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Lymphocytes possess ^-adrenoceptors (Williams et al.. 1976) which respond to noradrenaline (NA) released by sympathetic nerves within the lymphoid organs and to adrenaline (Ad), release of which is controlled by splanchnic nerve input to the adrenal medulla. B cells possess more ^-adrenoceptors than monocytes and monocytes more than T cells in aggregate (Khan et al.. 1986) . In humans, T cells of the suppressor subset (CD8*, 9.3) possess three times as many ^-adrenoceptors as cells of the cytotoxic subset (CD8*, 9.3*) and CD4* cells (helper cells and the effectors of delayed type hypersensitivity responses) possess very few (Khan et al.. 1986). The fact that suppressor cells possess more receptors than other T-cell types might suggest that whatever control the SNS exerts over T cells will be effected primarily through suppressor­ cell responses to SNS-derived signals. The number of (3-

adrenoceptors on lymphocytes is not fixed. Their number rises, for example, on T cells driven to proliferate in vitro by mitogenic lectins (Westlv and Kellev. 1987), although a decline has been reported on splenocytes following immunization with SRBC (Fuchs et al.. 1988).

Glucocorticoids reverse this down-regulation to some extent (Davies and Lefkowitz. 1984) .When ^-adrenergic agonists bind to ^-adrenoceptors, the consequence is an abrupt increase in intracellular cyclic adenosine monophosphate (cAMP). A transient rise in cycle AMP is important in the genesis of the immune response. To start the response, cells of the immune system must be triggered to move from the resting (G^) stage of the cell cycle into G^, and agents that elevate intracellular cAMP can provide this signal. In later stages, elevated levels of cAMP are associated with decreased cellular proliferation and increased differentiation. Sympathetic nervous system terminals may release other biogenic amines in addition to NA. Adrenaline (Ad) (from the adrenal medulla) and serotonin (from platelets) can be taken up by and subsequently released from SNS nerve terminals. Lymphocytes possess receptors for other neurotransmitters including VIP, somatostatin, and substance P (Danek et al.. 1983; Pavan et al.. 1983; Pavan and Goetzl.. 1985; Pavan et al.. 1984). Acetylcholine is the neurotransmitter of the parasympathetic nervous system. Muscarinic, and possibly nicotinic, acetylcholine receptors have been demonstrated on lymphocytes. Cholinergic agonists promote lymphocyte proliferation in vitro (Gordon et al.. 1970; Richman et al.. 1981; Strom et al., 1974). Substance P is released from sensory nerve endings at sites of inflammation, for example within joints in rheumatoid arthritis or in the experimental model adjuvant-induced arthritis (Levine et al.. 1984). Released substance P

T ab le 1.1. Im m unoregulatory Effects of Several Hormones and p ep tid es’*

HORM ONE O R P E P T ID E IMMUNE FU N CTION A FFEC T ED

Inhibitory

G lucocorticoids Lym phocyte synthesis, inflam m ation

C orticotropin M acrophage activation, synthesis of IgG and in terfe ro n -y

Chorionic gonadotropin A ctivity of T cells and n a tu ra l killer cells

ot-Endorphin IgG synthesis, T -cell proliferation

Som atostatin T-cell proliferation, inflam m atory cascade

V asoactive intestinal peptide T-cell proliferation and m igration in P e y e r’s patches

a-M elanocyte-stim ulating hormone Fever, prostaglandin synthesis, secretion of

interleukin-2

S tim ulatory

O estrogens Lym phocyte proliferation and secretion

G row th horm one Thym ic grow th, lym phocyte reactivity

Prolactin Thym ic activity, lym phocyte proliferation

T h yrotropin IgG synthesis

^ -E n d ro p h in A ctivity of T ,B , and n a tu ra l killer cells

S ubstance P Proliferation of T cells and m acrophages,inflam m atory

cascade

C orticotropin-releasing hormone Lym phocyte and m onocyte proliferation and activation

potentiates the ongoing inflammatory response by further activating the immune system.

The capacity of the nervous system to influence immune responses by direct effects upon receptors of immunocompetent cells, is further supplemented by the influence of the endocrine system which is exerted through a remarkable range of peptides, hormones and receptors classically associated with neuronal tissue or endocrine cells (Table 1.2.). Lymphocytes contain proopiomelanocortin

(POMC) mRNA, which codes for corticotropin, endorphins, and a-melanocyte-stimulating hormone and immunoreactivity corresponding to each of these peptides. They also have receptors for these peptides, glucocorticoids and CRF. The expression of the POMC gene in lymphocytes, as in pituitary corticotrophs, is increased by CRF and decreased by glucocorticoids. CRF is also secreted at sites of inflammation by monocytes and has proinflammatory actions fCrofford et al.. 1992). It is likely that POMC-derived peptides secreted at the local level have a role in the regulation of inflammation. For example, the intracerebral administration of a-melanocyte-stimulating hormone inhibits fever induced by IL-1 fLioton. 1990) and can inhibit the production of prostaglandin E (PGEg) by IL-1 stimulated fibroblasts (Cannon et al.. 1986). Whether corticotropin derived from lymphocytes is important in enhancing adrenocortical secretion is controversial (Olsen et al.. 1992). However, at least one case of Cushing's syndrome

caused by ectopic secretion of corticotropin by granulomatous mass has been reported (DuPont et al.. 1984). Lymphocytes reportedly contain immunoreactive thyrotropin, the secretion of which is activated by thyrotropin-releasing hormone and inhibited by thyroid hormone, as occurs in the pituitary gland (Smith. 1992). Lymphocytes also contain mRNA coding for GH and prolactin and reportedly secrete these hormones (Blalock. 1989; Kellev et al.. 1992; Smith. 1992). The secretion of prolactin by lymphocytes may be physiologically important because using antiprolactin antibody to inhibit the action of prolactin inhibits mixed- lymphocyte responses in v i t r o .

Since, the lymphocytes appear to be under the direct influence of both neural and endocrine system, interactions of these two system at this levels, could be of similar importance to that observed in the central nervous system during the initiation or maintenance of an immune reaction.

1.3. The effects of the immune system upon the nervous