Advances in Neuroimmune Biology

After a long period of specialization in science it has been gradually realized that the time has come for coordination, integration and interpretation in Biological Sciences. Advances in Neuroimmune Biology (ANIB) will fulfill, in part, this objective. ANIB deals with the immune-neuroendocrine circuitry as it integrates, coordinates and regulates all biological events in animals and men. This constitutes the Neuroimmune Super system (NISS), the ultimate central regulator of biological processes in animals. Homeostasis is discussed with respect to immune function. The role of the autonomic nervous system, immunological memory, Pavlovian conditioning of immunity, immune deficiency, stress, mast cells and neuroinflammation are included. Therapeutical application of the new knowledge is also considered.

The immune system of higher animals comprised of two parts: Innate – or Natural – (INIM-NIM) and Adaptive Immunity (ADIM). Innate resistance includes physical barriers (e.g. skin, cornea, mucous membranes, the blood-brain barrier - BBB) chemical defense (HCl in the stomach, bile acids in the intestines, enzyme based protection) and Species Specific Resistance (SSR) to viruses and other pathogens. SSR may occur because of the lack of proper receptors for the pathogen to establish itself in the resistant animal species. Therefore, SSR is a phylogenetically determined property of various animal species. Innate immunity includes polyspecifc immune mechanisms with germ line gene based antigen receptors (INIR/NIR) that recognize phylogenetically preserved, highly cross-reactive (homologous) epitopes, or homotopes. Because both the antigen receptors (e.g. toll-like receptors - TLR) and the homotopes (e.g., lipid A in bacterial lipopolysaccharide - LPS) are constant, and fully differentiated immune (monocyte/macrophages and other leucocytes) and somatic cells express TLR, the entire organism is capable of responding instantaneously to infection or injury. Innate phagocytes, primarily monocyte/macrophages, support the development of adaptive immunity, by presenting antigen and by contributing cytokines for cell activation. If natural immunity is depressed, ADIM will be deficient. The natural immune system provides continuous protection for the host animals or men against the effects of stress, treatment of cytostatic drugs, septic shock, infectious diseases, and numerous other noxious agents. Neuroendocrine, nutritional and environmental factors regulate natural immunity. The maintenance of good NIM defense is most important in modern medicine. Radiodetoxified endotoxin (RD-LPS) stimulates NIM, and activates the bone marrow. Animal experiments and human studies showed that RD-LPS is a promising preparation for the elevation of natural immunity. RD-LPS is a potent immunological adjuvant in the case of inactivated virus vaccines (e.g. influenza).

The present review deals with the reactions taking place in the central nervous system after antigen administration. The activation of brain cells and the involvement of various neurotransmitter systems after applying various antigens are described. The possible pathways of signal transduction from immune cells to the central nervous system (CNS) are analyzed. The knowledge acquired about the activation pattern of different neuron populations could help to clarify the mechanisms of immune-to-brain communication.

It has been realized for some time that exposure of the developing neonate from conception through birth to (toxic) environmental agents can affect the subsequent health and well-being of the offspring. While organogenesis (the first eight weeks of human gestation) is recognized to be a highly susceptible period for the induction of malformations, the fetal/neonatal developmental phases are now acknowledged to be just as sensitive for many well-documented developmental deficits, amongst which are immune-related disorders. In addition, developing predominantly from studies of maternal stress during pregnancy, a growing body of literature now exists to show that changes in the neurohormonal milieu of both mother/infant during pregnancy and weaning can change immune potential of the offspring. Perhaps even more provocative, there is data to suggest that immune changes in the pregnant mother can in turn modify behavior in offspring. The review below provides a framework for consideration of many of the factors contributing to such processes, and their possible mechanism(s) of action.

Microglia, the immune cells of the central nervous system (CNS), are busy and vigilant housekeepers in the adult brain. The main candidate as a chemoattractant for microglia at damaged site is adenosine triphosphate (ATP). However, many other substances can induce immediate change of microglia. Some neuropeptides such as angiotensin II, bradykinin (BK), endothelin, galanin (GAL), and neurotensin are also chemoattractants for microglia. Among them, BK increased microglial migration via B₁ receptor with different mechanism from that of ATP. BK-induced migration was controlled by a G_i/o protein-independent pathway, while ATP-induced migration was via a G_i/o protein-dependent and also a mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK)-dependent pathway. On the other hand, GAL is reported to have a similar signal cascade as that of BK, though only part of the signaling was similar to that of BK-induced migration. For example, BK activates reverse-mode Na⁺/Ca²⁺ exchange allowing extracllular Ca²⁺ influx, while GAL induces intracellular Ca²⁺ mobilization via increasing inositol-1,4,5-trisphosphate. In addition, GAL activates MAPK/ERK-dependent signaling but BK did not. These results suggest that chemoattractants for immune cells in the brain including ATP and each peptide may have distinct role under both physiological and pathophysiological conditions.

The sympathetic nervous system is one of the multiple channels that communicate between brain and immune system. In the brain-immune interactions, cytokines produced in the periphery and brain during inflammatory as well as non-inflammatory stress play important roles as signal molecules. For example, central administration of interleukin-1β (IL-1β) and interferon-α (IFN-α) suppresses splenic natural killer (NK) cell activity in rats, which is mediated by, at least in part, the sympathetic innervations to the spleen. The central administration of IL-1β and IFN-α increases splenic sympathetic nerve activity, and an electrical stimulation of the nerve results in a suppression of splenic NK cell activity through a β-adrenergic receptor-mediated process. Furthermore, it has been shown (1) that immobilization (IMB) stress produces an elevation of extracellular concentration of noradrenaline in the spleen, (2) that the IMB-induced reduction of splenic NK activity is partially blocked by splenic denervation, (3) that pretreatment with central injection of neutralizing anti-IL-1β antibody attenuates the IMB-induced NK suppression, and (4) that hypothalamic IL-1β and IFN-α mRNA is increased after 1 hr IMB. These findings, taken together, suggest that IL-1β and IFN-α produced in the brain may be key substances mediating the IMB stress-induced immunosuppression.

Immune cells (lymphocytes, monocytes and macrophages, granulocytes and mast cells) produce numerous hormones, store and secrete them. In addition these cells have receptors for hormones and signal transduction pathways. These functions are under the control of the central nervous system (neuro-immune regulation), and there is a dynamic multi-directional interaction within the neuroimmune circuitry. Considering the high amount of immune cells, their hormone production can rival to that of the “classical” endocrine glands. However, in contrast to the endocrine glands, which are in general mono-producers, 1.) the immune cells are poly-producers, the same cell can produce different hormones at the same time and also poly-receivers, having receptors for different hormones, 2.) immune cells are mobile and can transport the hormones in a packaged form, even though they are able to synthesize and secrete the hormones locally. 3.) immune cells have the capacity to recognize the site where their hormones are needed. It is proposed that under the control of the nervous system immune cells produce hormones for general regulation, for intrasystem regulation and for remote, local regulation. Hormone production is gender dependent. Receptors are affected by hormonal imprinting during the critical developmental periods of target cells and the imprinting influences also the hormone synthesis of immune cells for life. Some hormones can be demonstrated in the nucleus of mast cells, however their function is not known. The knock-out of one hormone's gene disturbs hormone balance in immune cells. The importance of the packed-transport hypothesis is discussed.

Although NK cells are innate lymphocytes and have long been well known for their cytotoxic actions against tumor and virus infected cells, accumulating data indicate that they play an important immunoregulatory role in the pathogenesis of autoimmune diseases, such as MS and EAE. Especially, in recent years growing body of evidence suggest that NK cells have the potential to eliminate harmful self-reactive T cells and act as modulator of adaptive immunity. Here we review the recent advances in the research of NK cells related to EAE and MS, including general properties of NK cells, NK cells and EAE, and NK cells and MS, with emphasis on the mechanism of NK cell regulatory roles in EAE and MS.

Participation of the pineal gland and melatonin in the innate immune response is part of a dynamic and intricate network that acts throughout the inflammatory response, integrating signaling pathways and regulatory processes at the molecular, cellular and organism levels. The pineal gland is a target for pathogen-associated molecular patterns and for inflammatory mediators, and melatonin, which may be produced by the pineal gland or by activated immune-competent cells, plays a role in modulating inflammatory responses. Nocturnal melatonin surge is suppressed at the beginning of an inflammatory response in order to allow a full mounting of an innate immune response at any hour of the day. Melatonin produced at the site of a lesion by activated immune-competent cells favors phagocytosis and reduces inflammatory reactions that could promote tissue lesion. Here, we discuss the mechanism underneath this crosstalk between the pineal gland and the innate immune response and extend the concept of an Immune-Pineal Axis.