Stressorassociated regulation of immunity

Stress, as defined by Hans Selye, is the response to deviation from the normal resting condition (i.e. homeostasis). It is generally accepted that stressor administration causes complex neurologic and neurochemical changes as the host attempts to adapt to the demands of the situation. These CNS changes regulate many physiologic processes, including those involved in the generation of an immune response. Immunomodulatory 'stress' protocols have involved different periods of exposure to either physical stimuli (e.g. electric shock, rotation, restraint, temperature, noise) or so-called psychosocial stressors (e.g. differential housing, maternal separation and handling in experimental animals; bereavement, divorce and school examinations in humans). Immunologic outcomes measured in such studies have been: the development of primary and secondary antibody and cell-mediated immune responses to experimental antigens, microbial pathogens and tumor cells in vivo-, the numbers of B cells and T cell subsets in various lymphoid compartments; the magnitude of mitogen- and/or antigen-induced lymphocyte proliferation in vitro; the production of, and response to, cytokines; NK cell cytotoxicity; and macrophage activation. Considering the variability among these studies with respect to the nature, duration and intensity of the stressor, the age, sex, species and strain of the stressed organism and the parameters of the immune function studied, it is not surprising that different effects of stress on immunity have been reported. Thus, the same stressor can effect enhancement or suppression of different immune responses; different stressors can have different effects on the same parameter of immunity; the same stressor applied for varying periods of time may have different effects on the same parameter of immunity; and changes in a single parameter of immunologic reactivity in response to different stressful stimuli are not necessarily unidirectional. By and large, however, stress in experimental animals and humans has been reported to depress the particular parameters of immunity that were being examined.

Stress has a variety of neuroendocrine effects, and immune responses are affected by the neuroendocrine milieu in which leukocytes function. However, it is far from clear which (and how) stress-associated neuroendocrine changes are responsible for which stress-associated immunomodulatory events. For example, the hypothalamo-pituitary-adrenal (HPA) axis is activated during stressful situations, and there are numerous reports of stress-induced adrenocort-ically-mediated immunosuppression. However, there are also several reports of stress-induced alterations of immunologic reactivity that occur in adrenalecto-mized animals. Although hypophysectomy obviates the effects of stress on some measures of immune function, stress-induced suppression of others are potentiated by this procedure. Because of the involvement of the HPA axis in stress-induced analgesia, many investigators have looked for, and found, a role of endogenous opioids in stress-associated immunomodulation in a variety of species including fish, mice, rats and humans. However, not all stress effects on immunity can be blocked by naloxone or naltrexone and/or mimicked by exogenous opioids such as endorphins and morphine. Finally, although levels of catecholamines and other neurotransmitters are known to be altered in response to stress, and many studies have revealed a role of norepinephrine on immune function, few studies have attempted to correlate stress-induced changes in plasma catecholamines with altered immune function.

For immunologists, the fact that physiologic responses to stressors are immunomodulatory has practical implications that relate to experimental design as well as experimental theory. For example, putative pheromones from stressed (footshocked) mice conveyed to KLH-immunized recipients can affect cytokine production by lymphocytes in vitro and the immune responses they regulate in vivo. An extension of these observations to a situation in which manipulations of mice in an animal room can be communicated to and effect immune responses of other animals in that same room is not an unwarranted assumption. A second example of practical import for immunologists is that the differential housing of mice (housed one versus four per cage from the time of weaning) reproducibly and significantly influences antigen-stimulated in vitro production of TH1- and TH2-derived cytokines by splenocytes from mice immunized with either KLH or herpes simplex virus (HSV).

In the pheromone studies mentioned above, the immunologic effects on recipients of 'stress odors' occurred in a manner consistent with the theory that depressed cellular but enhanced humoral immune responses in pheromone-exposed BALB/c mice are reflective of an altered 'balance' between production of Th1 and TH2 lymphocyte-derived cytokines. However, the immunologic effects of differential housing on immune responses of either BALB/c or C57/BL6 mice to either KLH or HSV do not fit all predictions inherent in the theory of a differentially 'balanced' cytokine response and strain-associated dominance of humoral or cellular immunity. That is, regardless of strain or antigen, individually housed animals produce more antibody, have greater delayed-type hypersensitivity responses, and make more interleukin-2 (IL-2), IL-4, interferon y (IFNy) and IL-10 than do group-housed animals.

The observations that physical and psychosocial stressors can modulate immunity on the one hand, and modify disease progression on the other, has led to popularization of the idea that stress plays an important role in the pathogenesis of immunologically relevant diseases (e.g. cancer, viral and bacterial infections, autoimmunity, allergy). At this time, however, the cause-effect relationships between a stressor-altered immune system and disease progression must be viewed more as a reasonable and attractive hypothesis than as hard fact. Specifically, it has yet to be reproducibly documented in experimental animals (let alone in humans) that stress-

associated alterations of some facet of immuno-competence are, at least partially, responsible for disease pathophysiology.

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