Current Immunology Reviews (Discontinued) - Volume 6, Issue 3, 2010

The central nervous system (CNS) is an immune-privileged organ because a selective permeability to exchange blood cells and substances from the circulatory system. Nevertheless, increasing evidence indicates that an extensive bi-directional communication takes place between the CNS and the immune system. Thus, the psyconeuroimmunology has emerged as a relative novel discipline to study interactions among psychological processes, brain functioning and the immune system. This especial issue of the Current Immunology Reviews contains nine comprehensive articles addressing the interactions between the immune and nervous systems in either physiological or pathological conditions. In an excellent review, Cordiglieri and Farina explain the role of astrocytes in initiating and tuning cerebral immune responses. Authors state that astrocytes promote or confine inflammatory processes and, in consequence, play a role in neuroprotection and CNS repair. Astrocytes act as immune-competent cells by secreting cytokines and chemokines, and participating in innate immunity. As reviewed by Tian and Rauvala, the communication between immune system and CNS is bi-directional, in fact, neurons participate in immune responses by controlling responses of microglia and T lymphocytes. Interestingly, the immune system also controls proliferation, differentiation, migration and self-renewal of adult neural stem cells, which reside in the wall of lateral ventricles of brain. Modulation of neural stem cells are mainly mediated by IL-6, IL-18, TNF-α, CNTF, LIF and IFN-γ [1-3]. Neuroinflammation plays a role in the etiology and/or progression of several neurological disorders. As reviewed by Ramos and Duran, rheumatoid arthritis is a systemic inflammatory disorder that affects the central and peripheral nervous system. As in other rheumatic diseases, TNF-α is one of the main mediators of CNS damage. Orozco et al. reviewed the effects of inflammatory reactions on neuronal excitability, cell survival impairment, and permeability to blood-borne molecules and cells. These pathological events and high levels of IL-1, IL-2, and TNF-α have been associated with epilepsy development and seizures. Cytokines and chemokines also modulate cognitive and emotional processes in the absence of overt immunological, physiological, or psychological challenges. Psychological stress and glucocorticoid-related immunosuppression is reviewed by Jauregui et al. They explain that stress increases the levels of glucocorticoids, which target resident microglia and decrease the ability of these brain cells to proliferate, to produce pro-inflammatory cytokines, and to produce toxic radicals. Brain Leonard summarizes evidence indicating that IL-1, IL-4, IL-6, IL-10, IL-13, IFN-α and TNF-α can affect cognitive and emotional processes as observed in major depression [4, 5]. Pro-inflammatory cytokines affect neuronal signaling by enhancing the glutamatergic system, which stimulates the tryptophankynurenine pathway. In an excellent review, Muller and Schwarz explain that high levels of IL-8 during pregnancy are associated with an increased risk for schizophrenia in the offspring. In this landmark review, the authors indicate that infections of the CNS in early childhood increase risk for developing psychoses and that IL-6 serum levels are elevated in patients with an unfavourable course of mental disease. This issue concludes with the striking proposal of Momin et al. who addressed the oncogenic and tumor-supporting potential of mesenchimal stem cells (MSCs) within the context of cancer treatment. This review states the risk for malignant transformation of MSCs, the in vivo interactions with tumor stroma and the immunosuppressive qualities of MSCs that facilitate evasion of the immune system by tumors. In summary, increasing evidence indicates that cytokines and chemokines modulate cerebral functions through multiple signaling pathways. All these interactions affect neural remodeling, synaptic plasticity, neurotransmitter releasing, neuronal regeneration, brain aging, cognitive and emotional processes, and mental disease progression. All these events modulate cognitive and emotional processes, and brain disease predisposition/progression.

Astrocytes are the most abundant cell type of the Central Nervous System (CNS) and exert several important functions. Firstly, astrocytes strongly contribute to mechanical holding of the nervous tissue and to blood brain barrier generation and maintenance. Besides this structural role, astrocytes regulate neuron-glia communication by secreting neurotrophic factors and modulating neurotransmitter release and metabolism, control cerebral blood flow, keep CNS protected from pathogens while allowing passage of nutrients and maintaining tissue homeostasis. This review will focus on the ability of astrocytes in initiating and tuning cerebral immune responses, and will emphasize the importance of these astrocytic properties in both neuroinflammation and neuroprotection settings.

The central nervous system (CNS) is now known to actively communicate with the immune system. While studies on glial cells, especially microglia, have highlighted the importance of this cell type in innate immune responses of the CNS, the immune functions of other cell types, especially neurons are largely elusive. However, recent findings suggest that neurons also actively participate in immune responses by controlling glial cells and infiltrated T cells. The aim of this review is to address the immune function of both glial cells and neurons, and the roles they play in regulating inflammatory processes and maintaining homeostasis of the CNS.

New neurons are continuously produced in most, if not all, mammals. This Neurogenesis occurs only in discrete regions of the adult brain: the subventricular zone (SVZ) and the subgranular zone (SGZ). In these areas, there are neural stem cells (NSCs), multipotent and selfrenewing, which are regulated by a number of molecules and signaling pathways that control their cell fate choices, survival and proliferation rates. It was believed that growth and morphogenic factors were the unique mediators that controlled NSCs in vivo. Recently, chemokines and cytokines have been identified as important regulators of NSCs functions. Some of the most studied immunological effectors are leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), interferon-gamma (IFN-γ), insulin-like growth factor-1 (IGF-1), tumor necrosis factor alpha (TNF- α), and the chemokines MCP-1 and SDF-1. These substances exert a considerable regulation on proliferation, cell-fate choices, migration and survival of NSCs. Hence, the immune system is emerging as an important regulator of neurogenic niches in the adult brain, but further studies are necessary to fully establish the biological meaning of these neural effects.

Joints but specifically the synovial is the most important target in rheumatoid arthritis (RA) yet the disease is a systemic inflammatory disorder where extraarticular manifestations are common. Among extraarticular organs and systems affected by RA, central and peripheral nervous system involvement is frequent and associated with significant morbidity and, in some cases, reduced life span. It may produce a myriad of symptoms and signs ranging from subtle numbness in a hand, to quadriparesis and sudden death. Central and peripheral neurologic damage may arise from structural damage produced by RA in diarthroidal joints, by the systemic inflammatory process of the disease itself or by the drugs used to treat it. Neurologic syndromes in these patients may appear suddenly or developed slowly through months, and emerge early or after years of having RA. Neurologic manifestations may be easily overlooked or incorrectly assigned to peripheral arthritis unless the attending physician is aware of these complications. In this article, we review neurologic involvement in RA patients with emphasis on clinical approach for early detection.

Clinical and experimental data support the hypothesis that immune mechanisms may be a factor in a number of epilepsies such as Rasmussen's encephalitis, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and temporal lobe epilepsy. Surgical epilepsy specimens have shown immunologic abnormalities, suggesting a broader role for immunopathology in the etiology of epilepsy. Inflammatory reactions occur in the brain in various central nervous system diseases, including autoimmune, neurodegenerative, and epileptic disorders. Proinflammatory and anti-inflammatory cytokines and related molecules have been described in the CNS and plasma, both in experimental models of seizure and in clinical cases of epilepsy. Inflammation involves both the innate and the adaptive immune systems and shares molecules and signaling pathways that are also activated by systemic infection. Experimental studies in rodents show that inflammatory reactions in the brain can enhance neuronal excitability, impair cell survival, and increase the permeability of the blood-brain barrier to blood-borne molecules and cells. The immune response is altered with the development of epilepsy, and seizures result. We provide an overview of the current knowledge implicating brain inflammation as a common predisposing factor for epilepsy, focusing particularly on clinical and basic evidence.

A growing body of evidence suggests that glial cells are involved in practically all aspects of neural function. Glial cells regulate the homeostasis of the brain, influence the development of the nervous system, modulate synaptic activity, and carry out the immune response inside the brain. In addition, they play an important role in the restoration of the nervous system after damage, and they also participate in various neurodegenerative disorders. In a similar way, the importance of stress and glucocorticoids (GCs) on brain function is being increasingly recognized. Within the brain, stress hormones target both neurons and glial cells. Through their actions on these cells, glucocorticoids exert organizational functions on various processes of the developing brain and contribute to neuronal plasticity in the adult brain. Moreover, stress and glucocorticoids have become especially attractive in the study of a number of neurodegenerative disorders. However, studies on the mechanisms behind glucocorticoid-induced regulation of brain function have been classically focused on their effects on neurons. In this review, we start by describing the main functions of glial cells and then proceed to present data highlighting the effects of stress and GCs on brain function. We conclude the review by presenting recent evidence linking stress and glucocorticoids to glial cell function.

Chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis and the immune system, acts as a trigger for anxiety and depression. Both experimental and clinical evidence shows that a rise in the concentrations of proinflammatory cytokines and glucocorticoids, as occurs in chronically stressful situations and in depression, contribute to the behavioural changes associated with depression. A defect in serotonergic function is associated with hypercortisolaemia and the increase in proinflammatory cytokines that accompany depression. Glucocorticoids and proinflammatory cytokines enhance the conversion of tryptophan to kynurenine. In addition to the resulting decrease in the synthesis of brain serotonin, this leads to the formation of neurotoxins such as the glutamate agonist quinolinic acid and contributes to the increase in apoptosis of astrocytes, oligodendroglia and neurons. The importance of the inflammation hypothesis of depression lies in raising the possibility which psychotropic drugs that have a central anti-inflammatory action might provide a new generation of antidepressants.

Although an immune dysfunction and the involvement of infectious agents in the pathophysiology of schizophrenia are discussed since decades, the field never came into the mainstream of research. In schizophrenia a blunted type-1 immune response seems to be associated with a dysbalance in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan - kynurenine metabolism resulting in increased production of kynurenic acid in schizophrenia. This is associated with an imbalance in the glutamatergic neurotransmission, leading to an NMDA antagonism in schizophrenia. The immunological effects of antipsychotics rebalance partly the immune imbalance and the overweight of the production of the kynurenic acid. This immunological imbalance results in an inflammatory state combined with increased prostaglandin E2 (PGE2) production and increased cyclo-oxygenase-2 (COX-2) expression. COX-2 inhibitors have been tested in clinical trials, pointing to favourable effects in schizophrenia.

Ovarian cancer is one of the most fatal female neoplasms due to its aggressive behavior and late diagnosis. Despite improvments of the surgical approach and the use of chemotherapy, the survival rate observed in patients with advanced ovarian cancer is still unsatisfactory. The presence of cancer modulates adversely the immunological response of the host. Immunosurveillance over the tumor could be at least partly restored by the use of immunotherapy based either on techniques which allow to recognize and directly inhibit tumor cells, or on methods which mobilize and augment an anti-tumor host response. The first kind of strategy uses monoclonal antibodies directed against cancer specific antigens (CA-125) and molecules responsible for tumor growth and spreading (HER-2, EGFR-1, VEGF). The second kind of strategy modifies the host immune status by use of different techniques. Some of them are based on the administration of cytokines given in order to facilitate anti-tumor immunity. Recent studies have explored novel techniques which use hybrid cytokine/monoclonal antibodies targeted to specific cancer antigens, cancer antigen-pulsed and cancer cell-fused dendritic cells, or modification of regulatory or cytotoxic T cells. New methods of immunotherapy appear on the horizon, however, their efficacy still awaits confirmation in clinical trials.

To induce immunity against infectious diseases, vaccination at mucosal sites represents one of the major inventions in the field of healthcare. Since decades, various mucosal routes including nasal, oral and rectal have been exploited but the oral route is more patient compliance better than others due to its astonishing advantages as mucosal immunity generated by oral vaccines serves as a strong first line of defense. Proper stimulation of the cellular and humoral immune response is vital for the effective protection of mucosal surfaces against invasion of infectious pathogens. Recently, colloidal carriers like liposomes, niosomes, bilosomes, virosomes, ISCOMS, archaeosomes, chochleates, micronanoparticles and dendrimers have shown great attention for delivery of antigenic materials via gastrointestinal route. Moreover, delivery of mucosal adjuvant in combination with these carriers has also been proved as a successful strategy to enhance the stimulation of mucosal immune system. Further, selective and specific delivery of antigen to Peyer's patch or any other antigen presenting cells are appropriate for efficient uptake of antigen to and induce enhanced immune responses. In this paper, we have reviewed various carrier systems, immuno-adjuvants and targeting ligands to deliver vaccines efficiently through oral route providing non invasive method of immunization. Some of these have also been evaluated in the pre clinical and clinical trials. In future, these studies could help in developing vaccines at commercial scale having potential of eradicating life threatening infectious diseases.

Hypoxia is a frequent feature of tumor microenvironment and contributes significantly to tumorigenesis and cancer progression. Furthermore, it is increasingly recognized that the transcription factor called hypoxia inducible factor (HIF)-1 also promotes cancer immunosuppression. HIF-1 is activated during hypoxia by stabilization of the subunit HIF- 1alpha. Alternatively, growth factor stimulation or proinflammatory cytokines can activate HIF-1 also under normoxic conditions. Hypoxia directly converts certain immune effector cells into suppressor cells. Monocytes are recruited into tumors, differentiate into macrophages and accumulate in hypoxic areas where they acquire immunosuppressive characteristics. As a consequence of HIF-1 activation, the production of tolerogenic factors derived from cancer cells as well as from immune suppressor cells is increased. Several of the most important immunosuppressive molecules are under the transcriptional control of HIF-1, including vascular endothelial growth factor, heme oxygenase-1, inducible nitric oxide synthase and cyclooxygenase-2. HIF-1 interacts with several other transcription factors which are crucial for immunosuppression such as Stat3 that is over-activated in many tumor cells and in immune suppressor cells. Some factors which are expressed as a consequence of hypoxia through HIF-1 contribute to HIF-1 stabilization and activation. Hypoxia and HIF-1 facilitate the initiation of the intra- tumoral immunosuppressive state and contribute to its stabilization in regulatory networks.