What is neuroimmunomodulation (NIM)?To understand neuroimmunomodulation (NIM), it is first necessary to place it within the context of biology as a whole: NIM is one of the sciences of adaptation. Biological organisms and systems all obey two fundamental integrated processes: regulation and adaptation. Regulation is the process by which physical and chemical mechanisms are actually established as "living things"; each mechanism is regulated within a set operating range. At this point in the history of biology, the great majority of physiological and pathophysiological (medical) knowledge concerns regulation. Adaptation is the process by which regulation is varied, in order, to adjust (reset) the parameters of the operating range of each regulated mechanism to cope with external changes outside its present set operating range. Adaptation could be described as, the extremely sensitive, "fine tuning" process, for the "gross tuning" process of regulation. Knowledge of the physiology and pathophysiology of adaptation is relatively new, compared to regulation. By Dr Jed Gallagher BSc MSc - CFSsocNIMr What
does this mean for CFS patients? - CFIDS Homepage
NIM is an interdisciplinary science of physiological adaptation. NIM is one of the four interdisciplinary sciences of physiological adaptation: enzymes (molecular biology-genetics), chronobiology (the timing and sequences of bio-molecular mechanisms), nutrition (ingested bio-adaptive chemicals and genes), and neuroimmunomodulation (4). NIM is the physiological mechanism through which organisms are able to adapt their internal regulation at the whole organism level. Such a "holistic" mechanism, making the organism greater than the sum of its parts (organs), has been the subject of non-scientific speculation for many thousands of years but has only recently been "scientifically" discovered. The existence of the NIM mechanism of physiological adaptation can now also be understood as the physiological basis/focus for complimentary medicine from all around the world. NIM is the scientific term for the interaction/communication between the cells of the three control systems of the human body: the nervous system, the endocrine system and the immune system. For this reason, NIM is sometimes spelt, neuroendocrineimmunomodulation, which is technically more complete, but for historical reasons, the shorter version became the common term. It is the interaction between the three systems which enables and provides the mechanism for whole organism physiological adaptation. The term neuroimmunomodulation was coined by Dr N H Spector in the 1970s to define a new field for accumulating research evidence of nervous-immune systems interactions going back to the early 1900s (5). He first used the term at the International Physiology Congresses in Paris (1974) and New Delhi (1977). The supportive response of his colleagues led to The NIM Newsletter in 1979; the first time the term NIM appeared in print (6,7). Shortly after, in the early 1980s, the term NIM began to appear in scientific journals (8,9). A number of international workshops were convened during the 1980s (10,11,12,13). The early 1900s discoveries of NIM were made by Russian and other eastern European scientists using the well-known "conditioning technique" of their mentor, Ivan Pavlov (1849-1936). These scientists demonstrated that various immune responses could be psychologically "conditioned" (adapted) to occur, through the nervous system, in the absence of any actual threat to the immune system (4). However, the first discovery that NIM also involved the endocrine system was made in the late 1930s when Hans Selye (1907-1982) discovered that any physical, chemical, biological, or even psychological, event always produced the same type of integrated nervous-endocrine-immune adaptive response, to some degree. He called these events, stressors, and the physiological response, the general adaptation syndrome (GAS), or "stress" response. In other words, a stressor of any one of the three systems produced a single, integrated, adaptive response of all three systems: the GAS. The GAS produces a large number of nervous, endocrine and immune-related symptoms (14). Also, Selye discovered three further workings of the GAS which have important consequences (15,16). Firstly, every disease, in fact, has its own, specific, GAS signature. So, although GAS is a non-specific mechanism (in that, all diseases activate it), each disease produces a particular variant of the GAS, and therefore, a "specific" GAS symptom-picture made up of non-specific GAS symptoms. Secondly, what Selye called "cross-resistance" develops, in which the specific adaptation of the GAS to a specific disease (stressor), means that the GAS is then unable to adapt effectively to a concurrent second disease (stressor). For this reason, animals which are already adapting to a disease (stressor) are disproportionately affected by, and unable to cope with, concurrent stressors compared to healthy animals. Thirdly, prolonged stressors can chronically activate the GAS (an extremely potent biochemical system), becoming plastic, and producing what Selye called "diseases of adaptation", also known as stress-related disorders. So, although the activation of the GAS was originally beneficial in the acute stressor period, if this stressor continued for too long a time, the adaptive symptoms themselves actually become irreversible, even after the original stressor is removed. Because of Selye's imprecise coining of the term "stress" (he intended to translate it as "strain"), stress became synonymous only with psychological stressors, at the expense of physical, chemical and biological stressors. Further, coupled with the early NIM experiments in psychological conditioning, this ultimately led to the field of psychoneuroimmunology (PNI). PNI encompasses such subjects as psychosomatics and emotional stress-related disorders. Unfortunately, this has led to some confusion between PNI and NIM and it is sometimes thought that PNI and NIM are the same thing. But PNI is actually a narrower field within the broader field of NIM in general - concerning the effect of psychology on NIM and vice versa. Only in the 1980s and 1990s has the full importance of the latest research on NIM, as a basic science, come to be understood - that NIM is the mechanism of physiological adaptation. And, that the nervous-endocrine-immune systems, continuously adapt the body to all physical and psychological events by modulating each others functions. NIM is the most important discovery for physiology since Walter B Cannon (1871-1945) defined the theoretical principle of "homeostasis" in the 1930s and, for medicine, since Louis Pasteur (1822-1895) discovered the pathogenicity of micro-organisms. Indeed, it has been a widespread misconception that theoretical physiology was complete with Cannon. Only recently has NIM received a related entry under "homeostasis" in the US National Library of Medicine's Medical Subject Headings (MESH) (17). Previously it had been thought that each of the three individual NIM systems were functionally discrete, operating independently, particularly the immune system. This meant that the nervous system was regulated by neurotransmitters which were synthesised only by cells of the nervous system, the endocrine system was regulated by hormones synthesised only by cells of the endocrine system, and the immune system was regulated by cytokines synthesised only by cells of the immune system. It has now been proved that the cells of each one of the three systems actually synthesise ligands (hormones, neurotransmitters, and cytokines) of the other two systems, so that it is the ligands from all three systems which regulate each system and not only the ligands from the cells of the individual system itself. Furthermore, and even more importantly, it has also now been proved that ligands which regulate one system can also modulate, and so adapt, the regulation of another system. For example, the cytokines synthesised by the cells of the immune system not only regulate the immune system but they modulate the rate of synthesis of neurotransmitters by the nervous system and so, by extension, the regulation of the nervous system. This modulation occurs between all three systems to some extent but by far the greatest modulatory effect is that of the cytokines of the immune system on the nervous and endocrine systems. Disorder of the immune system is at the root of most NIM conditions. This integration has led to the understanding that, in physiology and pathophysiology, it is whole organism integration which ultimately counts, not just particular regulatory pathways. For example, the following quote, concerning cytokines, also applies to neurotransmitters and hormones, and their interaction: "There is increasing awareness that informational content does not reside in individual cytokines, but, rather, in the overall pattern of regulatory molecules to which a cell is exposed. In other words, individual cytokines are more like letters in our alphabet than like ideograms in the Chinese language. It is undoubtedly the combination of cytokines that bears the total message in vivo." (18) This bi-directional interaction between all three systems has had a major impact on theoretical and applied physiology. What had previously been understood as three separate regulatory systems, giving three different medical specialities: neurology, endocrinology, and immunology, is now found to be a single regulatory system with three modulatory "functional zones" (19). It is the understanding of the regulatory and modulatory interactions of these three systems, as a single system, that is the focus of the new scientific discipline of NIM. These consequences are still a long way from being worked through and the facts are still only slowly being absorbed into medical science. It prompted the scientists of the newly-formed International Society for Neuroimmunomodulation (ISNIM) to say, in 1992, that: "Ten years ago, NIM was regarded by many conventional scientists as a kind of witchcraft. Today, it may be the fastest growing area of research in the biomedical sciences. Important clinical applications will not be far behind." (20) The first congress of the ISNIM was held in 1990 (20). Further congresses followed through the 1990s (21,22). The first issue of the official scientific journal of the ISNIM, Neuroimmunomodulation, was published in 1994 (23). The ISNIM Newsletter, following on from the NIM Newsletter first published by N H Spector, began in 1997 (24). The 4th congress of the ISNIM is scheduled for 30 September to 2 October 1999 at the Palazzo dei Congressi in Lugano, Switzerland. NIM scientists are now starting to realise that the large number of poorly understood, systemic, chronic medical conditions which still exist are actually better understood as NIM disorders, that is, as disorders of physiological adaptation: allergy, asthma, multiple chemical sensitivity syndrome, lupus, rheumatoid arthritis, cancer, depression, silicone implant syndrome, Persian Gulf War syndrome, fibromyalgia, and of course, chronic fatigue syndrome (25,26). All of these conditions involve some abnormality of the immune system which is now known to have a regulatory and modulatory feed-back to the nervous and endocrine systems. NIM disorders involve the effects of the "fine tuning" of adaptation on the "gross tuning" regulation; such effects can either disrupt regulation to a disproportionately large extent to produce such disorders or produce relatively disabling subclinical disorders. Importantly, this disruption generally only manifests itself during stress when the NIM system is asked to perform; it is not usually detectable from base-line levels. It is now clear that adaptive disorders cover a much wider spectrum of diseases than just Selye's diseases of adaptation; that these other NIM disorders are not just versions of stress-related disease. However, like Selye's diseases of adaptation they always involve both genetic and acquired components in each individual. There now appear to be two other categories of NIM disorder. Firstly, NIM disorders which involve a dysfunction of non-GAS NIM pathways, which, also, then activate the GAS. Secondly, dysfunction specifically of the GAS NIM pathways; systemic diseases which are diseases of the mechanism of the general adaptation syndrome (GAS) itself. It is the GAS which normally produces the general, non-specific, adaptive symptoms produced by all diseases and other stressors. These GAS symptoms can be understood as host adaptive responses. For this reason, these two proposed further categories of NIM disorder, all cause a large number of non-specific nervous, endocrine and immune GAS symptoms such as chronic pain, chronic fatigue, chronic bowel upsets, water imbalance, temperature imbalance, sleep problems, headaches, hypersensitivity of the senses, cognitive deficits, etc. What does this mean for CFS patients? - CFSsocNIMr All, or any part, of this artilce may be copied without permission, providing an acknowledgement is made to the CFSsocNIMr, including the website address, linked where applicable, and the copy is sent to the CFSsocNIMr. Current Research Articles: Health Site Index - Top of page - Permacult Project
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