Neuroimmune Biology Volume 3, The Immune-Neuroendocrine Circuitry:
History and Progress

Figure 1: pp584-585

This figure shows the interaction of major systemic neuroimmune regulatory pathways with local paracrine-autocrine regulatory circuits. Some key organs are also shown with their major regulatory input. Each organ/tissue has its local circuits, which interact with the systemic network via innervation, hormones and cytokines. Mobile elements of the immune system home to all organs and tissues and participate in physiological and pathophysiological processes.  Neuroimmune regulation is fundamental to the development and function of all cells in the body from conception till death. Immunoregulation is used as an example for detailed explanation.
It is proposed that the development and maintenance of lymphocytes and other cells in the body in a functional state is dependent on competence hormones. Additional signals are required for fine tuned functional regulation that includes hormones, adhesion molecules, neurotransmitters, neuropeptides and cytokines. There is a hierarchy for the 3 major groups of signals as  given below:

1.  Competence signal.  During post-natal life pituitary GH and/or PRL deliver to lymphocytes and to all other cells in the body this signal. Many tissues also produce competence hormones ectopically, including the immune system. Ectopic PRL/GH fulfil a local autocrine/paracrine regulatory function during immune reactions. This local regulatory circuit makes rapid lymphocyte proliferation possible, which is a prerequisite of immune reactions. After lymphocyte activation some cytokines may be able to initiate/potentiate the competence signals within the immune system. This remains to be clarified.

2.  Stromal/adherence signals.  Antigen presentation by specialized cells is an adherence signal and a dominant lymphocyte activator.  This is accompanied by additional co-stimulatory adherence signals, eventually leading to lymphocyte activation.  Adherence signals also play a role in the induction of immunological tolerance, in lymphocyte survival, and in the induction of programmed cell death (PCD). These signals fulfil tissue-, site- and cell-specific regulation in the body, i.e. the function/fate of individual cells are determined at this level.

3.  Cytokine signals.  Lymphocyte activation is completed by cytokine signals, which lead to cell proliferation, differentiation, and functional activation. Cytokines may also perform inhibitory function (e.g. TGF-beta, interferon-gamma) or cause PCD (e.g. tumor necrosis factors).

 a.  Signal modulation.  Some steroid hormones, catecholamines, endorphins/ enkephalins and chemokines are capable of modulating the process of signal delivery from the cell membrane to the nucleus by regulating Ca2+ influx, cAMP and cGMP.

 b.  Signal regulation.  Glucocorticoids, sex and other steroid hormones (SH), tri-iodothyronin (T3) and vitamin D3 control lymphocyte signalling by the regulation of nuclear transcription factors. These steroid hormones and T3 play a regulatory role also in cell differentiation and in the elimination of unwanted cells via the induction of PCD.

 c.  Local hormone activation.  Bioactive thyroid and steroid hormones are locally generated from inactive precursors by immunocytes (e.g. T3, E2, androstenediol, androstenetriol, and vitamin D3) while the primary function of others (corticosteroids, estradiol, progesterone, aldosterone) is systemic immunoregulation. The thymus itself is also a steroidogenic organ.

 Quiescent lymphocytes do not synthesize DNA and exert minimum metabolic activity.  Pituitary GH/PRL, some adhesion signals and serum IGF-I play a key role in the maintenance of these lymphocytes until functional activation occurs. Neurotransmitters and neuropeptides are locally acting functional regulators, basically acting as signal modulators and cytokines. Some neuropeptides may be able to deliver competence signals.

 The primary and secondary lymphoid organs, the mucosal and cutaneous lymphoid systems contribute leukocytes to the circulation that mediate systemic immunity. Circulating leukocytes also penetrate tissues and become “stromal cells”. These sessile lymphoid elements fulfil important local regulatory function. The adrenal, thyroid and gonads produce important immunoregulatory hormones. The liver contributes to immune function by producing serum IGF-I, by promoting the induction of oral immunological tolerance and it plays a major role in the acute phase response. The pancreas produces insulin and the submndibular gland nerve growth factor, which are major immunoregulators. These glands also produce glandular kallikrein, which have a major immunoregulatory function. All other tissues and organs have an input into the neuroimmune regulatory network via nerve impulses and by cytokine production.

Abbreviations: ACTH = adrenocorticotropic hormone; ALD = aldosterone; CAT = cathecolamines; CNS = central nervous system; CTK = cytokines; FSH = follicle stimulating hormone; GC = glucocorticoids; GH= growth hormone; IGF-I insulin-like growth factor-I, INS = insulin; LH = luteinizing hormone; NGF = nerve growth factor; PRL = prolactin; SH = sex hormones; TSH= thyroid stimulating hormone; T4 = thyroxin; VD3 = vitamon D

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