Neuroimmune network

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Neuroimmune network

A substantial body of information now indicates that the nervous and immune

systems are integrated and form an interdependent neuroimmune network (see

also: Cytokine network ) with a complex and extensive array of endocrine,

neurocrine, paracrine and autocrine interactions between different cell

types (Petrovsky et al). The field concentrating on studies of interactions

between the immune system and neuroendocrine organs (including, for example,

brain, pituitary, thyroid, parathyroid, pancreas, adrenal glands, testes,

ovary) has a number of names, includingPsychoneuroimmunology

andNeuroimmunoendocrinology ( Ader; Ader et al; Blalock). The most recent

term introduced is that ofNIM (Neuroimmunomodulation ).

A reciprocal flow of information between the two systems and thus the

existence of functional connections between the nervous and the immune

system is suggested by several observations showing that the two systems

communicate with an array of mechanisms, via soluble mediators as well as

cell-to-cell contacts (Goetzl et al; Roszman et al). Neural targets that

control thermogenesis, behavior, sleep, and mood can be affected by

pro-inflammatory cytokines which are released by activated macrophages and

monocytes during infection. Within the central nervous system production of

cytokines has been detected as a result of brain injury, during viral and

bacterial infections, and in neurodegenerative processes.

Like many other physiological responses immune reactions can be conditioned

in a classical Pavlovian fashion (Cohen et al). Physical or emotional stress

and psychiatric illness activate the endocrine system and can compromise

immunological functions (Khansari et al; Laudenslager et al; Reichenberg et

al; Raison et al). Their profound effects on immune responses can, in turn,

elicit marked physiological and chemical changes in the brain. Some of the

pathfinding molecules creating the complex pattern of neuronal connectivity

in the brain and nervous system, the semaphorins and their receptors,

Netrins , are expressed also in cells of the immune system and as such are

components of a complex circuitry of positive and negative signans

controlling neuroimmune functions.

Direct modulation of the immune system by neuroendocrine influences can be

inferred also from the innervation of immune organs such as spleen, thymus,

and lymph nodes by sympathetic and parasympathetic neurons (Esquifino et

al). For example, about two thirds of mast cells in the rat intestinal

mucosa have contacts with subepithelial peptidergic neurons. autonomic

innervation of lymphoid tissues thus provides a basis for the neural

regulation of immunity.

A direct participation of the sympathetic nervous system in immune functions

is evidenced also by the observation that sympathectomy and lesioning of

specific regions of the brain can both enhance and/or suppress immune

responses. Defined hypothalamic ablation has been shown, for example, to

reduce the number of large granular lymphocytes, the activity of natural

killer cells, the ratio of T-helper T-suppressor cells, and the level of

circulating B-cells. Some semaphorins that play an important role in

creating the complex pattern of neuronal connectivity by serving as nerve

growth cone contact and chemotropic guidance signals are known also to

affect B-cell functions.

Firing rates of hypothalamic neurons have been shown to be altered during

immune responses. Anterior hypothalamic ablation has been shown to be

associated with diminished immunoreactivity. Hypophysectomy is known also to

cause an impairment of humoral and cell-mediated immunity, which can be

corrected by treatment with neuromodulatory mediators such as Prolactin , or

Growth hormone (see also: Dwarf mice ). Hypophysectomy in rats and mice has

been shown to decrease antibody responses, to prolong survival of grafted

tissues, to decrease lymphocyte proliferation, to reduce spleenic natural

killer cell activity, and to cause an inability to develop adjuvant

arthritis.

A neural supply of immune organs allows for local delivery of neuropeptides

and other neuromediators at high concentrations, which can then act on

receptors expressed on immunocytes (Singh et al). The reciprocal entry of

immune cells into the nervous system has been observed also. Monocytes,

macrophages and T-cells are able to cross the blood brain barrier.

Macrophages can persist for very long intervals as resident microglia of the

brain and constitute approximately 10 percent of the total glial cell

population. Activated T-cells are retained for days if they react

specifically with central nervous system antigens. A variety of stimuli have

been shown to induce expression of MHC molecules on astrocytes, microglia,

and oligodendrocytes, which then can function to present antigens and to

become targets for cytotoxic T-cells. Functionally significant

concentrations of some neuropeptides are found also at sites of immune and

inflammatory reactions (see also: Inflammation ).

Many different classes of molecules, including cytokines , neurohormones,

neurotransmitters, and many non-peptide mediators are involved in the

amplification, coordination, and regulation of communication pathways within

the neuroimmune system. It appears that these substances act on their

classical neuroendocrine target cells and also serve as endogenous

regulators of the immune system, acting on receptors expressed by the immune

cells and thus possessing autocrine and/or paracrine functions. Circulating

peripheral immune cells thus may establish a mobile source of

neuromodulators, allowing these molecules to reach virtually all types of

cells within an organism. It should be remembered that most, if not all,

endocrine glands contain a high number of lymphoid cells . For example,

these cells can make up to 20 percent of the total cell number in the case

of the adrenal gland. Moreover, many classical cytokines of the immune

system have been shown to be produced by a variety of brain cells, including

neurons and glial cells.

Neurohormonal involvement in immune reactions has been known for some time,

in particular through the immunosuppressive effects of glucocorticoid

hormones. Production from the adrenal gland of corticosterone in rodents and

of cortisol in humans is stimulated by ACTH (see: POMC , proopiomelanocortin

). Hypophysectomy causes adrenal atrophy because of adrenal dependence on

pituitary-derived ACTH . Steroid hormones inhibit secretion of ACTH by the

pituitary and also turn off the production of specific hypothalamic release

factors, which positively regulate the synthesis of pituitary hormones

(Blalock et al; Berczi et al).

Pituitary and/or hypothalamic hormones in turn are usually controlled

negatively by end products of the particular neuroendocrine cascade;

glucocorticoid hormones, for example, suppress ACTH production (see also:

GIF , glucocorticoid increasing factor ). These interactions form the basis

of the physiologically important regulatory entity known as

theHypothalamic-pituitary-adrenocortical axis ( abbrev. HPA ) orStress axis

, which thus integrates functions of the hypothalamus, the pituitary, and

the adrenal glands (see also: Acute phase reaction ) and which involves the

activities of various cytokines (Turnbull et al). Recent evidence indicates

that a similar situation exists in the immune system; for example,

ACTH/endorphins and Growth hormone production by lymphocytes is regulated by

corticotropin releasing factor and growth hormone releasing hormone ,

respectively.

Other neuromodulators released from the neuronal systems and influencing

cells of the immune system include, for example, Alpha-MSH and

Beta-Endorphin (see: POMC , proopiomelanocortin ), follicle stimulating

hormone (see also: Activin A , Follistatin ), Angiotensin , Growth hormone ,

Luteinizing hormone , IGF , neuronal differentiation factors (see below),

Prolactin , Somatostatin , SP (substance P ) and related Tachykinins ,

Suppressin , Thymic hormones , Thyrotropin , Vasopressin , VIP (vasoactive

intestinal peptide ), and many other small oligopeptides, neurotransmitters,

and non-protein molecules (see also: Neuropoietins , Neurotrophins ).

Many of these neuromediators and neurohormones have been shown to be

released also by cells of the immune system in response to cell activation .

Immune cells have been shown to produce authentic neuromodulatory molecules

identical with those produced also by brain and nerve cells as well as

genetically determined variants arising both by alternative splicing of mRNA

and by unique proteolytic cleavages of the prepro-protein (see, for example:

POMC ). Immune cells also appear to utilize authentic receptors for these

factors as well as receptors that differ in specificity, affinity, and

signal transduction mechanisms from those in the nervous system. Precisely

how these factors can modulate immunity and/or neuronal processes (cell

growth, survival, and differentiation) remains to be determined.

In addition to classical neuromodulatory factors, classical cytokine

mediators including, for example, IL1 , IL2 , IL6 , TNF-alpha , LIF , IFN

(interferons ), thymic hormones , and bFGF , also have potent neuroendocrine

activities (Nistico et al; Payne et al; Solvason et al, Hall et al; Hermus

et al; Goetzl et al; Blalock et al).

IL1 is produced by pituitary cells. It has been shown to be as potent as

corticotropin-releasing hormone in some systems to induce the production of

ACTH (see: POMC ). Primary isolated pituitary cells can respond to IL1 by

releasing ACTH , Growth hormone , Luteinizing hormone , and Thyrotropin .

IL1 inhibits the production of Prolactin by these cells. Antibodies to

corticotropin releasing factor can block corticosteroid induction when IL1

is injected intravenously. The enhanced synthesis of ACTH causes a rise in

corticosteroids which can, in turn, decrease IL1 production by macrophages.

IL1 has also be shown to be a potent inducer of neuronal differentiation

factors and instructive factors that can alter, for example, utilization of

neurotransmitter types in specific neurons (see below).

Enhancement of POMC gene expression and a differential release of different

pituitary hormones in vitro has been described also for IL2 , which

stimulates release of ACTH , Prolactin , and Thyrotropin while inhibiting

the basal release of Luteinizing hormone , follicle stimulating hormone ,

and Growth hormone . A possible feedback mechanism for processes mediated by

IL1 is suggested by the fact that IL1 induces T-cells to produce IL2

although IL2 has not yet been shown to act directly at the level of the

hypothalamus.

It has been shown that IL6 , which is produced also by pituitary cells, is

also a more potent secretagogue for ACTH than corticotropin-releasing

hormone in some systems. Intravenous injection of IL6 causes a

dose-dependent increase in plasma ACTH levels. As seen with IL1 this rise of

ACTH can be blocked by administration of antibodies directed against

corticotropin-releasing hormone. Again, regulatory feedback loops are

suggested by the inhibition of IL6 production by dexamethasone.

TNF-alpha is produced by astrocytes and probably also by pituitary cells. It

stimulates adrenal and inhibits thyroid functions. All interferons (see: IFN

) have been shown to act within the hypothalamic-pituitary-adrenal axis.

IFN-alpha has been observed to cause a rise in Growth hormone , ACTH , and

cortisol in some systems while lowering levels of Growth hormone and

Thyrotropin in others. IFN-gamma has been shown to inhibit corticostatin

releasing hormone-induced ACTH secretion by cultured pituitary cells.

A protein that inhibits the proliferation of a myeloid cell line and induces

differentiation of macrophage characteristics, LIF (leukemia inhibitory

factor ), has been shown to be identical with the cholinergic

differentiation factor CDF , a protein that influences a fundamental aspect

of neuronal identity, i. e. neurotransmitter and neuropeptide phenotype.

These findings suggest analogies with the control of phenotypic decisions

made in the hematopoietic system (see: Hematopoiesis ) in which a plethora

of chemically diverse Hematopoietins induce distinct but partially

overlapping differentiation responses. Similarly, ARIA (acetylcholine

receptor inducing activity ; Heregulin ) and its receptor, the neu oncogene

, have been implicated in Schwann cell functions and adenocarcinoma

pathology and may thus be components of regulatory circuits linking

neuroimmune processes with tumor physiology. Neuroendocrine and neural

factors are known to regulate hematopoiesis by influencing the bone marrow

microenvironment (Maestroni).

One of the interferons (see: IFN ), IFN-beta , has been found to be an

unconditioned stimulus signal responsible for the bidirectional

communication which links the central nervous system with the immune system

(augmentation of natural killer cell activity).

The brain and other neuronal tissues have been shown to be the most abundant

sources of bFGF . bFGF has important functions in the development and

maintenance of the nervous system, stimulating glial cells to proliferate

and having a variety of trophic effects on neurons. Its synthesis is

upregulated, among other things, by IL1 , TNF-alpha , and TGF-beta . In the

pituitary bFGF regulates the secretion of Thyrotropin and Prolactin .

Neuroimmunoactive factors thus are components of a complex circuitry of

positive and negative signals and (auto)regulatory feedback and feedforward

loops controlling neuroimmune functions and maintaining homeostasis by

allowing cross-talk between the two systems. The complexity of the

neuroimmune network is illustrated by the number and variety of hormonal and

neural actions of individual modulatory factors and the observations that

endocrine target cells for these factors themselves are able to produce

them. These mediators can act coordinately on the same cells or sequentially

on different cells, they can induce or repress the synthesis of cytokines

and/or their receptors or receptor subunits, and generally alter patterns of

Gene expression following interaction with their receptors. Many of these

factors share common elements, including common receptor subunits and/or

common intracellular signalling molecules (see, for example: gp130 ; SOCS ,

PIAS ).

It has been suggested that the immune system possesses sensory functions

(Blalock). Leukocytes are capable of identifying stimuli/stressor signals

that are not recognizable by the central and peripheral nervous system (see

also: Acute phase reaction ). Cytokine receptors on cells of the immune and

nervous system seem to play a sensory and regulatory role enabling the brain

to monitor the progress of immune responses. The brain may be able also to

modulate immune responses, for example, by using its neuroimmunomodulatory

factors to alter the functional capacities of immune cells. Some of these

factors may be able also to induce subtle shifts in immune cell populations

that secrete immunomodulating cytokines (see also: T-helper cells) into the

conditioned medium . It seems clear now that the nervous system and the

immune system are not independent systems but are closely associated and use

the same language in a shared molecular network of cytokines , hormones,

neurotransmitters and also intracellular signaling substrates. The cellular,

neurochemical, and immunological properties of the brain or at least parts

of its structure suggest that the brain itself functions as an immune organ

(Galoyan). In addition, a variety of neuromediators and neurohormones,

including the corresponding receptors, have been shown to be expressed also

by epidermal and dermal cells and also by immune cells transiently present

in the skin, suggesting the existence of a neuroimmunocutaneous system

(Misery et al).

Many of these observations now help to clarify phenomena that have long been

described but have had no physiological explanation. They have caused

already a radical revision of many long-established and widely accepted

postulates and will continue to do so. In humans, a mild stimulation of the

primary host defense has negative effects on emotional and memory functions,

which are probably caused by the release of cytokines (Reichenberg et al;

Martignoni et al). The activity of many cytokines is modulated by various

stimuli, including trauma and infection. Physical activity also affects

local and systemic production of cytokines at different levels, with

cytokine responses often showing similarity with those observed in response

to trauma, infection, and inflammation (Moldoveanu et al).

The complexity of the system suggests that there will be no single unifying

role of one individual factor in nervous and immune system interactions. In

fact, the plethora of factors determining the final result of interactions

between different systems has precipitated a certain crisis of theoretical

neurobiology because it has become increasingly more difficult to formulate

general theoretical concepts and coherent views of brain functions within

the framework of other organ systems. We have begun to understand how

disruptions of feedback regulation between neuroendocrine and immune systems

contribute to the development of neuropsychiatric and immunologic disorders.

Eventually, the elucidation of the mechanisms underlying communication

systems within the body will help to integrate such diverse and seemingly

incompatible fields as psychology, psychopathology, psychosomatic medicine

Ayurveda (a comprehensive Indian system of medicine based on Hindu

philosophy), and physiology (Dube et al; Biondi et al).

date of last revision: January 2002

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