Thymic T-cell tolerance of neuroendocrine functions: physiology and pathophysiology.

Intimate interactions between the two major systems of cell-to-cell communication, the neuroendocrine and immune systems, play a pivotal role in homeostasis and developmental biology. During phylogeny as well as during ontogeny, the molecular foundations of the neuroendocrine system emerge before the generation of diversity within the system of immune defenses. Before reacting against non-self infectious agents, the immune system has to be educated in order to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves anergizing mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T-cells. During ontogeny, T-cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, then bone marrow) enter the thymus and undergo a program of proliferation, T-cell receptor (TCR) gene rearrangement, maturation and selection. Intrathymic T-cell maturation proceeds through discrete stages that can be traced by analysis of their cluster differentiation (CD) surface antigens. It is well established that close interactions between thymocytes (pre-T-cells) and the thymic cellular environment are crucial both for T-cell development and for induction of central self-tolerance. Particular interest has focused on the ability of thymic stromal cells to synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors recapitulates at the molecular level the dual role of the thymus in T-cell negative and positive selection. Thymic precursors not only constitute a source of growth factors for cryptocrine signaling between thymic stromal cells and pre-T-cells, but are also processed in a way that leads to the presentation of self-antigens by (or in association with) thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens usually correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens does not seem to be restricted by MHC alleles. Through the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T-cell system might be educated to tolerate main hormone families. More and more recent experiments support the concept that a defect in thymic tolerogenic function is implicated as an important factor in the pathophysiology of autoimmunity.     

Neuroendocrine-immune (NEI) circuitry from neuron-glial interactions to function: Focus on gender and HPA-HPG interactions on early programming of the NEI system

Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life. Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function. Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity. The neuroendocrine-immune system is very sensitive to preperinatal experiences, including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities. We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level. In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators. Hence, neuron-glial signalling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers. The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized. The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.     

Cross-regulation in development of neuroendocrine and immune systems

Cross-regulatory effects of immune and neuroendocrine systems on their appearance and functioning occur during a whole life period. At different stages of ontogenesis, the functions of these systems are diverse. In perinatal ontogenesis hormones, neuropeptides and neurotransmitters control the processes of growth and differentiation of various embryo tissues, particularly lymphoid. In the postnatal period, their functions are mostly in homeostasis maintaining of the immune system in response to changes of the environment. Conversely, transmitters of the immune system, such as cytokines, whose synthesis is increased in inflammation, and thymic peptides, program the development of the neuroendocrine system of the embryo. The perinatal period is crucial for final appearance of these systems. Changes in one of the interacting systems, caused by negative environmental factors at this stage, usually provoke changes in other developing systems for a long period. Plasticity of physiological systems in perinatal development allows the organism to adapt to changed conditions. However, these changes can limit physiological functions in interacting systems and induce the appearance of various pathologies in postnatal life.     

Immune proteasomes in the developing rat thymus

The age dynamics of the content of the immune proteasome subunits LMP2 and LMP7 in rat thymus during prenatal and early postnatal ontogeny was studied. The LMP2 and LMP7 immune subunits were detected by Western blotting already by the 18th day of embryonic development, their amount increased to the 21st day to the level characteristic of the postnatal state. Double immunofluorescent labeling showed that in the thymus tissue the largest amount of LMP2 and LMP7 is localized in epithelial cells, whereas the level of their expression in thymocytes is lower. The results suggest that the establishment in thymus of selection processes, which depend on activity of immune proteasomes, can take place already in prenatal ontogeny. Analysis of age dynamics of the natural apoptosis level in thymocytes also favors this supposition. The presence of immune proteasomes in thymocytes during perinatal ontogeny suggests that, besides the antigen presentation, immunoproteasomes may possess other important functions.     

Neuroendocrine control in social relationships in non-human primates: Field based evidence

Primates maintain a variety of social relationships and these can have fitness consequences. Research has established that different types of social relationships are unpinned by different or interacting hormonal systems, for example, the neuropeptide oxytocin influences social bonding, the steroid hormone testosterone influences dominance relationships, and paternal care is characterized by high oxytocin and low testosterone. Although the oxytocinergic system influences social bonding, it can support different types of social bonds in different species, whether pair bonds, parent-offspring bonds or friendships. It seems that selection processes shape social and mating systems and their interactions with neuroendocrine pathways. Within species, there are individual differences in the development of the neuroendocrine system: the social environment individuals are exposed to during ontogeny alters their neuroendocrine and socio-cognitive development, and later, their social interactions as adults. Within individuals, neuroendocrine systems can also have short-term effects, impacting on social interactions, such as those during hunting, intergroup encounters or food sharing, or the likelihood of cooperating, winning or losing. To understand these highly dynamic processes, extending research beyond animals in laboratory settings to wild animals living within their natural social and ecological setting may bring insights that are otherwise unreachable. Field endocrinology with neuropeptides is still emerging. We review the current status of this research, informed by laboratory studies, and identify questions particularly suited to future field studies. We focus on primate social relationships, specifically social bonds (mother-offspring, father-offspring, cooperative breeders, pair bonds and adult platonic friendships), dominance, cooperation and in-group/out-group relationships, and examine evidence with respect to the ‘tend and defend’ hypothesis.     

Pulmonary neuroendocrine cells in physiology and pathology

Pulmonary neuroendocrine cells are scant and widespread within the pulmonary epithelium. The function they play is not fully known, more studies are needed to clearly define it. They have been implicated however, as either the culprit or victim of many pulmonary diseases. That is the reason, why so many scientists take interest in the pulmonary neuroendocrine system. This paper reviews current information regarding pulmonary neuroendocrine cells, their origin, morphology, ontogeny, role, neuroendocrine cell markers, dysplasia and hyperplasia of pulmonary neuroendocrine cells in various conditions, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, typical carcinoid, atypical carcinoid, small-cell lung carcinoma, large-cell neuroendocrine carcinoma and the unusual spectrum of pulmonary neuroendocrine tumours.     

Femoral ontogeny and locomotor biomechanics of Dryosaurus lettowvorbecki (Dinosauria, Iguanodontia)

Ontogenetic changes in femoral morphology and locomotion were analysed in the iguanodontian dinosaur Dryosaurus lettowvorbecki using cross-sectional data and applying principles of beam theory. The results presented here suggest that locomotor ontogeny in D. lettowvorbecki was more complicated than has generally been recognized. The percentage cortical area (a measure of the relative amount of bone) increases abruptly over a relatively short period during early ontogeny and then remains uniform during subsequent increases in body size. Modifications in cross-sectional shape also occur with increasing size, as demonstrated by differences in second moment of area ratios. The patterns of change in these properties indicate that the orientation of mechanical loadings acting on the femur of D. lettowvorbecki differed at various stages of growth and development. It is suggested that the alterations in femoral architecture described here reflect a shift from quadrupedality to bipedality early in the ontogeny of this animal.     

Interdependence between neuroendocrine programming and the generation of immune recognition in ontogeny

Sequential, chronologically, and quantitatively critical inoculation of different allogeneic hybrid cells into mice during the neonatal and perinatal period results in an indefinite prolongation of the perinatal stage during which tolerance can be readily induced. Consequently, a permanent specific tolerance to the sequentially inoculated alloantigens and a parallel alteration and retardation in the maturation of the developing endocrine system which normally controls immune differentiation are observed. The endocrine and immune parameters are altered only when the successive presentation of alloantigens is begun at birth, as this is a critical stage of development at which both the neuroendocrine (hypothalamic-pituitary) and the thymo-lymphatic systems are still highly undifferentiated. The phylogenetically and ontogenetically interlocked and interdependent thymo-lymphatic and neuroendocrine networks thus constitute a basic homoeostatic regulatory system in which signals of both endocrine and antigenic nature are detected and elaborated with consequent proper response in a homeostatic fashion. On the basis of these considerations and the experimental findings that support them, the generation of tolerance and immunity (recognition of self and nonself components of the body) appears to be a part of the definitive brain programming for neuroendocrine and immune functions in early ontogey. This would constitute an augmented interpretation of the concept of immune tolerance as “specific central failure of the mechanisms of response” originally put forth by Medawar (1956, Proc. Roy. Soc.146B, 1).     

The diffuse endocrine system: from embryogenesis to carcinogenesis

In the present review we will summarise the current knowledge about the cells comprising the Diffuse Endocrine System (DES) in mammalian organs. We will describe the morphological, histochemical and functional traits of these cells in three major systems gastrointestinal, respiratory and prostatic. We will also focus on some aspects of their ontogeny and differentiation, as well as to their relevance in carcinogenesis, especially in neuroendocrine tumors. The first chapter describes the characteristics of DES cells and some of their specific biological and biochemical traits. The second chapter deals with DES in the gastrointestinal organs, with special reference to the new data on the differentiation mechanisms that leads to the appearance of endocrine cells from an undifferentiated stem cell. The third chapter is devoted to DES of the respiratory system and some aspects of its biological role, both, during development and adulthood. Neuroendocrine hyperplasia and neuroendocrine lung tumors are also addressed. Finally, the last chapter deals with the prostatic DES, discussing its probable functional role and its relevance in hormone-resistant prostatic carcinomas.     

Ontogeny of neuroendocrine centers in the eyestalk of Homarus gammarus embryos: an anatomical and hormonal approach

Summary

The ontogeny of the eyestalk neuroendocrine centers of the European lobster, Homarus gammarus, throughout embryonic development has been studied using light and electron microscopy, and the localization of specific neuroendocrine substances has been identified by immunocytochemistry. The procephalic lobes, which are the prospective eyestalks, develop progressively during embryonic development. In the nauplius stage two neuron masses are well defined. The visual structure originates from one of them and the neuroendocrine structure from the other. The four definitive optic ganglia are present at the mid-metanauplius stage and retain their appearance and location in larvae and adults. The organ of Bellonci, an internal sensory structure, appears at the mid-metanauplius stage and is mainly characterized by onion bodies. The medulla terminalis X-organ complex, an important neuroendocrine system, is present and already functional at the beginning of the embryonic metanauplius stage. Two neurohormones have been visualized immunocytochemically: the crustacean hyperglycemic hormone (CHH) and the gonad inhibiting hormone (GIH). Both neuropeptides are localized in the perikarya of neuroendocrine cells of the X-organ as well as in their tracts joining the presumptive sinus gland. However, the sinus gland has only been observed in the early larval stages just after hatching.     

Ontogeny of primary lymphoid organs and lymphoid stem cells

Cells of the immune system go through a series of important developmental steps that begin early in embryonic life and include, first, the various waves of hemopoietic-cell production in the embryo and, second, the homing of these cells to the hemopoietic organs, which are the sites of hemopoiesis and lymphopoiesis in embryonic and adult life. The avian embryo is an important model for investigating these early steps; and this paper presents a comprehensive review of the work done on the early ontogeny of the avian immune system.     

Variability in leucocyte profiles in thin-billed prions Pachyptila belcheri

Because immune function competes for the resources that can be allocated to other activities, studies of immunological ecology may offer a powerful tool for explaining how reproductive effort links to reproductive costs and how conditions experienced early in their development affect growing chicks in later life. We studied the distribution of leucocyte types and the development of H/L ratio, which is indicative of heightened energetic stress, throughout the season 2004-2005 in chicks and adults of thin-billed prions Pachyptila belcheri. Adults decreased body condition throughout the season and increased H/L ratios. Likewise, chicks increased H/L ratios during the season, but this was age-related rather than condition-dependent. Chicks from earlier hatched eggs had lower H/L ratios initially, but this relationship became weaker with increasing age and had disappeared by fledging. The results suggest that the stress index may be a useful measure of condition in adult thin-billed prions, at least on a population level, although a larger sample size or repeated samples from the same individuals may be required to confirm the relationship on an individual level and to distinguish between seasonal and body condition effects. The data on chicks highlight our lack of knowledge of the ontogeny of immune function in wild birds. Studies of adults and chicks over several seasons may reveal how resources are allocated between immune and other functions under contrasting environmental conditions.     

Isolating the effects of ontogenetic niche shift on brain size development using pumpkinseed sunfish ecotypes

A functional relationship between relative brain size and cognitive performance has been hypothesized. However, the influence of ontogenetic niche shifts on cognitive performance is not well understood. Increases in body size can affect niche use but distinguishing nonecologically relevant brain development from effects associated with ecology is difficult. If survival is enhanced by functional changes in ecocognitive performance over ontogeny, then brain size development should track ontogenetic shifts in ecology. We control for nonecologically relevant brain size development by comparing brain growth between two ecotypes of Pumpkinseed sunfish whose ecologies diverge over ontogeny from a shared juvenile niche. Brain size differs between ecotypes from their birth year onwards even though their foraging ecology appears to diverge at age 3. This finding suggests that the eco‐cognitive requirements of adult niches shape early life brain growth more than the requirements of juvenile ecology.     

Regulation of pituitary peptides by the immune system

It has long been thought that the central nervous system is able to influence the progression of disease. Furthermore, there is now overwhelming evidence that the communication pathways are bidirectional. A variety of immune system peptides are now known to be capable of transmitting information from the immune system to the central nervous system. These immunotransmitters include interleukins, interferons and thymosine peptides which have the capability of modulating slow-wave sleep as well as the release of neuro- and pituitary peptides. In some instances, release of these peptides during early development may have long lasting, if not permanent effects upon the normal development of neuroendocrine circuits. Collectively these various brain mediated events appear to contribute in various and diverse ways to defense against pathogens. It is becoming more and more apparent that certain abnormalities within the immune system may be the consequence of a neurological abnormality. The converse is also true.     

From the neuroendocrinology of lymphocytes toward a molecular basis of the network theory

The cells of the immune system produce and respond to hormones that were once thought to be restricted to the neuroendocrine system. By applying a novel methodology based on the molecular recognition hypothesis, the isolation and purification of receptors shared between the immune and neuroendocrine systems was accomplished. Biochemical analysis revealed them to be virtually identical with respect to their physicochemical and functional properties. Thus, bidirectional communication between the immune and neuroendocrine systems seems to result from a common set of hormones and receptors which are shared by the two systems. Furthermore, the molecular recognition hypothesis has revealed that homologues of the binding sites of these same hormone receptor pairs may be contained within the hypervariable regions of immunoglobulins and therefore constitute part of the immunologic network.     

Neural and Pavlovian influences on immunity

The traditional view that the nervous and immune systems are functionally independent (aside from general stress effects and autoimmune disorders of the nervous system) is being challenged by a new view that the nervous system regulates the activity of the immune system. If this is true, it should be possible to change the activity of the immune system by means of Pavlovian conditioning, just as it is possible to condition other physiological events influenced by the autonomic nervous system or neuroendocrine substances. Evidence for autonomic and neuroendocrine modulation of immune activity is briefly reviewed; and, the various studies reporting conditioned immune effects, the physiological mechanisms most likely involved, and their possible significance are discussed.     

The ontogeny of the entocytherid ostracod Uncinocythere occidentalis (Kozloff & Whitman, 1954) Hart, 1962 (Crustacea)

The Entocytheridae is a cytheroidean family that is known for its commensal mode of life on other crustaceans. However, due to their small size and large sexual dimorphism in the sizes of the carapace, the ontogeny of the entocytherids is poorly understood. This paper documents the basic body plans and pore systems of the entocytherid Uncinocythere occidentalis (Kozloff & Whitman, 1954) Hart, 1962 through ontogeny and compares them with other podocope groups. U. occidentalis has seven juvenile stages, one less than other cytheroidean groups. The general appearance of the limbs during the ontogeny of U. occidentalis is similar to that of other podocope ostracods, such as Limnocythere inopinata (Cytheroidea) Loxoconcha japonica (Cytheroidea),Eucypris virens (Cypridoidea), and Neonesidea oligodentata (Bairdioidea) with the exception of the maxillula. The adult maxillula of U. occidentalis is reduced to just a palp and third masticatory lobe (endite), and the third masticatory lobe and branchial plate of this appendage form later in the ontogeny compared with other podocope species (i.e., these features show post displacemental ontogenetic development). The number of the pore systems of the earliest juvenile (A-7) of U. occidentalis is 10, and is different from that of the corresponding stage of other cytheroidean groups which have 9. This fact, together with the different mode of development of the maxillula, indicates that the entocytherids are not only highly specialized to their commensal mode of life but that they are also phylogenetically distant from most other cytheroidean families, possibly differentiating from the others during the early evolution of the cytherids.     

Fungi: individuals, populations, and speciation

Under considerations are specific features of the fungal individuals associated with their mycelial life mode and affecting their population structure and speciation. Special attention is paid to the sympatric speciation which can be caused by trophic niche segregation, by use of different host plants, by invasion to the plants at different stage of their ontogeny, and by differences in the weather requirements. Decrease of genetic interchanges in subdivided populations promoting speciation without spatial isolation is achieved by homotallism and pseudohomotallism, by a cassette mechanism of switching among various breeding systems, and by complete lost of sexual process. Recombination reduction in agamic fungi is achieved by means of vegetative incompatibility. As the latter is similar functionally to the immune system (recognition of an alien culture and death of conjugated cells), it is possible that the fungi were the first to have developed mechanisms of sympatric speciation on the basis of the simpliest immune system.     

Effects of early partial decapitation on the ontogenic development of chicken lymphoid organs. I. Thymus.

For the present study we used the classic model of early partial decapitation (DCx) of chicken embryos (Fugo, J. Exp. Zool., 85: 271-298, 1940; Betz, Gen. Comp. Endocrinol., 9: 172-186, 1967) in an attempt to analyze the neuroendocrine immune relationships during ontogeny. The elimination of the prosencephalon in chickens at 33-38 hr of incubation induced profound structural, histochemical, and morphometric changes in the embryonic development of the thymus gland. These included a greater development of the cortex than of the medulla, an increased mitotic index, high numbers of pyknotic cells, and enlarged connective tissue trabeculae containing numerous large lymphoid cells; hypertrophied reticular-epithelial cells; delayed appearance of medullary epithelial cysts; and intrathymic granulopoiesis. Furthermore, preliminary radioimmunoassays revealed a sharp increase in the values of circulating thymic hormones, mainly thymosin beta 4 in 17-day-old embryos. The results are discussed with regard to the possible role of prolactin, thyroxine, testosterone, and thymic hormones in the ontogenic development of the chicken thymus.