Interferon and CNS

Interferons (IFNs) are glycoproteins known as cytokines. These cytokines got their name by Isaacs and Lindenmann [1] after their ability to interfere with viral growth and production. Isaacs and Lindenmann worked at the Medical Research Council Laboratory in Mill Hill, outside London and were the first to publish a paper on these proteins. Drs. Isaacs and Lindenmann [1] had been studying the effects of different agents on viral growth using infected egg membranes with live viruses and found that the viruses failed to grow. They concluded that something had interfered with the growth process of viruses. They isolated this protein and called it interferon (IFN), since it interfered with viruses’ growth. Viral infection triggers a complex regulatory product of inborn modifiers, designed to defend against foreign invaders. These modifiers have notable role in the first line of defense against viral infection and improve the body’s natural response to infection and other diseases. In general, interferons are produced by cells when a subject is invaded by viruses.

The IFN is released into the blood stream and intercellular fluid to induce the production of an enzyme that counters the viral infection by preventing the viruses from replicating in the body [2]. Beside the activation of the immunity, IFN produces a broad spectrum of non-immunological host defenses in the countered reply to infection, including fever, anorexia, and sleep. It was found that a variety of stimuli act on different cells and organ systems to give rise to various endogenous types of IFNs. Three different families of IFNs are produced. They initially were classified as leukocyte, fibroblast and immune IFN according to their supposed production of cell and organ sites.

These 3 classes are now classified into three different types on the basis of antigenicities of their proteins and biological properties: alpha, beta and gamma [2-8]. IFN-alpha is produced by epithelial cells. IFN-beta is produced by fibroblast cells, whereas IFN-gamma is produced by cells of the immune system. These three classes are now classified into three different types on the basis if antigenicities of their proteins and biological properties [9]: type I, II, and III. Over 20 type I interferons, which include IFN-alpha and IFN-beta, have been identified and share the ability to bind to Type I IFN (IFNAR) receptors. IFN type I are family of structurally related specific proteins found only in vertebrate [10]. Type II IFN consists of single type IFN-gamma, which is markedly different from type I IFNs, and bind to IFN-gamma receptor (IFNGR). Type III IFNs are described recently and consist of three lambda groups [11]. All the IFNs are proteins (lymphokines) normally produced by the body in response to infections.

Alpha IFN is a protein with immunomodulatory, antiproliferative and antiviral properties. IFN-alpha plays a critical role in maintaining the balance of the immune system by stimulating natural killer (NK) cells and is used in the treatment of hairy cell leukemia and AIDS-related Kaposi’s sarcoma. Exogenous IFN-alpha initially has been induced by infection of white blood cells in cultures.

Beta IFN shares about 60% homology with IFN-alpha and exists in a single molecule form. In vivo, production of IFN-beta is produced by fibroblasts that are stimulated by viruses or by synthetic inducers. IFN-beta is an immunoregulatory cytokine that reduces relapse frequency in multiple sclerosis (MS) and ameliorates experimental autoimmune neuritis. More recently, there are observations suggesting that IFN-beta treatment is beneficial in chronic inflammatory demyelinating polyradiculoneuropathy [12-17].

Gamma IFN is a macrophage activating protein that modulates a variety of biological pathways potentially relevant to muscle wasting and immune dysfunction and plays a fundamental role in mediating the hypercatabolic state of multiple cell types following burn trauma. IFN-gamma has no homology to IFN-alpha or IFN-beta. The human IFN-gamma appears to exist in a single molecule form and is produced by T lymphocytes. The IFN-gamma gene possesses several introns, whereas the genes of the other IFNs subtypes are devoid of introns [18]. IFN-gamma is a prototype of two classes of substances – lymphokines and interferons [19]. The genomic structure of IFN-gamma is now known.

The doses of IFN used in patient treatment at clinics are given in International Unit. An International Unit (IU) of IFN is defined as the amount that inhibits viral replication by 50% [19,20].

Since IFN used in immunologic therapy is synthesized and released naturally in the body, it was thought to be nontoxic [21]. However, several adverse effects are reported as a result of exogenous IFN treatment such as sensory and motor abnormality, fever, anorexia, confusion and depression. All these symptoms are central nervous system (CNS) mediated phenomena [22-28]. The IFN system is more complex than originally anticipated and it was later shown that the IFNs have not only antiviral characteristics but also many multi-cellular effects. In this chapter we discuss some of the IFN effects on the CNS.

Interferon receptors and interferon binding in the CNS

The IFNs receptors are composed of multiple distinct glycosylated transmembrane polypeptides, a number of protein tyrosine kinases, and interact transiently with variety of other proteins and transcription factors, phosphatases, signaling receptors, and adapter proteins coupling the receptors to alternative signaling pathways. IFN receptors have been identified in the CNS, immune system and endocrine system [29,30]. IFN participates in the regulation of various cellular processes and exerts effects on the neuroendocrine, CNS and immune system [29-42].

Interferon receptors are found in macrophages, monocytes, T-lymphocytes, glia, and neurons. Interferons modulate gene expression via simple, direct signaling pathway containing receptors JAK tyrosine kinases and STAT transcription factors. Tyrosine kinase activation is a common mechanism for triggering eukaryotic signaling pathways [43,44]. Interferons bind to specific receptors on the cell surface receptors resulting in a complex cellular response associated with changes in the expression of a large number of genes [45]. This binding elicits a variety of cellular responses. The IFN receptors have extracellular ligand-binding domain and intracellular kinase domain which is activated following ligand-induced dimerization [43].

The IFNs are classified into at least five classes: alpha, beta, gamma, tau, and omega [43]. As mentioned before, the IFNs family is divided into two groups – type I and type II IFNs. IFN-alpha and IFN-beta belong to type I IFN family of cytokines [9,30,46,47]. Type I IFNs share a common receptor and exhibit similar biological activities [43]. The type I IFN-alpha and IFN-beta (IFN-alpha/beta) are comprised of the products of multiple IFN-alpha genes – up to 12 – and a single IFN-beta gene [48,49]. Type II IFN, also known as IFN-gamma, activates JAK/STAT pathway through its alpha and beta subunit receptors [50,51] to activate JAK1 and JAK2 kinases followed by tyrosine phosphorylation of STAT1 [51-55].

The brain is relatively isolated from the immune system due to the presence of the blood brain barrier (BBB), which limits the penetration of circulating cytokine and antibodies [56]. However, small amount of exogenous IFNs do penetrate to the brain [27,57-59]. Systemically alpha-IFN administration enter the brain through areas where the blood brain barrier is more permeable [2,3,60-65]. IFN-alpha binds to brain tissue, and the binding varies among brain regions.

The existence of specific binding sites within the CNS may, however, represent the link between IFN-alpha and its effects on neuronal activity. IFN-alpha also binds to opiate sites on biological membranes and in experiment using radiolabeled opioid receptor ligand. Moreover, IFN-alpha inhibit dihydromorphine binding in mouse brain homogenates [66] and IFN-alpha treatment also exhibits inhibitory effects on the binding of [3H] naloxone and enkephalin of rat brain membrane in vitro [67], suggesting interaction between the IFNs and the opioid system [38,39,68-75]. Structural and functional similarities have been demonstrated between human leukocyte IFN-alpha and endorphin [66,76].

Interferon and the endocrine system

The detection of adrenocorticotropic hormone (ACTH) and endorphin-like substances from lymphocytes infected with the Newcastle disease virus (NDV) was one of the first studies demonstrating that the immune system is producing peptides and that these peptides interact with the neuroendocrine system [66,77-79]. Leukocyte IFN provides an afferent link between the immune and the endocrine system [80,81]. Moreover, it was shown that IFN-alpha shares a common binding site to specific receptors as ACTH [29,31,33,34,82]. IFN-alpha has been found to modulate corticotropin-releasing factor (CRF) and the hypothalamic-pituitary-adrenal (HPA) axis, and regulate the diurnal activity levels [83]. Cytokine production including IFN-alpha is not restricted to the immune cells. They are also produced and released by the CNS and the endocrine system [66,77-79]. These cytokines exert direct effects on the CNS, on the immune system, as well as on the endocrine system [77,79,83,84].

Sequential similarities between IFN-alpha, ACTH and melanocyte-stimulating hormone (MSH) have been reported [23,85-87]. The similarities of these structures may explain the presence of common functional characteristics found between MSH, ACTH, IFN-alpha, and immunological activity. Moreover, IFN-alpha stimulates ACTH secretion [80,86,88,89]. Systematic (i.p.), central (i.c.v.) and local (microiontophoretic) treatment of IFN-alpha within the hypothalamic paraventricular nucleus (PVN) inhibit the HPA axis [84,90,91], such as the glucocorticoid hormones, which modulate immune activity [79,91]. It was demonstrated in electrophysiologically identified neurosecretory PVN neurons, which regulate adrenocortical secretion, that IFN-alpha treatment decreases their neuronal activities. This decrease in PVN neuronal activity indicates that IFN-alpha participates in the regulation of adrenocortical releasing secretion.

The central nervous system, the immune system, and the endocrine system contain IFN receptors. Moreover, these three systems synthesize and release IFNs. In addition, the experiments reviewed in this chapter suggest that the CNS, the immune system and the endocrine system communicate with each other. Some environmental cues such as stress or mental disorders alter the activities of these three systems, which result in the modification of immunocompetence and incidence of disease [92-96]. In turn, activation of the endocrine system or the immune system results in production and releasing of IFN-alpha, which stimulates the CNS and modulates its neuronal activity.

The immune and endocrine systems are essential in protecting the body from infection and disease as well as regulation of metabolism and other physiological processes. The change in neuronal activity induced by IFN results in altering the neuroendocrine system’s function, and thereby provides a feedback, which is involved in the regulation of the immune system [35,91,94,97-101]. In conclusion, all of the above sections support the notion that the IFNs are neuroregulators and suggest that IFNs are the messengers that provide the communication between the CNS, immune system, and the endocrine system.

Interferon and temperature regulation

Fever is the physiological response to infection between the peripheral immune system and the central nervous system. Moreover, fever is regulated by the central nervous system (CNS), mainly in two sites within the hypothalamus: the hypothalamic preoptic (PO) area and the anterior hypothalamic (AH) area. The PO/AH area contains three types of neurons sensitive to cold only, to heat only, and to different degrees of temperature. These neurons are involved in determining the temperature set point. Therefore, the PO/AH area is suggested as the site of regulating temperature [22,78,102-104]. Fever is initiated by activation of these thermosensitive neurons.

Hypothermia is thermoregulatory response to systemic inflammation that is often regarded as maladaptive to the host [105]. The mechanisms regulating hypothermia are not fully understood, but cytokine such as the IFNs have been shown to modulate the neuronal activities of temperature sensitive neurons in the PO/AH area. The hypothalamus is in close contact with the circulatory system by circumventricular organ system that allows direct contact between them. The consequences of this direct communication allows direct contact with both systems to elicit fever by the circulatory pyrogens that activate the hypothalamic temperature ‘set point’.

Local application of interleukin-1 (IL-1) and IFN-alpha to thermosensitive neurons in the PO/AH area altered the PO/AH neuronal activity [84,101,106-110] that resulted in induction of fever. Therefore, IFN-alpha has been considered as an endogenous pyrogen [25,77,78,111]. The PO/AH area is the most probable site of the pyrogenic action of the IFN [22,102].

Fever is a host defense response to various exogenous pathogenic organisms and their products, such as lipopolysaccharides, and is mediated centrally by endogenous pyrogens which include the IFNs family [106]. The production of the pyrogenic endogenous cytokine resulted from the host defense response to the various exogenous pathogenic organisms [106]. The terms ‘granulocytic pyrogen’ and ‘endogenous pyrogen’ were used to describe substances with biological properties of fever induction. It became evident that pyrogenicity is a fundamental biologic property of several cytokines included the IFNs family [105]. Injection of IFN-alpha intravenously (i.v.) or intracerebroventricularly (i.c.v.) in rodents, cats, and rabbits elicits fever without the production and involvement of the natural endogenous pyrogenic substance interleukin 1 (IL-1), which leads to the suggestion that IFN-alpha is an endogenous pyrogen [77,102].

It was reported that the IFN induced fever resulted from its effects on PO/AH thermosensitive neurons. These activities are blocked by naloxone, an opiate antagonist and failed to respond to antipyrogent agents such as sodium salicylate, which is known to block the neuronal responses to endotoxin and leukocytic pyrogen [25,106,107,109,110,112]. This suggests that IFN-alpha induces fever, at least in part by direct effects on PO/AH thermosensitive neurons, which involve also the opiate receptor mechanism [108,110]. In addition, this led to the postulation that IFN in the brain produces fever by two-step mechanism. The first is the immediate action on opioid receptors on PO/AH thermosensitive neurons and subsequently follow by the release of prostaglandin that elicits fever [25,106,111].

Interferon and food regulation

Eating is a regulatory behavior that contributes to caloric homeostasis. Food intake provides nutrients to support the continuous energy demands, as well as maintains a stable body weight. Utilizing stereotaxic lesion in rats in distinct brain regions, such as ventromedial hypothalamus (VMH) or lateral hypothalamus (LH) resulted in obese or aphagia animals [38,113-115]. For example, bilateral VMH lesions or deafferentiation resulted in marked hyperphagia (and obesity) and faster gastric emptying resulting in more frequent eating [38], while bilateral LH lesion elicits aphagia (absence of eating) and reduced parasympathetic tone, which results in reducing the rate of gastric emptying and prolonging the time interval between eating, similar to anorexia.

Indeed, local application of IFN-alpha using microiontophoretic procedure with multibarrel electrode on VMH and LH neurons [35,116,117] elicits different response, i.e. decreased activity of LH neurons and increased VMH neuronal activity. Similar observations were obtained using coronal brain slice sections [75,118,119] containing both the VMH and LH areas and recording single neuronal activity simultaneously in both sites with glass microelectrode before and after glucose and IFN-alpha administration. In this study, it was observed that in the VMH, glucose perfusion elicits mainly a decrease in firing rate, whereas in the LH, glucose perfusion elicits mainly an increase in firing rate. When IFN-alpha was perfused alone, the opposite effects were observed, mainly a decrease neuronal activity in LH and mainly an increase in neuronal discharges in the VMH.

When both agents given simultaneously together, the presence of IFN-alpha prevents the glucose effects, i.e., the glucose elicited decrease in firing rate in LH was prevented [25,27,111,117,118,120,121-123]. Similar observations were reported by others using different preparations [25,35,116,117,118,124]. The reciprocal interaction between VMH and LH in the mechanism of food intake has reported previously using different approaches [39,114]. There is compelling evidence that the cytokine target the hypothalamus [118,119], where nutritional and other signals for appetite and energy homeostasis are integrated to control food intake and energy expenditures via both sympathetic and parasympathetic push pull function [125]. These observations suggest that endogenously IFN in the brain [2,4,5,126] is involved in feeding regulation as a neurotransmitter or as a neuroregulator.

Other cytokines, such as tumor necrosis factor (TNF) or IL-1, exert similar effect to IFN in inhibiting glucose-sensitive neurons in so-called the ‘hunger center’ (or LH), which resulted in feeding suppression [120,127,128]. Most of the glucose sensitive neurons altering their activity to IL-1 or TNF were also sensitive to IFN-alpha [25,111,127]. It has been reported [101,118,129] that patients treated daily with IFN-alpha show prominent side effects such as anorexia and lose more than 10% of their body weight [28,129,130,131,132]. The anorexic state produced by IFN-alpha is reversible and after discontinuation of IFN-alpha therapy all patients usually return to normal weight within 7 to 10 days [129]. A similar decrease in food intake was observed in animals following IFN treatment [101,118,127,131,133]. This weight loss presumably is the result of increased VMH activity and decreased LH activity.

Although cytokines such as IFN suppresses food intake independently to fever, it is possible that the increase in temperature caused by IFN treatment results with inhibition of feeding, and the fever modulates the activity of glucose-responsive neurons in the VMH and LH [108,111]. Since IFN produces also sleep and sleep prevents eating, less eating results in weight loss. This is another possible explanation how IFN affects feeding behavior [38,101,128,134-136]. Furthermore, in healthy subjects, plasma IFN level is increased after eating during the day with peak level at 18:00 h and the lowest level in early morning [7,137]. These daily variations in the endogenous IFN level in healthy humans are linked to external cues such as physical activity, feeding and sleep [7]. Such observation can explain how IFN elicits feeding suppression and anorexia [25,27,136].

Interferon and sleep

Sleep is a behavioral state that alternates with waking. An ascending brainstem projection regulates the sleep-waking cycle. The output of ascending reticular activating system (ARAS) divides into the thalamocortical system, the thalamohypothalamus and the thalamoforebrain systems. Therefore, day sleep modulation agent has effects on the ARAS. It is known that cytokines such as IFN are somnogenic and are involved in the sleep-wake regulation via altering the neuroendocrine system, neurotransmitters and nitric oxide [138]. The primary determinant in identifying stages of sleep is the electroencephalogram (EEG). The EEG is a gross potential recorded from the surface of the scalp of humans and can be recorded from cortical and subcortical structure [139].

The frequencies of the EEG potentials recorded varying between 1 to 40 Hz with amplitudes that range from 20 to 100 μV, i.e., the behavioral signs of sleep vary regularly during the sleep time between the following stages: (a) a wake stage is indicated by low amplitude desynchronized fast (30 Hz) EEG activity; (b) a drowsy stage indicated by 7-13 Hz – alpha wave and is known as stage 1 sleep; (c) high amplitude low frequency 4-7 Hz – theta wave is classified as step 2 sleep spindle; (d) EEG recording exhibiting 12-14 Hz includes sleep spindle and K complexes known as step 3 sleep; (e) the next stage of sleep is defined by deep sleep – 1 to 4 Hz high amplitude waves known as stage 4 sleep; and (f) the last stage of sleep is characterized by activity similar to the awake one such as low amplitude desynchronized fast activity, and the electromyogram (EMG) from the head, neck and general skeletal muscles activity is dramatically reduced except for the middle ear muscle and the eye which exhibit rapid eye movement (REM). This stage of sleep is known as REM sleep.

IFN-alpha given to a healthy human [140] impaired the quality of night sleep, suppressed the slow wave sleep, and increased the time spent in shallow sleep. The time spent in REM sleep was also decreased which suggest that IFN-alpha may be a factor responsible for alterations of sleep [140]. EEG and EEG-like activity recording from several cortical and subcortical sites in albino Sprague-Dawley rats before and after systemically IFN-alpha injection resulted in alteration of the EEG recording first in the hypothalamus, followed by somatosensory cortex, limbic structures and motor cortex respectively [139]. This effect of IFN-alpha in modifying the ARAS that results in output signals, which is the underlying cause of its diverse effects on the 24h rhythms in physiology and behavior like sleep [141]. The somnogenic actions of IFN-alpha/beta have been initially reported [27,28,84,100,101,107,134-136,139,142,143]. It was only recently recognized that also IFN-gamma elicits dose-dependent characteristics increased in non-rapid eye movement sleep (N-REM) accompanied with slow wave EEG activity [144].

Changes in sleep pattern are common symptoms of infectious disease. The initial sleep alteration induced by infection is an increase in non-rapid eye movement (N-REM) sleep and increase in the delta wave activity of the EEG [144,145,146]. Similar observation was obtained following IFN injection [136]. For example, IFN-alpha/beta enhance EEG synchronization in rats, rabbits, and humans [134,135,136,139], while IFN-gamma promotes N-REM sleep in humans [144]. Men with difficulty maintaining normal sleep had a significantly lower IFN-gamma to IL ratio by a factor of 4 [147]. Alcoholic subjects show profound sleep disturbances. Their IFN-gamma to IL ratio is 10. They also exhibit reduced level of NK cell activity coupled with losses of delta sleep and increase REM sleep [148]. All of these observations suggest that the IFN modulates sleep patterns by altering the ascending reticular activating system.

Interferon and opioids

Drug dependence has been considered to be primarily a CNS phenomenon [71,149]. One means whereby the degree of opioid dependence is assessed is by administrating an opioid antagonist like naloxone in animals treated chronically with opiate to precipitate stereotypic withdrawal behavior [150-152]. It was found that selective destruction of specific brain sites in morphine dependent animals attenuated the severity of systemically naloxone precipitated withdrawal [124,153,154]. Moreover, intracerebral microinjection of naloxone only to the above specific brain areas of opiate-dependent animals precipitated withdrawal that is identical to that following systemic naloxone administration indicating that several specific brain areas are involved in the withdrawal behavior [73].

The involvement of the immune system in some of the various aspects associated with the chronic use of opioids was suggested a long time ago by Andral in 1844 [155] and more recently by others [36,39]. The immune system’s cells possess opiate receptors [156], which when activated induce a variety of functional modifications such as the establishment of profound immune suppression following chronic opiate treatment [149,157]. The ability of the immune system and the CNS to communicate and interact with each other was demonstrated [35,39,41,66,70,73]. Hypothalamic lesions or ablations modulate immune components and reaction [158,159] and hypothalamic neurons alter their neuronal firing rates following an immune challenge [159,160].

The participation of the immune system in modulating central opioid actions has been recognized by the finding that various immunomodulator agents such as IFN [36,39-41,70,73,150,151,161], cyclophosphamide, cortisol [162], cyclosporine [36] and immune suppressive doses of gamma irradiation [163,164] attenuate the severity of naloxone precipitate withdrawal in opiate dependent rats. These observations provide additional evidence that the immune system and immunomodifiers such as IFNs participate in opiate activity. In addition, the neuronal activity of the cortex, hypothalamus and hippocampus neurons were modulated following systemic or local IFN application or manipulation of the immune system [35,39,117,118,139,158,159,165-169]. These studies suggest that the immune system compartment or immune cell products (immunomodulator agents) act on the CNS and is involved in regulating function including the opiate mediated response [40], and that there is a reciprocal pathway of communication between the immune system and the CNS.

Interferon was reported to modulate opiate mediated phenomena by a direct action within the CNS, thus directly supporting the contention that immune-derived peptide can convey information from the immune system to the CNS [35,39,73,142,150,151,161,165,166,170,171]. Using neurophysiological recording procedures, Dafny et al. [36] have demonstrated that IFN-alpha administration results in an alteration of the neuronal activity of brain regions participating in the expression of opioid activities both when IFN was given alone or in the presence of opioid [70]. It is important to emphasize that IFN exerts its effects upon opioid receptor and upon a distinct receptor complex [39,41,70,168]. IFN-alpha modulates opioid activity at the level of single neurons in discrete CNS sites and modifies behavioral paradigms, supporting the concept that IFN-alpha is a neuromodulator of immunologic origin [39,41,70]. Thus, IFN-alpha is one of the cytokine products released by the immune system that possesses immunological, endocrinological, and neuromodulatory properties.

Administration of morphine resulted in decreased level of endogenous circulating IFN-alpha as well as decreasing the capability of cells to produce IFN-alpha [172]. The level of IFN-alpha inhibition was directly related to the morphine dosage [173]. IFN-alpha shares some pharmacologic properties similar to beta-endorphin, such as the production of analgesia and catatonia as well as affinity for 3H-morphine binding sites in mouse brain membrane [33,80]. We conclude that this reduction in endogenous IFN resulted in morphine dependent addiction [68,99] and hypothesize that IFN-alpha is the endogenous cytokine which serves to prevent the development of tolerance and dependence to the endogenous opioids. In a series of experiments, IFN-alpha given intracerebroventrically (i.c.v.) and systemically (i.p.) attenuated dramatically the severity of opiate withdrawal behaviors [35,39,72,150,151,174].

Using several electrophysiological procedures such as sensory evoked potential, EEG, single neuron recording, microiontophoretic and systemic application of IFNs, morphine, and naloxone [35,39,99,117,118,139,167,168,169] suggest that there are at least three different functional and/or receptor sites for IFN-alpha within the CNS: 1) a site where IFN-alpha caused excitation, and this excitation is blocked/reversed by the opiate antagonist naloxone, which may represent the kappa or the delta opiate receptor sites [109]; 2) a site where IFN-alpha caused reduction (inhibition) in neuronal activities, and this effect is also antagonized by naloxone, which may represent the mu receptor type; and 3) a site that IFN-alpha caused excitation in neuronal activity but naloxone was unable to antagonize the IFN-alpha induce excitation [35,168].

In an experiment using molecular procedures, it was demonstrated that i.c.v. injection of IFN-alpha suppressed the cytotoxic activity of the cells in spleen of mice, and this effect is prevented by pretreatment with naloxone [175,176,177]. Moreover, in in vivo preparations from rat brain membrane, IFN-alpha treatment has been shown to inhibit the binding of [3H] naloxone [67], demonstrating a competition between IFN-alpha and naloxone for membrane binding sites. This observation may explain the mechanism of how IFN-alpha attenuates the morphine withdrawal behaviors in morphine dependent animals [67,70]. In conclusion, IFN-alpha and opioids are modulatory agents mediating brain endocrine and immune interaction through complex mechanisms involving multiple receptors and sites, and acting at different levels of integration [170,171,178].

Author(s) Affiliation

C Reyes-Vasquez – Departamento de Fisiologia, Division de Investigacion, Universidad Nacional Autonoma de Mexico, Apdo. Postal 70250, Mexico 20, D.F. Mexico
N Dafny – Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, and The University of Texas Graduate School of Biomedical Sciences, P. O. Box 20708, Houston, TX 77225, USA

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Cover Image: Dual role of IFN-γ in innate and adaptive immune cells in EAE. From Stage-specific role of interferon-gamma in experimental autoimmune encephalomyelitis and multiple sclerosis. By Gabriel Arellano, Payton A. Ottum, Lilian I. Reyes; Front. Immunol., 29 September 2015 https://doi.org/10.3389/fimmu.2015.00492