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PubMed1999

Balancing function vs. self defense: the CNS as an active regulator of immune responses.

Immunological privilege of the central nervous system (CNS) has often been viewed as the summation of mechanisms that are protective of, but extrinsic to, the CNS. Their primary role has then been seen as isolating the CNS from the organism as a whole. Experiments in recent years indicate that the CNS itself may have an innate immune system comprised of astrocytes and microglia capable of regulating the initiation and progression of immune responses. Thus, immunological privilege should be considered as an intrinsic property of the CNS that could involve direct CNS: immune cell interactions. Malfunctions of these intrinsic mechanisms could play significant roles augmenting or even initiating CNS-directed autoimmunity and inflammation.

Animals↗
PubMed1998

Contribution of T cells to the development of autoimmune diabetes in the NOD mouse model.

The nonobese diabetic (NOD) mouse spontaneously develops an autoimmune diabetes that shares many immunogenetic features with human insulin-dependent diabetes mellitus (IDDM), type 1 diabetes. The mononuclear cell infiltrates in the islet, which results in the development of insulitis (a prerequisite step for the development of diabetes) are primarily composed of T cells. It is now well accepted that these T cells play important roles in initiating and propagating an autoimmune process, which in turn destroys insulin-producing islet beta cells in the pancreas. T cells are subdivided into CD4+ helper T cells and CD8+ cytotoxic T cells. CD4+ T cells are further subdivided into Th1 and Th2 cells based on profiles of cytokine production, and these two T-cell populations counterregulate each other. Because many autoimmune diseases are Th1 T-cell mediated, current studies have focused on manipulating the Th1/Th2 imbalance to suppress the autoimmune process in the NOD model. Furthermore, the incidence of disease is much higher in females than that in males, suggesting an involvement of sex-steroid hormones in the development of diabetes. Understanding insights of the mechanism of immune-mediated islet cell destruction and the interaction between the immune and the neuroendocrine system may, therefore, provide new therapeutic means of preventing this chronic debilitating disease.

Animals↗
PubMed2000

Induction of resistance to active experimental allergic encephalomyelitis by myelin basic protein-specific Th2 cell lines generated in the presence of glucocorticoids and IL-4.

We have produced T cell lines with a Th2 phenotype in the presence of IL-4 and the glucocorticoid dexamethasone (DEX). IL-4 and DEX together were more effective in inducing a Th2 response than IL-4 alone. Myelin basic protein (MBP)-specific Th2 lines were obtained and their ability to induce experimental allergic encephalomyelitis (EAE) was studied. Lines treated with IL-4 and DEX did not transfer passive EAE and did not induce cellular infiltration into the central nervous system as opposed to the encephalitogenic Th1 lines. Lines treated with IL-4 and DEX did not protect animals from the effect of encephalitogenic Th1 lines when the two were injected together. However, a high proportion of animals injected with IL-4 + DEX-treated lines became refractory to the development of EAE after immunization with MBP; that is, it was possible to induce resistance to active EAE without prior episodes of disease. Interestingly, animals injected with T cell lines had accelerated antibody responses against MBP and the predominant isotype was dependent on the cytokines synthesized by the T cell line injected. There was not evidence that the resistance to active EAE was due to anergy of MBP-reactive cells or the action of CD8+ cells. Our data suggest that MBP-specific T cell lines prevent the induction of disease by deviating the reactivity to MBP from a cell-mediated to a humoral one and not merely from a Th1 to a Th2 response.

Adoptive Transfer↗
PubMed2003

Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases.

Inflammatory reactions in the central nervous system usually are considered detrimental, but recent evidence suggests that they also can be beneficial and even have neuroprotective effects. Intriguingly, immune cells can produce various neurotrophic factors of various molecular families. The concept of "neuroprotective immunity" will have profound consequences for the pathogenesis and treatment of neuroinflammatory diseases such as multiple sclerosis. It also will prove important for neurodegenerative disorders, in which inflammatory reactions often occur. This review focuses on recent findings that immune cells produce brain-derived neurotrophic factor in multiple sclerosis lesions, whereas neurons and astrocytes express the appropriate tyrosine kinase receptor TrkB. Together with functional evidence for the neuroprotective effects of immune cells, these observations support the concept of "neuroprotective immunity." We next examine current and future therapeutic strategies for multiple sclerosis and experimental autoimmune encephalomyelitis in light of neuroprotective immunity and finally address the broader implications of this new concept for other neuroinflammatory and neurodegenerative diseases.

Animals↗
PubMed2005

The adaptive immune response in neonatal cerebral white matter damage.

Hypotheses that inflammation contributes to neonatal cerebral white matter damage have evolved over the last three decades. The latest, expanded here, suggests that the adaptive immune system contributes to the intensity and duration of the processes that result in damage to cerebral white matter in the fetus and newborn. We propose several mechanisms by which fetal T lymphocytes could be activated during fetal exposure to infection. These include specific recognition of bacterial antigens, specific recognition of autoantigens, polyclonal activation by Toll-like receptors, and bystander activation by cytokines.

Adaptation, Physiological↗
PubMed1997

Melatonin: a clinical perspective.

Over the last several decades the pineal gland has emerged as an active neuroendocrine transducer of important environmental information. However, the current understanding of the function of its major hormone, melatonin, in humans remains ill defined and based exclusively on correlative observations. In a similar manner, the multitude of phenomenological descriptions of the effects of exogenous melatonin is contrasted by the limited understanding of the underlying mechanisms and the lack of firmly established clinical applications for the hormone. Future randomized, double-blind, placebo-controlled clinical studies will be necessary to determine the precise indications, treatment regimens, and safety of melatonin in clinical practice. The recent rapid progress in the area of melatonin research should lead to a better understanding of its role in human health and disease.

Humans↗
PubMed1989

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.

Animals↗
PubMed2004

Aberrant transcription of unrearranged T-cell receptor beta gene in mouse brain.

The nervous system and the immune system share several functional molecules involved in various cell-cell interaction events. In this study, we used in situ hybridization to identify immune molecules that are expressed by a restricted population of neurons in the mouse brain and found that mRNA for the beta subunit of T-cell receptor (TCRbeta) was predominantly and strongly localized to neurons in deep layers of the cerebral neocortex and weakly expressed in the thalamus. Developmentally, TCRbeta mRNA expression started at embryonic day 15 in the thalamic nuclei and at postnatal day 1 in the cerebral neocortex. The level of TCRbeta mRNA in the neocortex subsequently increased until postnatal day 21, and it remained high in the adult. Detailed analysis revealed that only the Cbeta2 segment of TCRbeta, not the Cbeta1 or Vbeta segments, was expressed by the brain neurons. By the 5' rapid amplification of cDNA ends method, we determined a brain-specific transcription start site in the Jbeta2 region locus, not in the Vbeta region locus. Furthermore, we confirmed that the aberrant transcription around the Jbeta2 region took place only in neurons and lymphocytes in transgenic mice. These results demonstrate that the transcriptional machinery for unrearranged TCRbeta expression is shared by the nervous and immune systems and raise a possibility of gene rearrangement in neurons under certain circumstances.

Alternative Splicing↗
PubMed2004

Up-regulation of activated macrophages in response to degeneration in the taste system: effects of dietary sodium restriction.

Dietary sodium restriction combined with unilateral chorda tympani nerve section leads to a rapid and specific decrease in neurophysiological taste responses to sodium in the contralateral, intact chorda tympani (Hill and Phillips [1994] J. Neurosci. 14:2904-2910). Previous work demonstrated that dietary sodium restriction may induce these early functional deficits by inhibiting immune activity after denervation (Phillips and Hill [1996] Am. J. Physiol. 271:R857-R862). However, little is known about the leukocyte response to denervation of taste buds in fungiform papillae. In the current study, it was hypothesized that T cells and macrophages are increased in the tongue after unilateral denervation in control-fed but not sodium-restricted animals. Adult, specified pathogen-free rats received unilateral chorda tympani nerve section or sham section followed by dietary sodium restriction or maintenance on control diet. At day 1, 2, 5, 7, or 50 postsectioning, immunostaining was used to detect the percentage of staining for activated macrophages, the number of alpha beta T cells, and the number of delta gamma epithelial T cells in the tongue. The number of lingual T cells did not significantly differ between treatment groups following denervation. However, there was a dramatic bilateral increase in ED1(+) staining for activated macrophages in control-fed rats that peaked at day 2 postsectioning. In contrast, sodium-restricted rats did not show an increase in activated macrophages above baseline at any time postsectioning. Further analysis of extralingual macrophages indicated that the deficit in immune activity in sodium-restricted rats is localized to the tongue and is not widespread. A model for immune modulation of taste receptor cell function is proposed based on these novel findings.

Analysis of Variance↗
PubMed2005

Changes in the density and distribution of sympathetic nerves in spleens from Lewis rats with adjuvant-induced arthritis suggest that an injury and sprouting response occurs.

Previously we demonstrated reduced norepinephrine concentrations in spleens from Lewis rats with adjuvant-induced arthritis (AA), an animal model of rheumatoid arthritis. This study extends these findings, examining the anatomical localization and density of sympathetic nerves in the spleen with disease development. Noradrenergic (NA) innervation in spleens of Lewis rats was examined 28 days following adjuvant treatment to induce arthritis or vehicle for the adjuvant by using fluorescence histochemistry for catecholamines, with morphometric analysis and immunocytochemistry for tyrosine hydroxylase. In AA rats, sympathetic nerve density in the hilar regions, where NA nerves enter the spleen, was increased twofold over that observed in vehicle-treated rats. In contrast, there was a striking twofold decline in the density of NA nerves in splenic regions distal to the hilus in arthritic rats compared with nonarthritic rats. In both treatment groups, NA nerves distributed to central arterioles, white pulp regions, trabeculae, and capsule. However, NA nerve density was reduced in the white pulp but was increased in the red pulp in AA rats compared with non-AA rats. These findings indicate an injury/sprouting response with disease development whereby NA nerves die back in distal regions and undergo a compensatory sprouting response in the hilus. The redistribution of NA nerves from white pulp to red pulp suggests that these nerves signal activated immune cells localized in the red pulp in AA. Although the mechanisms of this redistribution of NA nerves into the red pulp are not known, it may be due to migration from white pulp to red pulp of target immune cells that provide trophic support for these nerves. The redistribution of NA nerves into the red pulp may be critical in modulating immune functions that contribute to the chronic inflammatory stages of arthritis.

Animals↗
PubMed2005

Nuclear STAT3 translocation in guinea pig and rat brain endothelium during systemic challenge with lipopolysaccharide and interleukin-6.

During systemic inflammation, cytokines are released by immune-competent cells into the circulation, which in turn signal the brain to mediate brain-controlled signs of illness. Cytokine-responsive brain cells can be mapped by histological analysis of cytokine-induced transcription factors or transcription factor-associated molecules revealing different cell phenotypes that respond to activation of the immune system. Critical sites mediating cytokine-dependent immuneffector functions can be divided into two groups, one group of responding cells situated along a tight blood-brain barrier (BBB), and a second cell group in structures with an open BBB, e.g., the sensory circumventricular organs (CVOs). Previous reports from our group suggest that activation of the signal transducer and activator of transcription factor 3 (STAT3) during lipopolysaccharide (LPS)-induced systemic inflammation is mediated by interleukin-6 (IL-6) and occurs in astrocytes of the rat CVOs. Here we show in the guinea pig a time-dependent marked LPS-induced STAT3 activation within astrocytes and endothelial cells of the CVOs, within astrocytes located in brain structures with a functional BBB and within the brain endothelium of the entire brain. In addition, systemic treatment of rats with either rat recombinant IL-6 or LPS induced STAT3 activation in brain endothelial cells in a similar way as observed in the guinea pig brain, stressing the involvement of IL-6 in this phenomenon in a more generalized way. The STAT3-activated brain cells are located in critical target structures mediating cytokine action during LPS-induced inflammation. STAT3-controlled transcriptional activation with yet unknown cell-specific functional consequences seems to be involved in this process.

Animals↗
PubMed2004

Resident microglia from adult mice are refractory to nitric oxide-inducing stimuli due to impaired NOS2 gene expression.

Microglia are the immunoregulatory cells of the central nervous system (CNS) and share many characteristics with resident macrophages in extracerebral tissues. Nitric oxide (NO) is secreted by macrophages following induction of the NO synthase gene NOS2 by stimuli elicited during a T-cell response and/or by microbial products. NO regulates both innate and adaptive immune responses, such as killing intracellular pathogens and inhibiting T-cell proliferation. Regulation of NO production by microglia, however, is poorly understood. We find that microglia from healthy adult mice produce negligible amounts of NO compared with resident macrophages during restimulation of peptide-specific CD8 T cells, and therefore cannot block T-cell proliferation. The impaired NO response extends to exogenous NOS2-inducing stimuli, including cytokines, CD40 ligation, and lipopolysaccharide. In contrast, microglia produce proinflammatory cytokines in response to these same stimuli, and therefore possess a relatively selective block in NO production. We go on to show that resident microglia fail to produce detectable levels of either the NOS2 enzyme or NOS2 RNA in response to NO-inducing stimuli. We therefore propose that microglia in the healthy adult brain exist in an "NO-incompetent" state in which NO production is blocked at the level of NOS2 RNA. The inability of resident microglia in the healthy CNS to produce NO may allow these immunoregulatory cells to modulate immune processes temporally, and may serve to protect the CNS from irreparable damage at the onset of infection or injury.

Age Factors↗
PubMed2005

Pigment epithelium-derived factor induces pro-inflammatory genes in neonatal astrocytes through activation of NF-kappa B and CREB.

Pigment epithelium-derived factor (PEDF) is a potent and broadly acting neurotrophic factor that protects neurons in various types of cultured neurons against glutamate excitotoxicity and induced-apoptosis. Some of the effects of PEDF reflect specific changes in gene expression, mediated via activation of the transcription factor NF-kappa B in neurons. To investigate whether PEDF also modulates gene expression in astrocytes, we employed the use of RT-PCR to analyze the gene expression of certain pro-inflammatory genes and found that genes such as IL-1 beta, IL-6, TNF-alpha, MIP1 alpha, and MIP3 alpha were induced in PEDF-treated cultured neonatal astrocytes, but not in adult astrocytes. Electrophoresis mobility shift assay (EMSA) revealed that a time- and dose-dependent increase of NF-kappa B- and AP-1-DNA binding activity was observed in PEDF-treated neonatal astrocytes. Furthermore, rapid phosphorylation of CREB protein had occurred in PEDF-treated neonatal astrocytes. Upregulation of pro-inflammatory and AP-1-related genes by PEDF was blocked by overexpression of dominant negative CREB or a mutated form of I kappa B alpha. These results suggest that the induction of pro-inflammatory genes is mediated via activation of NF-kappa B, AP-1, and CREB in neonatal astrocytes. Taken together, these results demonstrate that PEDF is a multipotent factor, capable of affecting not only neurons, but also neonatal astrocytes, and suggests that it may act as a neuroimmune modulator in the developmental brain.

Animals↗
PubMed1988

Functional plasticity of microglia: a review.

The present review summarizes recently acquired data in vivo, which support a role of CNS microglia as a source of defense cells in the CNS capable of carrying out certain immune functions autonomously. We have kept the following discussion restricted to microglial cells and have not included work on the immunological functions of astrocytes, which has been recently reviewed elsewhere (Fontana et al.: Immunological Reviews 137:3521-3527, 1987). Resting microglia are scattered uniformly throughout the CNS forming a network of potential immunoeffector cells, which can be activated by stimuli ranging from peripheral nerve injury over viral infections to direct mechanical brain trauma. The term "activated microglia" is used here to describe proliferating cells that demonstrate changes in their immunophenotype but have not undergone transformation into brain macrophages. Such a transformation can be stimulated by neuronal death but not by sublethal neuronal injury. Microglia may function as antigen-presenting cells and may thus represent the effector cell responsible for the recruitment of lymphocytes to the brain resulting in an inflammatory reaction. The recent developments in the understanding of microglial cell function may lead to a redefinition of the often cited "immune privilege" of the brain.

Animals↗
PubMed2005

Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-beta-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons.

Chronic inflammation has been reported to be a significant factor in the induction and progression of a number of chronic neurological disorders including Alzheimer's disease and Down syndrome. It is believed that inflammation may promote synaptic dysfunction, an effect that is mediated in part by pro-inflammatory cytokines such as interleukin-1beta (IL-1beta). However, the role of IL-1beta and other cytokines in synaptic transmission is still poorly understood. In this study, we have investigated how synaptic transmission and neuronal excitability in hippocampal pyramidal neurons are affected by chronic inflammation induced by exposing organotypic slices to the bacterial cell-wall product lipopolysaccharide (LPS). We report that CA1 pyramidal neurons recorded in whole cell from slices previously exposed to LPS for 7 days had resting membrane potential and action potential properties similar to those of the controls. However, they had significantly lower membrane resistance and a more elevated action potential threshold, and displayed a slower frequency of action potential discharge. Moreover, the amplitude of pharmacologically isolated postsynaptic gamma-aminobutyric acid (GABA)ergic potentials, but not excitatory glutamatergic postsynaptic potentials, was significantly larger following chronic LPS exposure. Interestingly, co-incubation of the IL-1 receptor antagonist (IL-1Ra) concurrently with LPS prevented the increase in GABAergic transmission, but not the reduction in intrinsic neuronal excitability. Finally, we confirmed that LPS dramatically increased IL-1beta, and IL-1beta-dependent IL-6 levels in the culture medium for 2 days before returning to baseline. We conclude that CA1 pyramidal neurons in slices chronically exposed to LPS show a persistent decrease in excitability due to a combined decrease in intrinsic membrane excitability and an enhancement in synaptic GABAergic input, the latter being dependent on IL-1beta. Therefore, chronic inflammation in hippocampus produces IL-1beta-dependent and -independent effects in neuronal and synaptic function that could contribute significantly to cognitive disturbances.

Action Potentials↗
PubMed1990

Cerebrospinal fluid corticotropin-releasing factor levels and stimulation test in dementia of the Alzheimer type.

Experimental findings have recently suggested a toxic role for glucocorticoids in hippocampus, the main brain target for the adrenocortical hormones. In this study, we explored the activity of the hypothalamus-pituitary-adrenal (HPA) axis in a group of patients with dementia of the Alzheimer's type (DAT) and in a control group of age-matched subjects. We measured the corticotropin-releasing factor (CRF) levels in cerebrospinal fluid (CSF) and evaluated the plasma cortisol response to a CRF stimulation test. While no differences were observed in the results of the CRF test for two groups, CSF CRF values in DAT patients were found to be significantly higher than in controls. Bearing in mind the bidirectional relationships between the neuroendocrine and immune systems and the changes in some immunological parameters reported in DAT, the possible role of HPA axis hyperactivity in the pathogenesis of primary dementia is discussed.

Aged↗
PubMed1990

Phylogenetic approach to endocrine-immune system interactions.

The survival of organisms in a hostile and highly variable environment is dependent upon the proper balance of physiological processes. According to emerging views, homeostasis may be achieved by the coordinated activities of the three major integrative systems: the nervous, endocrine, and immune systems. Although each of these systems is replete with its particular molecules, cells, tissues, and organs, often not seemingly integrated into the whole organism, homeostasis is uncompromised and the three systems function properly. This mini-review contains the essence of newer approaches which emphasize those which are being developed in our laboratory. Our model is concerned with the regulation of the immune system by the brain in fish.

Animals↗
PubMed2002

Cytokine signaling in the brain: putting a SOCS in it?

A new family of cytokine-inducible proteins, termed "suppressors of cytokine signaling" (SOCS), was discovered recently; these proteins function as negative regulators of signaling pathways involved in the cellular actions of many cytokines, growth factors, and hormones. Gene manipulation studies in mice point to the central importance of individual SOCS proteins in maintaining homeostasis by limiting cellular responses to specific cytokines or growth factors in a variety of different physiological systems. Cytokines modulate a wide variety of biological responses in the CNS, so members of the SOCS family might play crucial roles in regulating intracellular signaling by these effectors in both normal and disease states. Although to date studies of the neurobiology of the SOCS family have been limited, we know that many SOCS genes are constitutively expressed in the developing and adult brain, whereas the expression of others, particularly the SOCS1 and SOCS3 genes, can be highly regulated. Furthermore, roles for the SOCS are now evident in the modulation of neuroimmunoendocrine functions affected by a variety of cytokines, including leptin and members of the growth hormone and the interleukin-6/gp130 superfamilies. Overall, these findings point to the SOCS as likely crucial negative modulators in the temporal and spatial regulation and intensity of cytokine signaling and therefore actions in the CNS.

Animals↗