Wilson: Williams Textbook of Endocrinology, 9th ed., Copyright © 1998 W. B. Saunders Company

NEUROENDOCRINE-IMMUNE INTERACTION

The immune system is a major adaptive system of animals, capable of recognizing foreign proteins, viruses, and bacteria as nonself and of mounting cellular reactions to defend the integrity of the host. Two general classes of cytokine responses by lymphocytes and monocytes are recognized--an acute response activated in the absence of prior exposure to antigen and a delayed response that depends on prior exposure to a specific antigen. ^[913]

Lymphocytes secrete immunoglobulins and lymphokines. Because some lymphokines are also secreted by other types of cells they have also been called cytokines. Lymphokines regulate differentiation, proliferation, and function of other lymphocytes and monocytes and exert diverse effects on many different tissues, including induction of fever, alteration of protein and lipid metabolism, and modulation of neuroendocrine function (see later). ^{[913][914][915][916][917][918]} Many endocrine and neural cells also synthesize cytokines that serve paracrine functions as diverse as activation or killing of cells. This section deals with the actions of cytokines in the neuroendocrine system.

The immune system is subject to neural and hormonal modulation; many of the same neuropeptides, protein hormones, and hormone receptors are expressed in nerve cells, endocrine cells, and lymphocytes, and the products of lymphocytes can influence neuroendocrine function. ^{[8][914][915][916][917][918][919][920][921][922]} An emerging literature suggests that stress, both emotional and physical, can modulate the immune response, at least in part by neuroendocrine mechanisms. ^{[917][923][924]}

Neuroimmunology is the study of immune reactions involving the brain, nerves, and muscles, e.g., autoimmune allergic encephalitis, multiple sclerosis, and myasthenia gravis. In the past this term was also applied to the study of neural modulation of the immune response, but a more specific term for the interaction of nervous and immune systems is neuroimmunomodulation. To emphasize the role of neuroendocrine mechanisms, the term neuroendocrine immunology has been coined. This section considers the effects of lymphokines on neuroendocrine function, the effects of hormones and peptides on immune responses, and the hormones and neuropeptides produced by the immune system.

Effects of Cytokines on Neuroendocrine Function: The Acute-Phase Response

The acute immune cell response to foreign antigens is triggered within a few minutes of exposure, whereas the delayed response may take 1 wk to 10 d to develop. ^[913] An important generalizing concept, proposed by Blalock, ^[8] is that the peripheral pool of lymphocytes and monocytes serves as a sensing mechanism by which foreign substances are recognized and thereby mobilizes neuroendocrine adaptive responses. This has been referred to as bidirectional communication between immune system and brain.

On exposure to foreign molecules or the products of tissue injury, lymphocytes, monocytes, and other tissues secrete a variety of regulatory peptides whose function is to neutralize, inactivate, and sequester these invading substances (Table 8-29) . ^{[913][914][915][916][917][918][919][920]} The acute-phase response mobilizes homeostatic mechanisms and initiates long-term adaptive immunity. Within a few minutes of an intravenous injection of the endotoxin of E. coli, lipopolysaccharide (LPS), e.g., there is an increase in the blood levels of several cytokines, TNF alpha, ^[916] IL-1beta, IL-6, and IL-1beta-receptor antagonist (Fig. 8-61) . Among the important metabolic effects (see Table 8-29) are induction of negative nitrogen balance; inhibition of synthesis of liver proteins such as albumin, thyroid hormone-binding globulin, ceruloplasmin, and apolipoproteins; a decrease in circulating levels of iron and copper; and increased synthesis of other liver proteins, including fibrinogen, alpha₂ -microglobulin, and amyloid precursor protein. Synthesis of triglyceride is inhibited and fat stores are mobilized through local lipolytic enzyme activation.

Systemic toxins and acute-phase cytokines change the set point of temperature regulation in the brain to cause fever, ''sickness behavior'' (inactivity, loss of interest, anorexia, and hyperalgesia), enhanced slow-wave sleep, and other behavioral disturbances ranging from malaise to delirium and coma. ^[925]^[926][927] The mechanism by which circulating cytokines and bacterial toxins change brain function has not been fully explained. Most workers believe that the blood-brain barrier excludes toxins and inflammatory cytokines from direct entry into the brain and that the effects are mediated at the brain surface (endothelia, periventricular organs [see earlier]) and visceral afferents from the vagus nerve (see earlier in the section on pituitary-adrenal regulation). Endothelial cells of the brain and ependyma-derived epithelia of the specialized periventricular organs synthesize and translocate a variety of molecules into brain, including inflammatory cytokines and small-molecular-weight second messengers including IL-1beta, IL-6, TNF alpha, several prostaglandins, NO, and still other cytokines, some of which are neurotoxic. Within the brain these various cytokines can induce synthesis of other cytokines by astrocytes, microglia, tissue macrophages, resident basophils, and, to some extent, neurons themselves.

The flood of cytokines impinging on the brain causes changes in the synthesis and release of several neurotransmitters and neuropeptides. Brain cytokine responses are both beneficial and destructive. Fever in some settings increases resistance to infection. The secretion of nerve growth factor, which exerts a beneficial effect on neuronal healing after brain injury, is enhanced by exposure to IL-1. However, excessive central brain cytokines lead to toxic levels of NO, potentiate excitotoxin effects of glutamate, and stimulate production of the Alzheimer protein precursor, which is toxic to neurons and exerts amnesic effects.

The cytokines have important neuroendocrine consequences, and altered hypothalamic-pituitary activity interacts with cytokine effects on individual endocrine organs. The following are additional cytokine effects on the endocrine system. Pituitary folliculostellate cells contain ^[928] and release IL-6 ^[929] and NO. ^[438] One or more secretory cells of the pituitary contain IL-1beta. ^[930] Furthermore neuronal pathways in the medial basal hypothalamus ^[923][924] contain IL-1beta, IL-6, and TNF, ^[724] and IL-6 is released from the hypothalamus after exposure to bacterial toxins. ^[933][934] Thus the potential exists for regulation of anterior pituitary function via endocrine effects (circulating cytokines from activated lymphocytes), neuroendocrine effects (exerted by the hypothalamus through the classic tuberoinfundibular portal vessel system), and paracrine control within the pituitary itself.

Cytokine-induced pituitary secretion has teleologic value as a host defense. ^{[917][918][936]} Pituitary-adrenal activation by toxin is the best understood of the endocrine interactions in the immune system. As noted earlier in the section on corticotropin regulation, release of CRH, vasopressin, and epinephrine leads to increased glucocorticoid secretion, which serves to modulate an inflammatory response that could be damaging to the host. ^{[917][935][936]} The major action of the cytokines is on the hypothalamic control element. Rats with congenital deficiency of CRH secretion (the Lewis rat) are vulnerable to hypersensitivity arthritis, ^[920] and patients with rheumatoid arthritis have a reduced pituitary-adrenal response to operative stress. ^[937]

The occurrence of SIADH in patients with pneumococcal pneumonia, pulmonary tuberculosis, and bronchiectasis is attributable to cytokine-induced release of vasopressin. ^[938] Inhibition of pituitary-thyroid function by inflammation is mediated by cytokines acting at multiple levels of the pituitary-thyroid axis, including peripheral thyroid hormone metabolism. ^{[917][925][936]} Conversion of T₄ to T₃ and the production of thyroid hormone-binding proteins are inhibited by several inflammatory cytokines, leading to the ''sick euthyroid syndrome.'' At the level of the thyroid, synthesis of thyroid hormone, iodination of thyroglobulin, and responses to thyrotropin are all impaired, and the inappropriately low circulating thyrotropin levels are due to impaired pituitary responsiveness to TRH, impaired secretion of hypothalamic TRH, and enhanced hypothalamic secretion of somatostatin. Both the pituitary and the thyroid express IL-1 when exposed to circulating toxins, suggesting that paracrine-autocrine cytokine production also plays a role in local responses. In contrast to the pituitary-adrenal response to inflammation, which has homeostatic value, the benefit of induced hypothyroidism, if any, has not been demonstrated in the human ^[917] but is beneficial in rats with induced pneumonia. ^[939]

Pituitary-gonadal function is also impaired in inflammation through changes in the hypothalamus, pituitary, and gonads. The magnitude of LH and FSH pulses is reduced or suppressed completely, IL-1 is induced locally in both ovary and testis, and systemic and paracrine effects of IL-1 suppress synthesis and secretion of steroid hormones in both organs and reduce the response to gonadotropins. Loss of the normal LH and FSH ultradian rhythm is attributable to suppression of LHRH secretion by cytokine-stimulated secretion of hypothalamic CRH and vasopressin. ^[940][941] No clear homeostatic benefit results from suppressed gonadal secretion in inflammatory illness, but this question has not been studied adequately.

In the human GH secretion is enhanced by inflammatory stimuli (and massive stresses like burns and surgery), whereas in the rat low concentrations of cytokines stimulate and high concentrations suppress GH secretion. These changes are brought about by altered secretion of GHRH and somatostatin. Elevated GH secretion may reduce the negative nitrogen balance of infection and other stresses and possibly stimulates lymphocyte-monocyte reactivity.

PRL secretion in humans and rats is enhanced by inflammation and by inflammatory cytokines but the mechanism of this response has not been elucidated. A homeostatic action of PRL has not been demonstrated but the effect of PRL as a lymphocyte-regulating hormone suggests that it may function to regulate immunocompetent cells (see later).

Neuroendocrine Regulation of the Immune Process

The nervous system can influence immune function through a number of routes ^[942] --hypothalamic-pituitary function; autonomic nervous system innervation of spleen, liver, gut, and lymphoid organs ^[923][924] ; circulating catecholamines; sensory neuron peptides such as somatostatin and substance P; induction of fever; and changes in diet and activity. A less well-established route is the direct secretion into the blood of immune-regulating factors from the brain. ^[943]

The most important pituitary-dependent hormone that influences immune reactions is cortisol, which inhibits most aspects of the immune response, including proliferation of lymphocytes; production of immunoglobulins, cytokines, and the inflammatory mediators that follow antigen-antibody binding; and cellular toxicity including the production of inflammatory leukotrienes. ^[935] These inhibitory reactions form the basis of the anti-inflammatory actions of glucocorticoids (see Chapter 12) and occur within the range of values induced by stress or inflammation. The pituitary-adrenal response to stress may serve to modulate the intensity of the immune response and its inflammatory components, including changes in vascular tone and vascular permeability. ^[935] Loss of this function makes animals with adrenal insufficiency vulnerable to inflammation. The fact that the products of inflammation such as IL-1 can activate the hypothalamic-pituitary-adrenal axis (see earlier) suggests the operation of a negative feedback control loop to regulate the intensity of inflammation. ^[529] Because pituitary-adrenal function is almost completely controlled by the brain, this system is an excellent example of neuroimmunomodulation.

The physiological effects of other anterior pituitary hormones on the immune response are more subtle. ^[918] GH-deficient mice have thymic atrophy, involution of lymphatic tissue, and T-cell impairment, abnormalities that are reversible by GH treatment. ^[944] In addition, the decrease in GH secretion with aging may cause the decline in immune function with aging because thymic atrophy in the aged rat is reversed by GH treatment. ^[944][945] PRL can also stimulate immune function. ^{[946][947][948][949][950]} Human T and B lymphocytes and some lymphoma cells contain membrane PRL receptors; the immunoincompetent state in hypophysectomized mice is corrected by PRL administration; antibodies to PRL inhibit lymphocyte proliferation in several cell lines; and cyclosporine, an immunosuppressant drug, blocks the lymphocyte-stimulating effects of PRL. ^[951] Lymphocyte PRL dependency may be a manifestation of a response to both pituitary PRL and an autocrine or paracrine system, because lymphocytes can also synthesize and secrete PRL. ^[8] The effects of hyperprolactinemia and of PRL suppression on human immune function have not been elucidated.

A role for gonadal function as a modulator of the immune process has been suspected because of the gender differences in the prevalence of the autoimmune diseases. ^[952] The sex ratio for Hashimoto's thyroiditis, e.g., is 25:1 in favor of women. Women with systemic lupus erythematosus who are given contraceptive steroids may show an exacerbation of disease, ^[952] and estradiol potentiates mitogen-induced B-cell stimulation in men. ^[953] Lymphocyte function varies during the menstrual cycle, T-lymphocyte function being reduced in the first half of the cycle.

Pituitary hormones that bind to receptors on lymphocytes include vasopressin, oxytocin, the endorphins, alpha-MSH, and LH. ^[8]Table 8-26 summarizes some of the immunoregulatory effects of these substances, some of which appear to act both centrally and peripherally in mediating responses to inflammation. Corticotropin, vasopressin, and alpha-MSH are inhibitors of pyrogen-induced fever ^[954] ; nerve endings containing these peptides are localized in central temperature-regulating areas, ^[955] and in the periphery alpha-MSH counteracts several effects of IL-1 on monocyte and fibroblast function. ^{[956][957][958]}

Other neuropeptides that influence the immune response include substance P, somatostatin, CRH, and VIP. The concentrations required for biologic effect are seemingly too high to be physiologically relevant, but these peptides may be released locally in high concentration from sensory nerve endings ^[959][960] and from immunocompetent inflammatory cells.

Immunocompetent cells secrete many peptides and hormones (Table 8-30 ) . Perhaps the best example of paracrine control of lymphocyte function by a secreted cytokine is that of CRH. Activated lymphocytes secrete CRH, and CRH in turn enhances lymphocyte activation. ^[250] CRH in inflammatory joint fluid of patients with rheumatoid arthritis is probably secreted by activated lymphocytes and monocytes. ^[250] Since CRH is an activating peptide and since CRH receptors are present on activated monocytes, this system could operate as a positive feedback system to increase the intensity of inflammation.

It has also been postulated that arthritis may be potentiated by substance P released from sensory neurons in the joint. ^[960] Substance P and its cosecreted peptide substance K (both derived from the same prohormone) have vasodilating properties and are mediators of the wheal-and-flare response to tissue injury.

Somatostatin can inhibit immunoglobulin E-dependent stimulation of basophils and the in vitro proliferation of T and B lymphocytes. ^[918][961] VIP is generally an inhibitor of lymphocyte function and may act to restrict lymphocyte traffic through Peyer's patches in the gut. ^[962]

The secretion of pituitary hormones by lymphocytes is reportedly regulated by the same factors that regulate the pituitary. For example corticotropin secretion by lymphocytes is suppressed by glucocorticoids and stimulated by corticotropin-releasing factor; thyrotropin immunoreactivity of lymphocytes is stimulated by TRH and suppressed by thyroid hormone; and lymphocyte GH is stimulated by GHRH and suppressed by somatostatin. ^[8] The endocrine significance of hormone secretion by lymphocytes is uncertain. For example the claim that the lymphocytes of hypophysectomized mice infected with Newcastle virus can synthesize enough corticotropin to stimulate the adrenal cortex ^[963] has been criticized on methodologic grounds; ^[964] however, a case of Cushing's syndrome was apparently caused by excessive corticotropin secretion from a large inflammatory mass. ^[965] There is also controversy as to whether corticotropin receptors are present on lymphocytes. ^[966][967]

Psychoneuroimmunology

Efforts to identify neural pathways of immune regulation were initiated because of evidence suggesting that psychological stress and depression can change human immune function, ^{[923][924][968][969][970]} that immune responses in animals can be conditioned in a classic pavlovian paradigm, and that neural lesions can inhibit various aspects of the immune response. These changes could affect immune surveillance and have implications for the course of cancer, for the course of acquired immunodeficiency syndrome (AIDS), and for the initiation or aggravation of autoimmune diseases, including those associated with the endocrine system such as Graves' disease and insulin-dependent diabetes mellitus. The extent to which such influences, if present, are mediated through known neuroendocrine pathways is unknown. Alternative regulatory pathways from the central nervous system to the immune system include the catecholamines (and cosecreted neuropeptides) of the autonomic nervous system that innervate lymph nodes, spleen, and thymus; adrenomedullary catecholamines; and the hormones that influence secretion of thymosin and other lymphocyte-regulating thymic hormones. Despite clear evidence that the nervous system can influence immune function through neural and neuroendocrine mechanisms, the role of these factors in human inflammatory disease remains to be defined.