 |
|
|
| Edited
by:
I. Berczi, Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada A. Szentivanyi, Department of Internal Medicine, College of Medicine, University of South Florida, Tampa, FL, USA Published
by: Elsevier Science
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| Description:
The book summarizes the current understanding of the Nervous - Endocrine and Immune systems with emphasis on shared mediators and receptors and functional interaction. In addition to the fundamental physiological and pathophysiological mechanisms, which are presented in detail, some clinically relevant subjects are also presented, such as inflammation, asthma and allergy, autoimmune disease, immunodeficiency and the acute phase response. A
comprehensive presentation of neuroimmune biology.
Audience: Neurologists, psychologists, psychiatrists, immunologists, endocrinologists, physiologists, practising clinicians, veterinarians, animal scientists. Contents: Foreword:
Preface:
Part
I: The nervous system, receptors, ligands and signal transduction
Acknowledgements. I.Introduction Introduction
History
The
discovery of immune neuroendocrine circuitry - A generation of progress.
II. The Nervous System - A historical perspective. Altered
effector responses.
Some
evolutionary morphoregulatory and functional aspects of the immune-neuroendocrine
circuitry.
Virus
associated immune and pharmacologic mechanisms in disorders of respiratory
and cutaneous atopy.
III. Receptors, ligands and signaling Adhesion
molecules
Immunoglobulins
Growth
and lactogenic hormones, insulin-like growth factor and insulin.
The
hypothalamus-pituitary-adrenal axis and opioid peptides.
The
hypothalamus-pituitary-thyroid axis.
Nerve
growth factror, leptin and neuropeptides.
Cytokines
and chemokines.
Steroid
hormones.
Regulatory
enzymes.
Part II; Neuroimmune Functiona and the Neuroimmune Regulatory Network IV. Neuroimmune function A. Physiology Immunocompetence
Antigen
presentation.
Immune
reactions.
The
hypothalamus-pituitary-adrenal (HPA) axis: A major mediator of the adaptive
responses to stress.
Immunoregulation
by innervation.
B. Pathophysiology Inflammation
in the airways.
Defensins:
antimicrobial peptides with a broad spectrum of biological activity.
The
acute phase response.
Autoimmune
disease.
Immunodeficiency
V. Immune-Neuroendocrine Circuitry The
immune-neuroendocrine circuitry.
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| (Article
used with permission, NIB 2003;3 pp281-299)
Immunocompetence ABSTRACT The evidence indicating that immune reactions, which are based on lymphocyte proliferation, are regulated by mechanisms that are involved in the growth control of all cells in higher animals is reviewed. Growth and lactogenic hormones (GLH) are required for the development and function of the immune system. It is suggested, that GLH deliver the first signal to cells, including lymphocytes, that prepares them for proliferation, differentiation and function. This signal is designated as the competence signal. It is required for lymphocyte growth and is obligatory for the maintenance of immunocompetence. The second group of signals, that control cell growth, is delivered by cell-to-cell and cell-to-matrix signaling and are designated as stromal or adherence signals. Adhesion molecules, tissue bound hormones, cytokines and matrix components mediate these signals. Within the immune system antigen presentation represents such a signal for which cell-to-cell interaction is obligatory. Adhesion molecules are fundamental to the organization of multi-cellular organisms and the signals delivered by them serve the basis of species, organ and tissue specific recognition. This recognition system has been perfected during evolution from self-recognition to individually specific antigen recognition. This system also plays a role in the elimination of degenerated and neoplastic cells. Cell-to-cell signaling has a dominant power over other signals to commit the cell to proliferation. The cell cycle is then completed after the delivery of cytokine signals. Cytokines are tissue hormones which are usually, but not always, secreted by the same cells that deliver the second signal. The nature and combination of these three groups of signals will determine the fate of each cell, which may be survival, proliferation, differentiation and function or alternately apoptosis. Hormones and neurotransmitters, that alter signal delivery, modulate further this basic pattern of animal cell growth. It is reasonable to conclude on the basis of current evidence that GLH maintain immunocompetence, which enables the immune system to respond to specific antigenic and mitogenic stimuli. 1. INTRODUCTION It has been known over a hundred years by now, since the pioneering experiments of Cushing and Ashner [1,2], that pituitary growth hormone (GH) is capable of stimulating the proportional growth of higher animals and man. Excess production of growth hormone will lead to gigantism or to acromegaly, whereas the deficiency of GH secretion will result in pituitary dwarfism. The serum level of GH is highest in infancy and early childhood and gradually declines with ageing. Elderly people may show GH deficiency. For a long time body growth was solely attributed to the secretion of GH and its decline with ageing was regarded as a sign for lack of demand for this hormone during adult life. However, recent observations indicate that all tissues bare receptors for GH and/or for prolactin (PRL), which may be regarded as a modified growth hormone. Under proper experimental conditions the biological activity of GH on adult tissues and cells is easily demonstrated [3,4]. 2. GROWTH AND LACTOGENIC HORMONES AND CELL GROWTH. Growth hormone stimulates the production of insulin-like growth factor I (IGF-I) in the liver and in other tissues and organs, including the immune system. IGF-I is a peptide hormone with structural relation to insulin and with crossreactivity at the receptor level. Insulin and IGF-I do not only bind to each other's receptor, but also mutually regulate receptor levels, which is proportional to their ability to occupy that particular receptor. Prolactin also has the capacity to stimulate IGF-I in the liver and in other tissues, which has been named by Nicoll and coworkers as synlactin.With the discovery of IGF many investigators assumed that growth hormone action is really mediated by IGF. This view is still held by a significant proportion of investigators [4-10]. Studies on the growth of cultured mammalian cell lines led to the discovery that serum derived growth factors were necessary. In each case at least two growth promoting hormones were required for the completion of the mitotic cell cycle. The first hormone (e.g. platelet derived growth factor, epidermal growth factor, or fibroblast growth factor) rendered the cells competent for proliferation, but cell division would not take place, unless the cells were stimulated also with a second hormone (e.g. IGF or insulin), which act in the late G1 phase. After the second stimulus the cells will progress in the cell cycle and mitosis takes place. Exposure to the competence hormone is mandatory for the cell in order to acquire the ability to respond to the progression growth factor in this model [11]. These observations led to a two signal hypothesis known as the competence-progression model of cell proliferation (Fig. 1).
Figure. 1 Growth factors and the cell cycle. A similar two signal hypothesis has been proposed for GH action on the growth of long bones (Figure 2). According to this model the biological effect of GH is necessary for target cell activation. One important aspect of GH action is the stimulation of IGF-I in the responding cells. In turn, the locally induced IGF-I will act as an autocrine and paracrine growth factor, completing the mitogenic cycle in GH targets [12]. By now this model of GH action is supported by a compelling body of experimental evidence. It is also apparent that there are other hormones/cytokines that are capable of inducing IGF-I in certain target cells. This implies that such hormones/cytokines also activate their targets similarly to that of GH, in a manner analogous to the competence-progression model of cell proliferation. Such hormones are IL-3, GM-CSF and TGF-beta1 in the bone marrow and estradiol for the mammary gland [13-16]. Thus the tropic effect of these hormones on their specific target organs is also based on two signals, analogous to the competence-progression model of cell proliferation.
Figure 2. A hypothetical model for the stimulatiory effect of GH on longitudinal bone growth. The PRL-dependent Nb2 rat T cell lymphoma cell line obeys the rules of the competence - progression model for cell proliferation. It responds to serum factors (IGF-I) only after being primed by PRL. Most importantly, the magnitude of the mitogenic response is directly proportional to the concentration of PRL used for priming (Fig. 3) [17]. In vivo observations in hypophysectomysed (Hypox) rats revealed that organ weight, DNA and RNA synthesis and cell proliferation in the bone marrow, thymus and spleen (Figs. 4 and 5) and immune reactivity require the presence of pituitary GH or PRL . These experiments show that lymphocyte proliferation in primary and secondary lymphoid tissue and immunocompetence are dependent on pituitary GLH. Redundancy was also demonstrated as either PRL or GH was sufficient to restore the immune system. Placental lactogen was also capable of restoration [18]. Like GH, PRL is also a pleiotrpic hormone with multiple targets. On the basis that GH is able to cause the proportional growth of the entire organism one may conclude that the entire body is a target for GH. PRL seems to affect most tissues except to stimulate body growth, though a limited growth promotion is present. Pituitary GLH induces IGF-I within the immune system as observed by several investigatotrs. Both GH and PRL was capable of inducing IGF-I within the thymus and spleen of Hypox rats (Fig. 6). This furnishes additional evidence for the ability of these hormones as growth promoters of the immune system according to the competence-progression model of cell proliferation [4,19-21].
There is evidence to indicate that GLH are essential for the maintenance
of vital bodily functions [22,23]. In mammals the fetus is exposed
to high levels of placental GLH as they are present in the amniotic fluid
in high concentrations [24]. During embryonic life placental GLH
play a fundamental role in the growth and development of the fetus and
of the immune system and pituitary hormones are not required as fetuses
with the congenital lack of the pituitry gland develop normally in utero
[25]. During postnatal life the pituitary gland assumes the role
of growth control in the organism [26]. Bone marrow and thymus function
and the maintenance of immunocompetence during postnatal life depend entirely
on pituitary GLH [4]. On this basis it has been proposed that GH
and PRL are the hormones of immunocompetence [27,28].
Figure
3. Enhancement of oPRL bioactivity in increasing concentrations of
rheumatoid and normal human sera.
Figure
4. The effect of hypohysectomy and additional treatment with pituitary
hormones on relative weights, DNA and RNA synthesis of thymus and spleen
of rats.
Figure
5. Nucleic acid synthesis in the bone marrow is dependent on growth hormone
and/or prolactin.
Figure
6. Insulin like growth factor-I mRNA expression in the thymus of
hypohysectomised rats after treatment with ovine growth hormone or prolactin.
3. GROWTH SIGNALING IN THE IMMUNE SYSTEM. Talmage made theoretical calculations and concluded that the mammalian genome could not possibly accommodate the enormous multitude of immunological specificity displayed by antibodies [29]. On this basis Burnet proposed the clonal selection theory [30]. This theory postulated that minor groups of lymphocytes (clones) are generated through somatic mutation. After the self-reactive clones had been eliminated in the thymus, the remaining clones will recognise and respond to specific antigenic determinants (epitopes) of a foreign antigen by proliferation (clonal expansion). The cells of the expanded clone will then differentiate into plasma cells and produce specific antibodies [30]. An overwhelming body of experimental evidence, including the molecular structure of antigen receptors of lymphocytes, supports the validity of this hypothesis [31]. It is now of general consensus, that lymphocyte growth is a prerequisite of the adaptive immune response. If lymphocytes are unable to grow, immune reactions are not possible. Since the seminal work of Landsteiner [32] it has been recognized that small molecules representing called haptens are not immunogenic, but become immunogenic if coupled covalently to macromolecules, called carriers, that express multiple epitopes. On the basis of this long recognized fact, Bretcher and Cohn [34] proposed in 1970 the two signal model for the initiation of the immune response (Figure 7). These authors argued that the first signal is delivered by the antigen and the second signal by a carrier-specific antibody, although they acknowledge that it could come from T lymphocytes that stimulate antibody production by B cells. Meanwhile Claman and co-workers discovered that the collaboration of thymus derived (T) and bone marrow derived (B) lymphocytes is necessary for an antibody response to occur (33). This led to the “bridging” hypothesis of Mitchison, whereby the contact interaction of T and B lymphocytes was necessary for an antibody response to occur (Figure 8) [35,36].
Figure
7. One and two signal theories of the immune response.
Today it is clear that the adherence interaction of an antigen presenting cell (APC) with antigen specific T lymphocytes is required for the initiation of an immune response. Initially the APC interacts with helper T cells and later on the helper T cell with B cells (antibody response) or immature antigen sensitive T cells (cell mediated immunity). This adherence interaction stimulates the secretion of cytokines from helper T lympocytes, which function as growth factors. The antigen signal is modified by additional “co-stimulatory” and inhibitory signals, which are also delivered by adhesion molecules [37,38]. The cytokine signal completes the mitogenic stimulus and enables the immature cell to proliferate (clonal expansion). Multiple cytokines are available to deliver this signal, which varies according to the type and stage of the immune response [31, 37,38].
Figure
8. The bridge hypothesis in its later form.
4. THE THREE-SIGNAL HYPOTHESIS
Figure
9. Growth control in higher animals.
If one carefully examines the theories for cell growth and for the initiation of an immune response, in fact they define three groups of signals: (i) the competence signal, (ii) stromal or adherence signals, and (iii) cytokine signals (Fig. 9). The model of Bretcher and Cohn [34], which was constructed on the basis of in vivo experiments ignores the first signal which is delivered to lymphocytes and antigen presenting cells by GLH. This signal was always available in the animal and immunocompetent lymphocytes could produce additional GLH as required for the paracrine-autocrine support of rapid lymphocyte proliferation. The situation was similar during in vitro experiments on cell collaboration. From the very beginning it was well recognized that fetal calf serum, which again contains GLH, was necessary in order to initiate immune reactions. Once the lymphocytes got activated they could produce their own GLH. But at that time nobody thought that this should be the case, as hormones were considered to fall outside of immunoregulators. The antigen signal is in actual fact an adherence signal as T cells must recognize antigen in the context of self-MHC cell surface molecules. The TCR/CD3 complex, MHC-I and -II, and the CD4/CD8 accessory molecules and immunoglobulin (Ig) itself are all members of the immunoglobulin family of adhesion molecules [37]. The competence progression model for cell proliferation ignores the necessity for cell-to-cell contact in the regulation of proliferation. This is known in the old literature as "contact inhibition". Rapidly growing cells in culture lose their sensitivity to contact inhibition, and often generate tumors if injected into animals. Some of the genes controlled by adhesion molecules are classified as "tumor suppressor" genes that are capable of inhibiting cell proliferation [39-41]. Hence, the competence progression model does identify signal number 1 and signal number 3 in our model for the growth of animal cells. 4.1. The significance of GLH in signalling. Mice with targeted gene disruption (knockout) that lack either PRL or its receptor (PRLR), or GHR or IGF-I are immunocompetent. It was proposed, therefore, that these hormones are not obligate immunoregulators, but rather, affect immune reactions as anabolic and stress modulating agents [42-44]. In actual fact the data obtained in knockout mice is a powerful confirmation of our original observations that GLH show redundancy in the maintenance of immunocompetence. Current evidence indicates the IGF-I may be substituted for in the immune system by IGF-II or insulin. Clearly, immune function, as many other functions in the body, are maintained by multiple hormones and cytokines that show overlap and redundancy [4,45].
Functional overlap and redundancy is the rule for type I cytokines (and
for other cytokines as well) in the immune system. The receptor for type
I cytokines consists of a ligand specific chain and of a shared signal
transducing chain. For instance in the first group, where IL-2, -4, -7,
-9 and -15 belong, there is a common gamma chain ( Prolactin and growth hormone do not share receptor chains with any of the above cytokines. Human GH and other primate GH are known to act on the PRL receptors and to exert lactogenic activity in many species, which indicates functional overlap within GLH hormones. The major signal transduction pathway, which involves the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) nuclear regulatory factors, is shared between cytokines and growth and lactogenic hormones. STAT knockout mice show severe developmental and immune deficiencies [48,49]. This emphasizes the significance of this signal transduction pathway in development and immune function.
Clevenger and co-workers produced data indicating that PRL is capable of
nuclear signalling [50]. Similarly, it has been proposed that IGF binding
proteins are capable of nuclear signalling [51]. The possibility
of nuclear signalling by peptide hormones is not yet generally accepted.
However, if correct, such a mechanism for PRL and IGF-IBP would mean that
these molecules are capable of bypassing the extensive regulatory mechanisms
of signal transduction by membrane bound receptors. One may visualize that
for a hormone, which acts as a survival factor for cells and indeed for
the entire organism, nuclear signalling would be of major advantage or
perhaps, even a necessity.
Lymphocytes are capable of producing both PRL and GH. There is evidence to suggest that lymphocyte-derived GLH is capable of paracrine and autocrine growth stimulation [52,53]. It is suggested that during immune reactions, such locally generated GLH is required to support the rapid proliferation of lymphocytes in the interest of promotion of an effective immune response. This situation has parallels with the development of the mammalian embryo, which gradually grows independent of the pituitary hormones and relies mostly if not exclusively on placental lactogenic hormones. Moreover, placental GLH actually have a major influence on maternal metabolism, which serves the interest of the fetus [54]. Naïve lymphocytes are in a quiescent state and do not synthesize nor do they respond to cytokines [55]. It is suggested that these cells are dependent on pituitary GLH and on IGF-I for survival in lymphoid organs and rapidly undergo apoptosis in Hypox animals. On the other hand memory cells are metabolically active and remain functional in Hypox animals. Memory T lymphocytes are glucocrticoid resistant and produce cytokines readily after stimulation with the spcific anigen. Memory cells are capable of recruting naïve antigen sensitive T cells [55]. The lymphocyte derived PRL gene was shown to have placental promoting sequences [56 ]. If such a gene becomes activated in memory cells they would be able to syntehesize PRL for autocrine stimulation in a pituitary independent manner and to assure survival even in hypohysectomized animals. The glucocrticoid resistance of memory cells would also be explained as PRL is an antagonis of glucocorticoids. This possibility remains to be established. 4.2 The importance of cell-to-cell signalling. Self recognition has been thought for a long time to be the exsclusive feature of the immune system. However, self recognition is easily demostrable in the most primitive multi-cellular animals, sponges. Sponges also control cell proliferation and differentiation. They are capable of rejection of grafts from another species of sponges, and show self defence against infection, which is mediated by phagocytic cells. One may easily disintegrate sponges by passing them through a screen. When brought together, the cells are capable of re-aggregation and regeneration to form a functional sponge unit. These facts demonstrate the ability of these seemingly loosely aggregated cells to behave in a highly coordinated fashion. Sponge cells will grow and differentiate into functional cells according to their topographical localisation [57]. Similar observations were made in higher animals. For instance, if cells from different anlages of the amphibian embryo are mixed, they will sort out in a pattern that resembles the initial organization of embryonic tissue. Such aggregation experiments may be performed also with embryonic cells from birds or mammals. Cell adhesion molecules present in embryonic tissue mediate re-aggregation and cell motility and play a key role in morphogenesis [58,59]. Embryonic morphogenesis is governed by cell-to-cell contact and by diffusible mediators. Adhesion molecules are non-diffusible and for this reason are capable of signalling single cells very specifically. It is very clear from embryonic development and from antigen-induced lymphocyte proliferation that adhesion signals are dominant over growth factor signalling. This is an ablsolute requirement for morphogenesis, which is based on the positional relationship of cells/tissues to each other. In general, adherence signals determine, according to the local tissue/organ requirements, whether or not the cell is going to divide, differentiate and take up a function, or simply be on standby (survive), or perhaps be committed to the pathway of programmed cell death (apoptosis) [28,60]. At the cellular level, this means that only certain cells will divide at any given time while others go into differentiation and take up the appropriate function according to their location in the body, or be on standby (stem cells, as well as differentiated cells) or may even be eliminated. Thus, the general growth stimulus is modified according to local needs so that the morphological and functional integrity of the organism is maintained at all times. GH is well recognized as a hormone capable of stimulating the proportional growth of all tissues and organs. This dominance of local regulatory mechanisms, that also include tissue bound hormones and cytokines, over the systemic (GLH) signals assures the development of a fully functional animal or human being. Injured nerve cells in the CNS can be reinduced to grow axons and establish functional connections if exposed to non-neural elements of the peripheral nervous system [61]. This illustrates very well that even in adult tissues that lost their capacity to grow stromal adherence signals are capable of inducing growth and regeneration. Plants show a remarkable morphological and functional differentiation. Some proteins extracted from plants and collectively named lectins [62] have the capacity to activate animal cells, especially lymphoid cells for proliferation and function, including immunoglobulin secretion, cytotoxicity, helper or suppressor activity [38]. Therefore, plant lectins function as regulatory molecules on animal cells and probably fulfil similar functions in the plants as well. Animal tissues also contain lectin-like molecules [62]. Adherence signals mediate positional regulation, which is species-, organ- or tissue-specific, and in the case of MHC and antigen receptor molecules, individually specific. The antigen receptor also shows epitope specificity. The antigen receptors of B and T lymphocytes, MHC antigens, CD4 and CD8, some receptors of natural killer cells and numerous other cell bound molecules belong to the immunoglobulin family of adhesion molecules. Both activating and inhibitory receptors are found in this group that carry ITAM (immunorecptor tyrosine-based activation motif) and ITIM inhibitiory motifs respectively (Figure 10, 11). Receptors with ITIM promote tyrosine phosphorylation and are stimulatory. Receptors with ITIM dephosphorylate tyrosine residues and are inhibitory. During lymphocyte activation stimulatory and inhibitory receptors co-aggregate (capping) and the result will depend on the ratio of enzymatic phosphorylation/dephosphorylation leading to stimulation/inhibiton, respctively [63,64]. This “higher order” of rceptor complexity may revolutionize our understanding of cell signaling. Suface receptors capable of initiating apoptosis, such as the Fas/Fas ligand, are also involved in regulation [38].
The restrictive power of cell-to-cell signaling is also fundamental to
the immune response. Clearly, an antigen specific lymphocyte clone must
not proliferate unless it is triggered by the specific antigenic epitope
in the context of self-MHC molecules. Without this restriction antigen-specific
immune reactions would not be possible. Further, MHC recognition
by suppressor T lymphocytes and killer inhibitory receptors in natural
killer cells serves as safeguards against the killing of normal non-infected
and non-cancerous cells [38].
Figure
10. Selected examples of accessory molecules between CD4+ T cells and antigen
presenting cells.
Figure
11. Capping of stimulatory and inhibitory receptors prior to T and NK cell
activation.
4.3 Cytokine signalling. bone marrow cells change their hemopoietic growth factor requirement as they go through the various differentiation pathways [65-67]. Cell-to-cell interaction between stromal cells and B cell precursors and IL-7 play an essential role in B lymphocyte development in the bone marrow. The thymic microenvironment is essential for normal T cell development. Here MHC-T cell receptor interactions and a special cytokine and neuroendocrine milieu regulate T cell maturation [38, 68-71]. During adaptive immune responses the cytokine requirement for the growth and differentiation of mature T and B lymphocytes is also subject to change according to the type and/or phase of the immune reaction elicited [31,37,38]. Therefore, cytokines do not only complete the signalling process for cell proliferation, but also appear to play a role in the determination of the type of effector cells that are generated during the proliferative response. Cytokine signals are usually, but not always, delivered by locally generated mediators. These signals antagonize apoptosis and complete the positional signalling cycle for growth, differentiaton, functional activation, etc. Insulin-like growth factors are both systemic and locally generated and insulin is a systemic hormone. As systemic mediators, these hormones deliver third signals to all cells in the body. The cells affected may be in an inactive quiescent state incapable of synthesis and circulating IGF and INS enable such quiescent cells to metabolise and survive. It was suggested that small naïve lymphocytes survive this way. IGF-I is also produced readily in tissues after GH/PRL stimulation as a cytokine and is able to complete the growth cycle in any tissue or cell. Both GH and PRL stimulate IGF-I in a variety of target cells (including T, B cells and macrophages) and thus generate signal number 1 and number 3 for cell proliferation. Moreover, GH itself can also exert an insulin-like action. However, given the heterogeneity of GLH and of their receptors, these hormones may be capable of delivering a number of signals other than the competence signal [3, 4, 45, 72, 73]. A detailed discussion of these questions is beyond the scope of this chapter. 4.4 Signal regulation and signal modulation Thyroid hormones, glucocorticoids, sex hormones and vitamin D regulate immune reactions via controlling nuclear transcription processes. These steroid hormones may mediate activation, inhibition and apoptosis within the immune system. This regulation is fundamental for normal immune function and for the adaptability of immune system to reproduction and for protection against stressful insults and of various other pathological processes. These hormones may be designated as nuclear signal regulators [71,73,74]. Cathecolamines regulate cyclic AMP, GMP and calcium influx. A number of other mediators, including opioid peptides, act through G-proptein linked adenylate cyclase receptors as well. Because Ca2+ is needed for cellular activation and phosphorylation is a fundamental mechanism of signal transduction by membrane bound receptors, these mediators are designated as signal modulators in immune activation and in cellular activation in general [73,75]. 5. CONCLUSIONS Lymphocyte growth obeys the general rules of growth regulation of the entire organism. In primitve multi-cellular animals, like the sponge, cell-to-cell recognition and communication is the basis of organization, and little is known about the role of soluble mediators. However, in embryos of higher animals soluble mediators are clearly important, which are necessary for cell growth and differentiation, which must fulfil the functional requirements posed by the position of a given cell in the body. During evolution and during embryonic development growth control is gradually taken over by the pituitary gland. In mammals this happens abruptly at paturition, when pituitary GH assumes the regulation of body growth and PRL joins in as a similar regulator, but with a very limited ability to promote body growth. The adaptive immune response is based on the recognition of MHC antigens presenting either self-related or foreign epitopes to T lymphocytes. Both the MHC molecules and antigen receptors are adhesion molecules, that belong to the immunoglobulin family. Therefore, the fundamental mechanism of self recognition has been modified to recognize non-self in the context of self. According to recent consensus, suppressor T lymphocytes actively recognize self antigens and exert a local suppression in the various organs and tissues against the development of effector (autoimmune) cells. When the self-MHC presents a foreign epitope, no suppressor cells would be present against such modified self antigen and consequently effector T lymphocytes can freely develop against them [38]. Therefore, the immune system is an essential part of growth control in higher organisms, that exercises quality control, allowing the growth of normal cells and destroying cells which display an altered phenotype (e.g. infected, cancer and degenerated cells). This way the homeostasis of the immune system, which is based on the equilibrium of effector and suppressor mechanisms is closely linked to the homeostasis and growth control of the entire organism. The growth promoting effect of GH and PRL is no different on lymphocytes from the effect of other cells in the body. This control is based on cell activation, which in practical terms must mean to shift the signalling balance by adhesion molecules towards activation. This is followed up by the production of IGF-I, which completes the mitogenic signal. Quiescent cells (e.g. naïve lymphocytes) will not be activated, but use serum-derived IGF-I and insulin for survival. Immature lymphocytes and leukocytes also depend on pituitary GH and PRL for survival. Once differentiation is initiated, new adhesion molecules are induced (e.g. the antigen receptor) and new cytokines will take over the stimulation of cell growth. The production of autocrine PRL and GH by activated cells boosts further cell proliferation. Some cells that show resistance to hypophysectomy, such as memory cells, are likely to have their GLH genes under the control of the placental promoter. Cytokines, such as interleukin-2, IL-3 and GM-CSF may actually be able to boost the competence signal in lymphocytes and in the bone marrow, respectively. Thus during the evolution of an immune response the immune system may gradually escape pituitary control by the production of competence hormones locally, which are capable of maintaining immune function in an autonomous fashion. In spite of this autonomy of memory lymphocytes, the immune system requires the continuous production of naïve lymphocytes to fight novel pathogens that might occur in the environment. A stable output of leukocytes of the bone marrow is also required for the maintenance of immune function and health. These remain pituitary dependent. Interestingly, during acute phase responses the GH/PRL-IGF-I axis is suppressed, which results in a profound suppression of the thymus. However, the bone marrow is actually activated. Under these conditions IL-6 and insulin are elevated. Because bone marrow function is glucocorticoid resistant, these systemic growth promoting mediators are free to act and, combined with locally produced growth factors, could explain the intensive bone marrow activation. This remains to be validated. Steroid, thyroid hormones and vitamin D regulate nuclear signalling proteins and for this reason are required for normal immune function. These hormones are the ultimate regulators of signling in all cells in the body, including the immune system. Other hormones, cytokines and neuropeptides (e.g. cathecolamines, chemokines and opioid peptides) modulate signalling by the regulation of Ca2+ and of the rate of phosphorylation. It may be concluded on the basis of available evidence that immunocompetence depends on pituitary and lymphocyte-derived GLH. Without these hormones the immune system looses cellularity and the ability to respond to antigenic and mitogenic stimuli. Moreover, the entire organism ceases to function if no GLH is available and death will ensue within a short period of time. This hypothesis is supported by observations in animals and man. Therefore, it is postulated that GLH provide vitality not only to the immune system, but to the entire organism.
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c
).
Signal transduction is possible only if the two chains are crosslinked
by the specific cytokine. Knockout experiments in this sytem showed that
the elimiation of specific cytokines or their specific receptor chains
produced minimal if any abnormalities. However, knocking out the shared
(
