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First Department of Pediatrics, University of Athens, Athens, Greece
Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
The stress and immune systems play crucial roles in maintaining homeostasis [1, 2]. The former is relatively nonspecific, in the sense that it is activated by any threat to general homeostasisincluding immune threats, when that threat exceeds a certain thresholdwhereas the latter is relatively specific, in the sense that it is primarily activated when injurious agents come into contact with the tissues of the organism. During the past few decades, it has become apparent that the stress and immune systems extensively interact with each other, influencing each other's activity, with the purpose of the successful defense against and adaptation of the organism to injurious agents. The study by Straub et al. [3] in this issue of the Journal of Infectious Diseases examines and eloquently describes the interaction of the stress and immune systems with regard to the powerful influence of the stress system on the quality of the defense of the organism against gram-negative versus gram-positive bacteria. This study highlights several key concepts that pertain to the interaction of these 2 systems that are important to review.
THE STRESS SYSTEM AND THE SYSTEMIC STRESS RESPONSE
Mammals survive threats to homeostasisor stressorsby a concerted adjustment of several biological/physiological functions that, together, lead to behavioral and physical adaptation to the stressful situation [1, 2]. The stress response is coordinated and mediated by the centers of the stress system in the brain, along with their respective peripheral limbs (figure 1A). The centers in the brain consist of the hypothalamic corticotropic-releasing hormone (CRH) and arginine-vasopressin (AVP) neurons of the paraventricular nuclei (PVN) and the brainstem noradrenergic neurons of the locus caeruleus/norepinephrine (LC/NE)central sympathetic systems. The peripheral limbs include the hypothalamic-pituitary-adrenal axis and the systemic sympathetic and adrenomedullary nervous systems. The central components of the stress system innervate and stimulate each other, participating in a positive, reverberatory feedback loop, with PVN CRH- and AVP-secreting neurons stimulating the brainstem LC/NE neurons and vice versa.
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Activation of the central stress system leads to the secretion of CRH and AVP into the hypophysial portal system and, hence, to the stimulation of pituitary adrenocorticotropic hormone and adrenocortical glucocorticoid secretion. This activation also leads to the stimulation of the systemic sympathetic and adrenomedullary nervous systems and, thus, to the peripheral secretion of NE, epinephrine, and several neuropeptides, such as immune CRH [4, 5].
The stress system receives input from and responds to the environment, the inner self, and the internal milieu of the body [1, 2]. It receives information neurally from the sensory organs, the areas of the brain that generate emotions, the neural afferent fibers of the autonomic nervous system, and the neural somatosensory afferent fibers; it also receives information humorally through the circulation, from injurious agents or signal-carrying moleculessuch as hormones, growth factors, neurotransmitters, neuropeptides, cytokines, and other mediators of inflammation.
THE IMMUNE SYSTEM AND THE LOCAL AND SYSTEMIC IMMUNE RESPONSE
The immune system is responsible for defense against different injurious agents, including foreign molecules from different kinds of microorganisms, intracellular host molecules released during cell necrosis, and host denatured or oxidized molecules. The immune or inflammatory response is activated by such injurious agents through several classes of recognition molecules or receptors. This response can be local and limited or systemic, spanning a wide range of clinical and biochemical manifestations. The biological programs that unfold during a systemic immune response and inflammation are heuristically called "the sickness syndrome," which is divided into sickness behavior, the acute-phase reaction, and the pain and fatigue system reaction (table 1) [4]. Once the magnitude of the immune response exceeds a certain threshold, activation of the stress response also occurs, with effects that antagonize or potentiate those of the immune response (table 1). Although we have traditionally characterized the stress response as either anti-inflammatory or immunosuppressive, this categorization is not entirely accurate, and it should not be thought to indicate that it is antidefensive [5, 6].
Indeed, the immune or inflammatory response is an integrated defense reaction of the organism that includes the inflammatory reaction, which has been divided into a pro- and an "anti-inflammatory" response (figure 1B). The proinflammatory versus the anti-inflammatory immune response, however, are the tandem ying and yang of the defense response, with the yang (the anti-inflammatory response) being crucial in returning the organism to its baseline homeostasis. Despite their different polarity and apparently opposing effects, both components of the defense responsepro- and anti-inflammatoryare defensive against injurious agents in their own right, as is evident in the study by Straub et al. [3]. Thus, proinflammatory activity and an efficient defense response are not synonymous or equivalent.
The parasympathetic nervous system is often not considered in the regulation of the stress and immune responses [1]. Acetyl-choline secreted by the parasympathetic nerve terminals, however, like the catecholamines and the glucocorticoids, also has potent suppressive effects on the innate proinflammatory response, converting it into an anti-inflammatory response [7].
DETERMINANTS OF IMMUNE SPECIFICITY
There are many factors that determine the specificity of an immune response. The type of tissue or organ affected, the location of the inflamed site in the body, the presence of local barriers (e.g., the peritoneum, meninges, blood-brain barrier, and synovium), the presence of local immune-related cells (e.g., mast, dendritic, and endothelial cells), the attraction of distant immune cells to the inflamed site, the biochemical or humoral microenvironment, and the endocrine and nervous systems all affect the type, degree, and specificity of inflammation. Recently, it has also become apparent that there are target tissue cellular factors that influence the specificity of an immune reaction of both classes and individual cells of a different or same lineage [79].
The functional specificity of our defensive immune response toward specific injurious agents is thus determined by a large number of molecules in the plasma membrane and cytoplasm. For example, NF-B, when not stimulated, is located in the cytoplasm and is kept inactive in complex with other molecules [7, 9]. A myriad of injurious agents and cytokines can stimulate NF-B, causing its translocation into the cell nucleus, where it interacts with the promoters of genes related to inflammation, either directly with specific response elements or through other transcription factors that regulate the expression of proteinssuch as the glucocorticoid receptorthat influence inflammation [10]. In the cell, there are 2 major signaling pathways of NF-B activationcanonical and noncanonicaland there are at least 5 NF-B signalosomes that can be formed: those formed after the specific activation of Toll-like receptors (TLRs), tumor necrosis factor superfamily receptors, NK cell receptors, T cell receptors, and B cell receptors [9]. Thus, immune or immune-related cell activation results from a highly stochastic, integrative process.
Pertinent to the study by Straub et al. [3], there is known functional specificity of the NF-B signaling system for gram-positive versus gram-negative bacteria. Thus, membrane TLR2 and the intracellular pattern recognition receptor nucleotide-binding oligomerization domainintracellular pattern recognition receptor (NOD2) bind to and are activated by peptidoglycans, the cell-wall constituent of gram-positive bacteria, whereas membrane TLR4 binds and responds to lipopolysaccharides, the cell-wall constituent of gram-negative bacteria. Interestingly, TLR2 mutations have been associated with susceptibility to infection by Staphylococcus aureus, NOD2 mutations with susceptibility to Crohn disease, and TLR4 mutations with susceptibility to gram-negative septic shock, infection by Neisseria meningitidis, severe respiratory syncytial virus bronchiolitis, and premature birth [9].
In the light of the above findings, it is not surprising that there are differences in the immune response against gram-negative and gram-positive bacteria, with the proinflammatory response protecting the organism against the former and the "anti-inflammatory" response protecting the organism against the latter. The activity of the stress response would then be expected to suppress the proinflammatory response and to stimulate the anti-inflammatory response, with possibly differing effects on overall host defense against the different pathogen types.
References
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