III. Therapeutic and clinical implications of systemic allergic inflammation
Stress, chronic inflammation, and emotional and physical well-being: Concurrent effects and chronic sequelae,☆☆

https://doi.org/10.1067/mai.2000.110163Get rights and content

Abstract

The importance of TH cells (specifically TH2 cells) that produce IL-4, -5, -10, and -13 in the propagation of chronic allergic inflammation is well known. However, the role of the hypotha-lamic-pituitary-adrenal axis and the sympathetic system as immunomodulators of events leading to inflammation is less well established. Increases in stress levels are associated with elevations in circulating glucocorticoids and catecholamines, which may influence disease pathophysiologic factors and severity through changes in the number and activity of TH-cell populations and through other means. For instance, stress has been shown to shift the relative proportion and trafficking of TH1 and TH2 cells to a TH2 phenotype. In this article, the current understanding of interactions of the stress and immune systems and the physiologic and pathophysiologic implications of these interactions in human health and disease are reviewed. (J Allergy Clin Immunol 2000;106:S275-91.)

Section snippets

Organization of the stress system

The HPA axis and the SNS are peripheral limbs of the stress system, whose main function is to maintain basal and stress-related homeostasis.1, 2 The central components of this system are located in the hypothalamus and the brain stem (Fig 1).2

. Major components of the central and peripheral stress system. The paraventricular nucleus and the locus ceruleus/noradrenergic system are shown with their peripheral limbs, the pituitary-adrenal axis, and the adrenomedullary and systemic sympathetic

The immune response and the inflammatory reaction

Any immune response, first, involves the recognition of a pathogen and, second, the mounting of a reaction against it. Broadly speaking, the different types of immune response fall into 2 categories: the innate (nonspecific) and the adaptive (specific) immune responses.6 Phagocytic cells (such as dendritic cells, monocytes, macrophages, and polymorphonuclear neutrophils) bind to microorganisms, internalize them, and kill them. Because phagocytic cells use primitive, nonspecific recognition

Adrenocortical hormones

The anti-inflammatory and immunosuppressive properties of glucocorticoids exerted through their ubiquitous intracellular receptors make them invaluable therapeutic agents in numerous diseases.7 The glucocorticoid receptor is a 777-amino-acid cytoplasmic protein with 3 major functional domains and several subdomains. The carboxyterminal region binds glucocorticoid, and the middle portion domain binds to specific sequences of DNA in the regulatory regions of glucocorticoid-responsive genes

Effects of the immune and inflammatory reaction on the HPA axis and the SNS

The last 2 to 3 decades provided evidence that, during an immune response, certain cytokines can signal the CNS, which, through a complex CRH-dependent pathway triggers the activation of both the HPA axis and the SNS.2 Most of the HPA axis-stimulating activity in plasma comes from 3 cytokines (TNF-α, IL-1, and IL-6), which are produced at inflammatory sites and elsewhere in response to inflammation. In most situations, TNF-α appears first, followed by simultaneous secretion of IL-1 and IL-6.

Defects of the HPA axis and/or SNS

Disturbances in the feedback between the HPA axis and the immune and inflammatory reaction have been observed in animals and humans (Table III).2An excessive HPA response to inflammation can mimic the stress or hypercortisolemic state, increase susceptibility to certain infectious agents and tumors, and increase resistance to autoimmune or inflammatory disease. Conversely, a defective HPA-axis response can mimic the glucocorticoid-deficient state and cause resistance to infections and neoplasms

Systemic inflammation and well-being

Like the stress response, the inflammatory reaction of an individual is crucial for survival of self and species.1, 2 Also like the stress response, inflammation is meant to be tailored to the stimulus and be time limited. A fully fledged systemic inflammatory reaction consists of activation of immune and immune accessory cells and resultant stimulation of 2 major programs: (1) the sickness syndrome and (2) the classic stress syndrome. As a result, the acute phase reaction and the pain program,

Therapeutic perspectives

Glucocorticoids and analogue agents that potentiate their actions are options for the treatment of autoimmune inflammatory diseases. By potentiating the secretion or the effects of hypothalamic CRH with CRH secretagogues, CRH agonists or CRH binding protein antagonists that cross the blood-brain barrier, the development of inflammatory disease in susceptible persons with a hypofunctional HPA axis may be prevented and, at the same time, correct CNS symptoms of CRH deficiency. Such an action

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    Dr. Chrousos is a Consultant Endocrinologist.

    ☆☆

    Reprint requests: George P. Chrousos, MD, NICHD, NIH, Bldg 10/9D42, Bethesda, MD 20892-1583.

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