress hormones, the glucocorticoids and catecholamines, on T helper 1 (Th1)/Th2 cells and type 1/type 2 cytokine production. Furthermore, acute stress might induce pro-inflammatory activities in certain tissues through neural activation of the peripheral corticotropin-releasing hormone-mast cell-histamine axis. Through the above mechanisms, stress might influence the onset and/or course of infectious, autoimmune/inflammatory, allergic and neoplastic diseases.

Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines and Susceptibility to Disease

An important function of the sympathetic nervous system is to maintain homeostasis by modulating the level of cellular activity in many diverse organ systems The sympathetic neurotransmitter norepinephrine modulates the level of T and B lymphocyte activity by binding to the beta2-adrenergic receptor (beta2AR) The present study was designed to elucidate the mechanism by which stimulation of the beta2AR affects both Th1/Th2 cell cytokine production and Th1/Th2 cell-dependent Ab production Clones of murine Th1/Th2 cells were exposed to the beta2AR agonist terbutaline before activation by Ag-presenting B cells Terbutaline exposure of Th1 cells before activation inhibited IFN-gamma production by Th1 cells and subsequent IgG2a production by B cells IgG2a inhibition was prevented by addition of the betaAR antagonist nadolol or exogenous IFN-gamma In contrast to Th1 cells, terbutaline did not affect either IL-4 production by Th2 cells or subsequent IgG1 production by B cells Although baseline levels of intracellular cAMP were similar in both subsets, terbutaline induced an increase in cAMP levels in Th1 cells only Radioligand binding studies showed that a detectable number of beta2AR binding sites were present on Th1 cells, but not on Th2 cells Immunofluorescence analyses showed that Th1 cells expressed a higher level of the beta2AR cytoplasmic carboxyl terminus than did Th2 cells These results show that expression of the beta2AR binding site by Th1 cells, but not by Th2 cells, establishes a physiologic mechanism for selective modulation of Th1 cell IFN-gamma production and IFN-gamma-dependent IgG2a production, provided that beta2AR stimulation occurs before cell activation by a B cell

N E Street

Papers

Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help.