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Deleterious versus protective autoimmunity in multiple sclerosis

Cellular Immunology (Available online 28 April 2015)

Graphical abstract

 

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Highlights

 

  • Deleterious autoimmunity in MS is mediated by auto-reactive Th1, Th9 and Th17 cells.
  • The dominant Th response in MS is dependent on patient’s individual characteristics.
  • Th cell induced microglia switch toward inflammatory phenotype is crucial in MS.
  • Autoimmunity mediated by Th2 and T regulatory cells exhibits protective effects.
  • The failure to perform adequate protective autoimmunity is associated with MS.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of central nervous system, in which myelin specific CD4+T cells have a central role in orchestrating pathological events involved in disease pathogenesis. There is compelling evidence that Th1, Th9 and Th17 cells, separately or in cooperation, could mediate deleterious autoimmune response in MS. However, the phenotype differences between Th cell subpopulations initially employed in MS pathogenesis are mainly reflected in the different patterns of inflammation introduction, which results in the development of characteristic pathological features (blood–brain barrier disruption, demyelination and neurodegeneration), clinically presented with MS symptoms. Although, autoimmunity was traditionally seen as deleterious, some studies indicated that autoimmunity mediated by Th2 cells and T regulatory cells could be protective by nature. The concept of protective autoimmunity in MS pathogenesis is still poorly understood, but could be of great importance in better understanding of MS immunology and therefore, creating better therapeutic strategies.

Keywords: Multiple sclerosis, Protective autoimmunity, Th1 cells, Th2 cells, Th9 cells, Th17 cells, Regulatory T cells.

1. Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by the formation of disseminated demyelinating lesions accompanied by axonal degeneration. Traditionally, inflammation in MS was thought to be autoimmune by origin, mediated by autoreactive, myelin specific CD4+T cells that orchestrate all pathological events involved in disease pathogenesis [1] . This generally accepted hypothesis was put into the question, by the unexpected discovery that CD4+T cells specific for myelin sheath antigens are also present in periphery blood of healthy individuals, even in an equal number as in patients suffering from MS [2] . However, these cells were not at the same activation state [3] , indicating that the presence of myelin specific CD4+T cells is not self-sufficient for autoimmunity; yet for disease onset are more important, if not critical, conditions that allow their activation and polarization. The activation process occurs in the periphery, probably in the cervical lymphatic nodes, but other CNS-draining lymph nodes also contribute to the induction and propagation of autoimmune response. Antigen-presenting cells (APCs) containing myelin were identified in the cervical lymphatic nodes of MS patients[4] and [5], and in animal model of MS, experimental autoimmune encephalomyelitis (EAE), myelin specific proliferation was detected in the cervical lymph nodes [5] . Maybe, the most illustrative evidence is that, prior to the clinical onset of EAE, myelin-specific CD4+T cells up-regulated activation markers in the cervical lymph nodes, when no T cell activation was detected elsewhere, including the CNS [6] . In EAE, encephalitogenic lymphocytes were also found in the lumbar lymph nodes and the spleen. Besides T cells specific for myelin peptide used in EAE induction, lymphocytes specific for other myelin-derived peptides were also present in these organs. This indicated that the process of intermolecular epitope spreading is occurring in CNS-draining secondary lymphatic organs and suggested their involvement in initiating and mounting of autoimmune response in MS [7] . Multiple mechanisms, mainly associated with infection, have been described to mediate the activation process, notably the molecular mimicry, bystander activation and epitope spreading [8] , and indeed more sever disease exacerbations are commonly associated with both viral and bacterial infections [9] . When activated, T cells migrate into CNS in two waves, initially across the vascular endothelium of the blood–cerebrospinal barrier, that is suspected to be necessary for subsequent disturbance of blood–brain barrier (BBB) permeability and brain parenchymal T cell infiltration, on the larger scale[10], [11], and [12]. In the encephalic compartment, upon recognition of myelin antigens presented by macrophages and dendritic cells in perivascular space, auto-reactive CD4+T cells produce a broad spectrum of cytokines, activate microglia and create pro-inflammatory environment that mediates myelin sheath damage – demyelination, but also axonal degeneration, which are two major characteristics of MS pathology[13] and [14].

Although, autoimmune response is still considered the key pathological feature of MS, some studies suggest that autoimmunity could also exhibit protective effect on CNS damaged tissue[15] and [16]. This newly postulated concept of protective autoimmunity in underlying pathogenesis of MS is still poorly understood, but could be of great importance in better understanding of MS immunology and therefore, creating better therapeutic strategy of the disease treatment.

2. Deleterious autoimmunity in MS

During the process of activation, maturation and migration, myelin-specific CD4+T cells are differentiated into effector, T helper (Th) cells. Depending on the cytokine profile and effector functions, Th cells are divided into subsets of Th1, Th2, Th9, Th17 cells; but the final number of these subsets is not yet conclusive [17] . The exact phenotype of T cells that drives deleterious autoimmune response in MS remains controversial.

2.1. Th1 mediated autoimmunity in MS

Until recently, it was believed that myelin specific CD4+T cells exclusively belong to the Th1 cell lineage, which develops when naïve CD4+T cells are exposed to interleukin-12 (IL-12) and interferon γ (IFN-γ). Cell signalling initiated by these cytokines, activates several transcriptional factors, but for complete Th1 cell differentiation, T-box transcriptional factor (T-bet) is needed and considered to be the master regulator of this cell linage. T-bet is crucial in promoting the production and secretion of IFN-γ, the hallmark cytokine of Th1 cells, but also in suppressing the differentiation programs associated with other Th cell subsets [18] . Besides IFN-γ, Th1 cells also produce interleukin-2 (IL-2), interleukin-3 (IL-3) and tumor necrosis factor α (TNF-α) [19] .

First evidence to suggest Th1 cell pathogenicity has been acquired on EAE, demonstrating that the transfer ofin vitroactivated myelin specific Th1 cells induces EAE in healthy animals[20] and [21]. Analysis of cells isolated from the CNS of EAE mice showed that infiltrating CD4+T cells predominantly produce the Th1 cytokines, IL-2 and IFN-γ [22] . More recent study has demonstrated that silenced T-bet expression protects experimental animals from EAE induction [23] . Data supporting Th1 cell involvement in MS pathogenesis have also been reported in human population. Specifically, during clinical investigation of immunomodulatory and therapeutic potential of artificially modified components of myelin, disease exacerbation occurred with predominant expansion of myelin specific Th1 cells in cerebrospinal fluid (CSF) [24] . The treatment of MS patients with IFN-γ resulted in an increased number of disease exacerbations [25] , whereas administration of IFN-γ neutralising antibodies appeared to have therapeutically beneficial effects [26] .

Based on histopathological analysis of sclerotic plaques, Th1 cells and IFN-γ are even directly linked with the demyelination processes. Namely, strong IFN-γ immunopositivity was observed at the margins of active MS plaques, and this immunopositivity was in correspondence to apoptotic oligodendrocytes, that form myelin sheath [27] . The subsequent experiments, performed on cultured human oligodendrocytes derived from non-MS adult brain tissue, identified the potential mechanism by which IFN-γ could promote oligodendrocyte apoptosis, demonstrating that IFN-γ up-regulates death (Fas) receptor on the oligodendrocyte surface [28] . The interaction between Fas receptor and Fas ligand, up-regulated on CD4+T cells upon activation, results in oligodendrocyte death. Neurotoxic effect of IFN-γ is also suggested, implicating this cytokine in neurodegenerative processes seen in MS [29] .

Although, clinical studies indicated the important role of Th1 cells and IFN-γ in the development of MS pathological substrate, some later experiments, carried out in EAE, failed to reconfirm indispensable significance of this key Th1 cytokine. Notably, mice defective in IFN-γ gene were suitable to EAE induction; even develop more severe clinical presentation [30] . Similar findings were obtained in mice deficient for p35 subunit of IL-12 receptor, what was unexpected considering that IL-12 is necessary for executing Th1 differentiation programme. Interestingly, mice deficient for the other subunit of IL-12 receptor – p40 were resistant to EAE. Those contradictory data were partially unpuzzled by the discovery of interleukin-23 (IL-23), which receptor is composed of p40 unit, but instead of p35, it has p19 unit. Mice deficient in p19 also resisted EAE induction [31] . Taken together, these results indicated that IL-23, rather than IL-12, is required for EAE development, what made crucial significance of Th1 cell in EAE induction questionable. Later, it was found that IL-23 is a cytokine necessary for the differentiation and stabilization of Th17 subset of CD4+T cells, which led to the intense research of Th17 cell pathogenicity in EAE and MS [32] .

2.2. Th17 mediated autoimmunity in MS

Th17 cells were first described a decade ago, as a subpopulation of CD4+T cells that produce large amounts of the interleukin-17 (IL-17) [33] . Further studies disclosed that this cell linage produces a much wider cytokine milieu, including IL-17A, IL-17F, interleukin-6 (IL-6), interleukin-9 (IL-9), interleukin-21 (IL-21), interleukin-22 (IL-22), IL-23, interleukin-26 (IL-26), granulocyte colony stimulating factor-macrophage colony (GM-CSF), TNF-α; however, IL-17A is still considered the hallmark cytokine of Th17 cells[34], [35], [36], and [37]. Besides the direct pro-inflammatory effect, IL-17A promotes production of other soluble mediators, including interleukin-1 (IL-1), IL-6, TNF-α, GM-CSF, matrix metalloproteinases (MMPs) and CX chemokines – CX chemokine ligand 8 (CXCL8) in different cells, what together indicates a distinctive pro-inflammatory nature of Th17 cell linage[38], [39], and [40]. Th17 differentiation pattern is not precisely defined, but it is associated with specific transcription factors, such as a retinoic acid-related orphan receptor γt (RORγt), which activation depends on the number of positive and negative regulators [41] . It was originally thought that transforming growth factor β (TGF-β), IL-6 and IL-1 are necessary for the Th17 cell differentiation, while the autocrine effect of IL-23 is needed for an expansion of the cell linage [42] . In humans, it has been shown that IL-1, IL-6 and IL-23 promote the Th17 cell differentiation, while TGF-β is expendable, although indirectly inhibits immune responses mediated by other Th cells [43] .

Numerous experiments conducted in EAE suggested IL-17 and Th17 cell relevance in the MS pathogenesis[32], [41], [44], and [45]. In the human population, RNA transcripts of IL-17 gene are found in demyelinating plaques of patients suffering from MS [46] , whereas IL-17 producing cells are identified in the active, but not inactive plaques [47] . Additionally, the disease activity is associated with the increased number of Th17 cells in the patient’s blood [48] ; but also in the CSF, what was not the case with Th1 cells [49] .

Besides data simply confirming Th17 cell involvement in MS development, there are also research affords to identify the exact pathogenic mechanisms by which Th17 mediated autoimmune response is initiated and how it promotes demyelination and neurodegeneration. Starting from Th17 cell differentiation in MS, it is shown that myeloid dendritic cells, isolated from CNS of EAE mice, are able not only to activate naïve myelin specific CD4+T cells, but favorably skewed them to differentiate into Th17 phenotype [50] . Those dendritic cells could potentially migrate from encephalic compartment to cervical lymphatic nodes, where CNS antigens are drained [51] , and there present myelin antigens to naïve myelin specific CD4+T cells, determining their Th17 differentiation programme. Indeed, APCs within the cervical lymphatic nodes have been found to contain CNS antigens, in patients with MS as well as in healthy controls[4] and [52]. Moreover, myelin debris and myelin containing APCs are also present in the subarachnoid and perivascular space of CNS, what could suggest CSF as the potential route of antigen and APC migration[51] and [53]. Following peripheral activation and differentiation, Th17 cells express high level of C–C chemokine receptor 6 (CCR6) on the cell surface[54] and [55]. On the other hand, the ligand for CCR6 – C–C chemokine ligand 20 (CCL20) is constitutively expressed by the vascular endothelium of blood–cerebrospinal barrier, what may explain high encephalitogenic potential of this cell linage [55] . T cell migration studies performed during EAE development, also identified blood–cerebrospinal barrier as the initial site of T cell entry into the encephalic compartment[56] and [57]. Furthermore, it was confirmed that IL-17 producing myelin-specific CD4+T cells firstly re-encounter target antigens in the subarachnoid space, where these antigens are expressed on the surface of local APCs [57] . Upon antigen recognition, Th17 cells release a various pro-inflammatory mediators including IL-17A, thus creating pro-inflammatory environment which could mediate CNS tissue damage in multiple terms.

Specifically, IL-17A by inducing generation of reactive oxygen species (ROS) in BBB endothelial cells, leads to activation of contractile machinery, down-regulation and disorganization of tight junctions, and consecutively results in BBB breakdown, that is a crucial, early event in the pathogenesis of MS lesions [58] . IL-17A is also shown to mediate disruption of the BBB by stimulating production of MMPs, which degrade the tight junction proteins [59] . Moreover, IL-17 and ROS lead to the overexpression of endothelial adhesion molecules, thus favoring massive transmigration of other inflammatory cells, including Th1 cells, across BBB and the formation of substantial inflammatory infiltrates[58], [60], and [61]. In support of this hypothesis, during EAE development in the brain, Th17 cell infiltration occurs prior to the disease clinical symptoms; whereas significant infiltration of Th1 cells is detected at later stages of EAE development [62] . Also, the increased number of Th17 cells in CSF of MS patients during relapse phase, suggests that these cells could have an important role in triggering the inflammatory processes in the brain [49] .

In encephalic compartment, Th17 cell driven autoimmune response has been directly implicated in demyelinating processes. It has been reported that IL-17, in synergy with TNF-α, promotes oxidative stress in oligodendrocyte, leading to apoptosis of these myelin-forming cells [63] . IL-17 could be also involved in the disturbance of remyelinating processes, considering that IL-17 exhibits strong inhibitory effects on the maturation of oligodendrocyte lineage cellsin vitroand reduces their survival [64] . Moreover, IL-17 treatment of neural stem cells derived from embryo brains, resulted in restricted proliferation and significantly reduction of oligodendrocyte precursor cell number [65] .

Although neurodegeneration and axonal injury in MS could be simply consequence of myelin sheath loss [66] , some data proposed Th17 cell involvement in this process. Byin vivomonitoring of EAE development, it has been discovered that myelin specific Th17 cells can directly interact with neurons. During this interaction, which remarkably resembles immune synapses, but without T cell receptor engagement, Th17 cells induced severe, localized fluctuation in neuronal intracellular Ca2+level, what is considered to be early hallmark of neuron damage [67] . Direct neurotoxic effect of Th17 cells is suggested even earlier, by demonstrating that Th17 cells in co-cultures kill human fetal neurons, however in this experiment, granzyme B is postulated to mediate cytotoxic effect [61] . In other animal models of neurological disorders, such as Alzheimer’s disease, the direct contact between Th17 cells and neurons is also reported. Specifically, an interaction between neuronal Fas and Fas ligand express by activated Th17 cells is documented, that results in neuronal apoptosis and death[68] and [69]. In a model of ischemic brain injury, IL-17 is also shown to promote neuronal dysfunction [70] , as well as apoptotic neuronal death [71] .

Recently, much is discussed about the involvement and significance of GM-CSF in the pathogenesis of EAE and MS. GM-CSF is a pro-inflammatory haematopoietic growth factor that supports the maturation, recruitment and activation of different innate immune cells, including macrophages, monocytes, neutrophils, dendritic cells, and microglia [72] . Physiologically, GM-CSF is an important mediator of infectious and antitumor immunity; however its implication in the pathogenesis of a wide spectrum of autoimmune disorders, including MS, is also well documented [73] . GM-CSF is a rare cytokine proven to be indispensable for EAE onset. Specifically, GM-CSF-deficient mice have been shown to resist EAE induction following immunization with myelin oligodendrocyte glycoprotein, whereas, GM-CSF treatment restored animal’s susceptibility to the disease and caused more severe clinical course, characterized by frequent relapses [74] . Early induction of inflammatory response in EAE is associated with GM-CSF capacity to activated resident microglia[75] and [76], but it is also shown that GM-CSF supports recruitment of peripheral macrophages and expansion of encephalitogenic T cells, what is important pathogenic factor in the further propagation of the disease [75] . In humans, increased level of GM-CSF has been reported in CSF of patient with relapsing-remitting MS, during the active phase; interestingly such an incensement was not detected during the stabile phase of the disease [77] . Blockade of GM-CSF activity might thus be a promising therapeutic approach in MS treatment, and MOR103, a fully human monoclonal antibody against human GM-CSF is currently being evaluated in clinical trial (phase 1b).

During EAE onset, encephalitogenic auto-reactive T cells are identified as the major cellular source of GM-CSF[75] and [78]. The phenotypic characteristics of these T cells are still controversial, considering that GM-CSF production is reported in Th1, Th2 and Th17 cells[79], [33], and [80]. However, pathogenic role of GM-CSF in EAE development is best studied in the context of Th17 cell mediated immune response [81] . It is shown that GM-CSF production by Th17 cells is crucial for their encephalitogenicity and capacity to induce EAE [80] . GM-CSF production by Th17 cells was stimulated by IL-23 and IL-1; on the other hand, GM-CSF favored IL-6, IL-23, or IL-1 production in APCs, what together establishes a positive feedback loop that results in further differentiation of Th17 cells and amplification of the inflammatory response[80] and [82]. Although, production of GM-CSF by activated human Th17 cells is reported [83] , Noster and colleagues showed that GM-CSF producing T cells isolated from CSF of MS patients co-expressed IFN-γ and T-bet but not IL-17 and RORγt [84] . Similar observations were made by Piper and colleagues, who identified IFN-γ+GM-CSF+T cells in the joints of patients with juvenile idiopathic arthritis. However, this cell population mainly arisen from Th17 cells in the presence of IL-12, thus the development of IFN-γ+GM-CSF+T cells was attributed to prominent plasticity of Th17 cell lineage [85] . Besides, T cells co-expressing IFN-γ and GM-CSF, specific subset of “GM-CSF only” producing Th cells that did not express cytokines or transcription factors characteristic for Th1, Th2, and Th17 cells was also detected in CSF of MS patients [84] . The authors postulated that this is completely new subset of Th cells (Th-GM), and indeed some supporting experimental data are reported associating this potentially new cell lineage with interleukin-3 (IL-3) secretion and the expression of signal transducer and activator of transcription 5 (STAT5) as a master regulator [86] .

2.3. Th9 mediated autoimmunity in MS

Potential Th9 cell contribution in the development of deleterious autoimmune response in MS is currently under the discussion. Th9 cells are newly defined effector CD4+T cells subpopulation characterized by the production of IL-9 and interleukin-10 (IL-10) [87] . The rise of this T cell linage is associated with TGF-β and interleukin-4 (IL-4), which downstream activation of several transcription factors required for the Th9 differentiation, including signal transducer and activator of transcription 6 (STAT6), PU.1 transcription factor, GATA binding protein 3 (GATA-3) and interferon regulatory factor 4 (IRF4)[88], [89], and [90]. Since these transcription factors are also expressed by other Th cells during their development (particularly Th2 cells), some authors consider Th9 cell to be a specific differentiation state of Th2 cells specialized in secreting large quantities of IL-9. In the presence of TGF-β and IL-4, Th2 cells indeed change their characteristic cytokine profile and shift to IL-9 secretion [91] , also Th9 cells massively produce IL-4 when cultured in Th2 polarizing medium, what together suggests close relationship between these two cell lines [92] . Most of our current knowledge about Th9 cells is still based onin vitroexperiments performed under precise culture conditions that allow balanced expression of transcription factors in order to form Th9 phenotype.In vivo, such conditions are rarely met, so there is a reasonable doubt of the very existence of these cells as distinct T cell subsetin vivo. Th9 cells, indeed, proved to be difficult to detectin vivo, considering aggravating fact that Th17 cell are also shown to produce significant amount of IL-9 in the presence of TGF-β [93] , as well as natural killer T cells [94] and regulatory T cells [95] . However, Purwar and colleagues did manage to identify distinct subset of CD4+T cells, involved in antitumor immunity, that produce IL-9 but not IFN-γ, IL-4 or IL-17 in human skin and blood [96] . Relatively small but stable population of CD4+T cells isolated from human blood and tissues was also recently reported as a main source of IL-9. These IL-9 secreting cells lacked the production of other Th specific cytokines (IFN-γ, IL-13 and IL-17) as well as an expression of transcription factors specific for regulatory T cells, what collectively supports the existence of Th9 cells in humans as independent and distinguish T cell lineage [97] .

Despite the secretion of immunoregulatory cytokine IL-10, Th9 cells do not suppress T cell proliferationin vitro [98] , yet many studies clearly demonstrated pro-inflammatory capacity of these cells, as well as their potential involvement in various autoimmune disorders, including EAE[99], [100], and [101]. First indications of Th9 pathogenic role in EAE were based on the fact that adaptive transfer of myelin-specific CD4+T cells, differentiatedin vitrounder Th9 polarizing conditions, induces EAE in healthy animals [102] . Also, animals deficient in IL-9/IL-9 receptor (IL-9R), or treated with IL-9 neutralizing antibodies were protected from EAE or exhibited delayed onset and ameliorated clinical symptoms[103], [104], and [105]. Later, encephalitogenic potential of Th9 cells was reconfirmed by the discovery that these cells express CCR6 which, similar to Th17 cells, enables their entry into the encephalic compartment via blood–cerebrospinal barrier [106] . It appears that Th9 and Th17 cell closely cooperate during the development of EAE. Specifically, IL-9 stimulates astrocytes to express chemokine ligand CCL20, thus favoring transmigration of Th17 cells into the encephalic compartment [107] . Moreover,in vitroIL-9 together with TGF-β can skew the naïve CD4+T cell differentiation toward the Th17 phenotype [37] . Li and colleagues reported that IL-9 neutralizing antibodies suppressed IL-17 production in myelin specific T cells and their potency in adoptive transfer of EAE [108] . During EAE induction, IL-9 deficient mice had less severe clinical presentation, which correlated with the decreased number of Th17 cells and lower expression levels of IL-17 in the CNS[105] and [108]. Th9 cells probably communicate with Th1 cells too, considering that the main cytokine of this cell linage – IFN-γ is shown to suppress the differentiation of Th9, bothin vitroand in EAE, what could explain more severe EAE phenotype development in IFN-γ deficient mice [104] . Although, many authors proposed clear pathogenic potential of Th9 cells in EAE and MS development, there are also reports indicating just the opposite. Elyaman and colleagues suggested that IL-9 is needed for adequate suppressive function of natural regulatory T cells, thus IL-9 could be significant in controlling deleterious autoimmune response in MS. In this study, IL-9R deficient mice developed more severe EAE, what has been associated with a defect in the suppressive activity of natural regulatory T cells [37] . Taken together, Th9 cells and IL-9 certainly have quite complex and pleiotropic functions during EAE development that need to be further investigated and clarified.

2.4. Deleterious autoimmunity and tissue damage in MS; from heterogeneity to homogeneity

Clearly, there are substantial data suggesting that Th1, Th9 and Th17 cells could be driving pathogenic lineage of deleterious autoimmune response observed in MS. Considering heterogeneity of MS pathological substrate [109] , it is possible that each of those Th subsets indeed have encephalitogenic capacity and by different pathogenic mechanisms (involving different cytokine milieu and effector cells) provoke disruption of BBB, demyelination and neurodegeneration, determining clinical manifestations that are mutually indistinguishable. In this context, transfer of myelin specific Th1, Th9 and Th17 cells in naïve recipients, resulted in EAE development, with different patterns of tissue pathology but similar clinical presentation [102] . Then, it is possible that the determination of dominant Th immune response in MS is more dependent on patient’s individual characteristics, including genetic predispositions toward certain Th immune response, as well as specifics of microenvironment circumstances that allow activation and polarization of myelin specific CD4+T cell. However, despite Th polarization, the end point of autoimmune inflammatory process in encephalic compartment results in the identical pathological features clinically presented as MS. Additionally, in humans, initial histopathological heterogeneity of demyelinating lesions in the earliest phase of MS is shown to disappear over time, becoming more uniform [110] . Therefore, besides limiting data proposing direct Th cell neurotoxic and oligodendrocytotoxic effects, it is more likely that pathology seen in MS is predominantly caused in non-specific manner, by the activation of resident glial cells and deleterious effects of the inflammation itself.

Due to constitutive expression of many functional cytokine receptors, microglia and astrocytes are susceptible to the effects of different Th cells[111] and [112]. Specifically, both Th1 and Th17 cells, as well as their products IFN-γ, IL-17 and GM-CSF, are shown to activate and skew microglia and astrocytes toward their pro-inflammatory (M1) phenotype, characterized by the enhanced production of various mediators required for propagation of the inflammatory process[75], [76], [113], [114], and [62]. This pro-inflammatory milieu, including pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), chemokines, MMPs, reactive oxygen and nitrogen species, adenosine-3-phosphate (ATP) and excitotoxins (glutamate, quinolonic acid), could promote oligodendrocyte, as well as neuronal loss in multiple terms[115], [116], [117], [118], and [119]. In EAE, microglia inhibition resulted in reduced clinical severity of the disease, whereas significantly less axonal and myelin destruction was detected in the brain [120] . Microglia activation has been also observed in brain tissue isolated from MS patients and implicated in lesion development [121] . Correspondingly, correlation between microglia activation and clinical disability of MS patients has been demonstrated by MRIin vivostudies [122] ; as well as association with oligodendrocyte and neuronal death [119] . In contrast to Th1 and Th17 cells, there are limiting data on Th9 cell effect on microglia and astrocytes activation. It is shown that IL-9 could promote expression of some chemokines (e.g. CCL20) in astrocytes [107] , also IL-9R deficient mice develop less sever EAE, characterized by decreased number of macrophages [103] , particularly IL-6 producing macrophages in the CNS [105] , what could suggest pro-inflammatory effect of IL-9 on innate immunity during EAE. On the other hand, it is well known that IL-9 supports mast cell migration, activation and the expression of mast cell pro-inflammatory cytokines [123] . Increased number of mast cells is identified in MS demyelinated lesions [124] , and indeed mast cells have been previously implicated in the pathophysiology of brain lesions associated with MS[125] and [126].

Accordingly, the differences between the employed T cell subpopulations in MS pathogenesis could be mainly reflected in the different patterns of inflammation introduction, but the consequences of this inflammatory process result in the same pathology (BBB disruption, demyelination, neurodegeneration) which is presented with the same clinical symptoms classified as MS. Such conception of MS development could be very important, because it could explain why some clinical trials investigating treatments that target a single Th cell subpopulation failed to provide clinical benefits in all patients[127] and [128].

The second important thing is that Th cell subpopulations are not uniformed by phenotype as once thought, yet show high degree of phenotype and function plasticity [129] . In that context, T cells producing both IL-17 and IFN-γ, are described, and even identified as the major population of myelin specific T cells infiltrating CNS during EAE development [130] . Furthermore, conventional Th17 cells, under precise microenvironment conditions, could rapidly shift to the Th1 phenotype characterized by IFN-γ, but not IL-17 production [131] . Th9 cells,in vivoare able to acquire ability to secrete IFN-γ in high percentage [102] . Such Th phenotype fluctuation as well as diversity, makes identification of exact Th subset that initiates deleterious autoimmune response harder, giving the pathogenesis of early MS even more individual aspect.

3. Protective autoimmunity in MS

Although, autoimmunity was traditionally seen as a reflection of the breakdown of immune tolerance that results in multiple immunological disorders, recently it is proposed that autoimmunity may also develop as a physiological response to CNS tissue damage and display protective effects. First evidence to support the theory of ’’protective autoimmunity’’ was based on observation of Moalem and co-workers, that passive transfer of myelin specific T cells in mice with injured optic nerve promotes neuronal repair and survival. Interestingly, it appeared that beneficial effect was antigen restricted, considering that transfer of T cells specific for antigens other than myelin fail to accomplish such effect [132] . The fundamental significance of CD4+T cell population in mediating protective autoimmune response was reconfirmed, by the discovery that deficiency of functional B and T cells induces impaired recovery after nerve injury that could be restored by passive transfer of CD4+T cells, but not CD8+T cells or B cells [133] . Later studies disclosed that T cell mediated protective autoimmunity occurs spontaneously and that all individuals are capable of exhibiting such phenomenon in the response to CNS injury, what proposed physiological origin of this process[16], [134], and [135]. Phenotype characteristics of these CD4+T cells are still disputable, but much is speculated about Th2 cell and T regulatory cell participation in this process.

3.1. Th2 mediated autoimmunity in MS

Th2 cells are CD4+T cell subset known to mediate host defence against extracellular parasites especially helminths, but also allergic reactions such as asthma. The Th2 cytokine profile is multifarious and characterized by the secretion of IL-4, interleukin-5 (IL-5), IL-9, IL-10, interleukin-13 (IL-13), amphiregulin and interleukin-25 (IL-25). The IL-4 mediated signalling and the induction of transcription factor GATA3 are necessary for executing Th2 cell differentiation programme [136] .

A potential Th2 cell contribution in protective autoimmunity is illustrated by the fact that brain injury itself can polarize the immune system toward a Th2 state and induce systemic immunosuppression, in order to provide protection from deleterious autoimmunity rise against revealed CNS antigens [137] . Furthermore, the presence of Th2 cells and their anti-inflammatory cytokines in the brain, including IL-10, tends to promote neuronal protection and survival [16] . In EAE model, protective proprieties of Th2 cells have been suggested even earlier, by demonstrating that EAE recovery correlates with mRNA transcript up-regulation of Th2 polarized cytokines in the brain [138] . Moreover, the induction of Th2 immune response, as well as a pre-existing predisposition toward a Th2 immune response, significantly delayed the onset and severity of EAE[139] and [140]. In humans, Oreja-Guevara and colleagues showed that glatiramer acetate (GA), drug currently in use for MS treatment, at least partially, its beneficial effects on disease activity, accomplishes by shifting autoimmunity toward the Th2 profiled immune response [141] . In this work, the authors postulated that GA beneficial effects seems to be mainly mediated by raising IL-4 and IL-10 levels which could down-regulate deleterious Th1 immune response. However, Th2 immune response could provide protective effects by other means. For example, Th2 cytokines are shown to skew macrophages/microglia to the alternative activated (M2) phenotype, which is characterized by the absence of MHC II molecules (needed for antigen presentation and T cell reactivation), secretion of anti-inflammatory cytokines like IL-10, TGF-β, interleukin-1 receptor antagonist (IL-1RA), up-regulation of arginase-1, an enzyme with capability to suppress activated microglia, but also down-regulation of enzymes involved in ROS formation, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase[142] and [143]. Specifically Th2 cells, via IL-4 secretion, are shown to inhibit free radical formation and release by microglia [144] . Additionally, the capacity of myelin phagocytosis is far greater in human M2 microglia compared to M1 phenotype [145] . Considering that the failure to phagocyte dead and damaged cells significantly impairs resolution of inflammatory processes and prevents remyelination, greater phagocytic potential could be another protective mechanism of the Th2 mediated alternative activation of microglia [146] . In EAE, mice injected within vitropolarized M2 monocytes showed less sever clinical presentation and reduced pro-inflammatory cytokine expression in demyelisation lesions [147] . Beside limiting neuron and oligodendrocyte impairment, Th2 cells also promote neuroregeneration and support neuron recovery and survival. It is found that myelin vaccination in combination with Th2 promoting adjuvant – aluminum hydroxide, supports axon regeneration in the corticospinal tract following spinal cord injury [148] . Subsequent experiments demonstrated that myelin primed Th2 cells could enter into the CNS and increase the expression of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) [149] .In vitrostudies, on glial cell cultures, proposed that neurotrophin production is the result of direct cell-to-cell contact of myelin specific Th2 cells with microglia and astrocytes [149] , but also of soluble mediators produced by Th2 cells [150] . These Th2 induced neurotrophic mediators are proved to have a significant role in oligodendrocyte survival and remyelinating processes and have been identified in the margin of active MS lesions[150] and [151].

In the regard of protective autoimmunity, it is possible that certain subclinical CNS mutilations, established in various terms, provoke autoimmunity against CNS antigens as a physiological response, in order to limit further damage. In MS, this autoimmune response could be inappropriate, mediated by Th cells other than Th2, and result in glia phenotype switching to pro-inflammatory, instead neuroprotective phenotype, thus promoting inflammation and further neuronal and oligodendroglial pathology. Such inappropriate autoimmune response in MS is likely to be genetically determined. In concordance to this, some mouse strains are more suitable to EAE induction than the others, due to their genetic propensity to Th1 or Th2 polarized immune response[134] and [152]. Also, transgenic mice over-expressing GATA3, with genetic settings skewed toward a Th2 immune response, exhibit reduced Th1 and Th17 mediated CNS inflammation, as well as minimal clinical symptoms, after EAE induction [140] . Interestingly, epidemiological studies carried out in human population, showed that the patients suffering from allergic asthma, the disease known to develop in individuals with genetic predisposition toward Th2 immune response, have much lesser risk for MS, when compared to general population [153] . On the other hand, individuals with MS also have a genetic predilection to develop other autoimmune disorders[154] and [155], suggesting that inadequate protective autoimmune response could be common mechanism of initiating deleterious autoimmunity with different tissue specificity.

3.2. Regulatory T cells in MS

In the physiological terms, particular subset of T cells termed as regulatory T cells (Tregs) have recently received an increased notice in establishing neuroprotective immunological networks in CNS. Tregs are cells actively engaged in the maintenance of immunological self-tolerance by different mechanisms, including direct inhibition of autoreactive T cell activation by secreting immunosuppressive mediators or cell-to-cell contact; or indirectly via inhibition of the stimulatory capacity of APCs [156] . The majority of Tregs are differentiated in the thymus as natural Tregs (nTregs) characterized by surface CD4 and CD25 expression and the transcription factor forkhead box P3 (FoxP3), which is essential for phenotypic and functional development of this cell linage. They display a T-cell receptor repertoire that is skewed toward the recognition of self antigens, but upon activation these cells instead of inducing inflammation, create immunosuppressive environment [157] . Besides nTregs, other cells originating from the thymus may also perform regulatory functions, such as natural CD8+regulatory T cells [158] . Tregs may also arise in the periphery, from uncommitted naïve T cells, as inducible Tregs (iTregs). This cell population includes T regulatory-1 cells (Tr1) which predominantly produce IL-10 and TGF-β [159] and Th3 cells that produce TGF-β [160] . Inducible CD8+regulatory T cells and regulatory invariant natural killer T cells are also described[161] and [162]. Interestingly, recent findings suggest that Tregs could be specialized to suppress a particular CD4+T cell subset by expressing transcription factors characteristic for that exact CD4+T cell subset. Accordingly, in response to IFN-γ, Tregs up-regulate Th1 specific transcription factor T-bet, migrate to the sites of Th1 mediated inflammation and suppress inflammatory process [163] . Similarly, expression of transcription factor IRF-4 (required for Th2 cell differentiation programme) in Tregs enables them to suppress Th2 mediated response efficiently [164] .

Multiple alterations in both number and function of Treg are identified in MS patient; however there are substantial difficulties in adequate data interpretation due to different markers of Treg identification used in the studies and the heterogeneity of Treg population itself. Both decreased and unaltered number of nTreg (identified as CD4+CD25+FoxP3+T cells) is reported in the peripheral blood of MS patients[165], [166], and [167]. On the other hand, majority of studies did report accumulation of nTreg in CSF of MS patients, suggesting their active migration to the site of inflammation and preferential shift toward the encephalic compartment as a physiological response to CNS autoimmune inflammation[166] and [167]. Interestingly, Tregs are significantly decreased in patients with stable MS, but their number is re-established to normal during a disease exacerbation, indicating that Tregs are not causing clinical relapses, but rather respond to inflammation, in order to restore immune homeostasis [168] . While numerical alterations in Treg population in MS appear to be inconclusive, a number ofin vitrostudies using Tregs isolated from MS patients have documented impaired suppressor function of these cells. Indications of Treg functional defects are based on the observation that Treg isolated from MS patients have significantly reduced inhibitory effect on antigen specific T cell proliferation induced by different myelin components, when compared to healthy controls[169] and [170]. Additionally, Treg obtained in relapse phase of the disease, failed to suppress proliferation and T-bet expression in conventional T cell population after stimulation, what indicated Treg insufficiency to limit Th1 mediated autoimmune response. In the same experiment, Tregs obtained during the remission exhibited normal immunosuppressive potential [171] . nTreg deficiency to suppress Th17 mediated immune response in MS is also postulated. Accordingly, reduced frequency, as well as suppressive function of a specific subset of nTregs expressing CD39 (shown to be responsible for the suppression of Th17 mediated immune response), is reported. [172] . Venken et al. suggested that decreased FoxP3 expression level in nTregs could be the cause of defective suppressor function of this cell linage in MS [167] , considering that FoxP3 is needed to maintain suppressive proprieties of nTregs [173] . In contrast, a more recent study proposed that Tregs expressing transcription factor forkhead box protein A1 (FoxA1), but not FoxP3, are the main Treg subset that develops in CNS as a respond to autoimmune inflammation. FoxA1 is responsible for the expression of programmed cell death ligand 1 (PD-lL) that mediates elimination of activated T cells by binding to its receptor (PD-1R). Adoptive transfer of FoxA1+Tregs inhibited EAE, also in MS patients; clinical response to treatment with interferon β (IFN-β) was associated with an increased frequency of suppressive FoxA1+Tregs in the blood [174] . Besides nTregs, the impairment of other Treg subsets is also reported. Lower frequency of CD8+regulatory cell is found in blood of MS patients during relapse phase [175] . Also, Tr1 mediated response is compromised in MS, considering that patient’s Tr1 cells produced less IL-10 than those obtained from healthy individuals [176] .

Considering that nTregs are specific for self-antigens, the immune response mediated by these cells could be characterized as autoimmune, but protective by nature. Protective capacity is primarily reflected in nTreg ability to suppress effector function of pathogenic auto-reactive Th lymphocytes; however, in encephalic compartment Tregs could provide neuroprotection by other means. Tregs direct apoptosis of pro-inflammatory M1 microglia, but also promote shifting to neuroprotective M2 phenotype [177] . They are shown to up-regulate expression of astrocyte-derived neurotrophic factors, BDNF and glial cell-derived neurotrophic factor (GDNF) that support remyelination and regeneration in the brain, but also significantly ameliorate neurotoxicity by inhibiting ROS generation and glutamate secretion[178] and [179]. Interesting finding is that Tregs can induce a Th1-to-Th2 shift, down-regulate Th1 cytokines, and up-regulate both Th2 and Th3 cytokines, which are proved to be neuroprotective [180] . In contrast, antagonistic interplay between Tregs and Th2 cells is also proposed [164] , so further research is needed to clarify the relationship between those two cell populations, which could both exhibit neuroprotective proprieties.

4. Conclusion

The diversity as well as a phenotype fluctuation of Th cells employed in MS development, indicates that the early disease pathogenesis is more dependent on patient’s individual characteristics and it is unlikely that a single, universal immunological pattern of deleterious autoimmunity development could be applicable to all MS patients. Th1, Th9 and Th17 cells are proposed to mediate deleterious autoimmunity in MS, however, the dominant Th immune response is determined by particular microenvironment factors that allow activation of myelin specific CD4+T cells, as well as patient’s specific genetic predisposition toward particular Th phenotype. Regardless of Th polarization, deleterious autoimmune response in encephalic compartment leads to the identical pathological features (BBB disruption, demyelination and neurodegeneration), clinically manifested with symptoms classified as MS. This could be explained by the fact that Th1, Th9 and Th17 cells utilize the same components of innate immunity in the brain (microglia, astrocytes even mast cells), inducing their shift toward pro-inflammatory phenotype. Such stimuli support the production of numerous different mediators, most of which are proven to have oligodendrotoxic/neurotoxic effect and mediate characteristic tissue damage seen in MS pathology. In contrast to deleterious autoimmunity, autoimmune response mediated by Th2 cells and Tregs develops as a physiological response to CNS tissue damage and tunes glia response toward tissue reparation and production of trophic factors that support neuronal survival and myelin repair. The failure to perform adequate protective autoimmunity is associated with MS development [181] , and indeed different numerical as well as functional abnormalities of both Th2 and Treg cell subpopulations are reported in MS patients. In this regard, MS could be a consequence of inadequate regulation of a delicate balance between deleterious and protective autoimmunity which is reflected on phenotypic characteristics of “executive” innate immunity in the brain. Such conception of MS has profound impact on future therapeutic strategies, and argues in favor of immunomodulatory therapy which should provide Th polarization shift from deleterious toward neuroprotective phenotype. Furthermore, it indicates that non-specific immunosuppression, as a therapeutic strategy still in use in MS treatment, suppresses harmful, but also potentially beneficial effects of autoimmune response. This possibility should not be underestimated considering that inflammation is shown to be necessary for remyelinating processes in areas of chronic demyelination [182] .

Declaration of interest

We have no conflict of interest to declare.

Acknowledgment

This paper was supported by The Ministry of Education and Science of The Republic of Serbia under the project number 41018.

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Footnotes

a Department of Immunology, Medical Faculty, University of Nis, Blvd. Dr. Zorana Djindjica 81, 18000 Nis, Serbia

b Department of Biochemistry, Medical Faculty, University of Nis, Blvd. Dr. Zorana Djindjica 81, 18000 Nis, Serbia

c Department of Pathology, Medical Faculty, University of Nis, Blvd. Dr. Zorana Djindjica 81, 18000 Nis, Serbia

d Clinic of Oncology, Clinical Centre, Blvd. Dr. Zorana Djindjica 48, 18000 Nis, Serbia

lowast Corresponding author. Tel.: +381 641393349.


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    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
  • Dr Claire S. Riley

    Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia University,...
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    Rebecca Farber, MD is an attending neurologist and assistant professor of neurology at the Neurological Institute, Columbia University, in New...

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