The Role of the Immune System in Huntington’s Disease

Ellrichmann, Gisa; Reick, Christiane; Saft, Carsten; Linker, Ralf A.

doi:https://doi.org/10.1155/2013/541259

Journal of Immunology Research

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Review Article | Open Access

Volume 2013 | Article ID 541259 | https://doi.org/10.1155/2013/541259

The Role of the Immune System in Huntington’s Disease

Gisa Ellrichmann,¹Christiane Reick,^1,2Carsten Saft,¹and Ralf A. Linker³

Academic Editor: Dan Frenkel

Received03 Apr 2013

Accepted19 Jun 2013

Published15 Jul 2013

Abstract

Huntington’s disease (HD) is characterized by a progressive course of disease until death 15–20 years after the first symptoms occur and is caused by a mutation with expanded CAG repeats in the huntingtin (htt) protein. Mutant htt (mhtt) in the striatum is assumed to be the main reason for neurodegeneration. Knowledge about pathophysiology has rapidly improved discussing influences of excitotoxicity, mitochondrial damage, free radicals, and inflammatory mechanisms. Both innate and adaptive immune systems may play an important role in HD. Activation of microglia with expression of proinflammatory cytokines, impaired migration of macrophages, and deposition of complement factors in the striatum indicate an activation of the innate immune system. As part of the adaptive immune system, dendritic cells (DCs) prime T-cell responses secreting inflammatory mediators. In HD, DCs may contain mhtt which brings the adaptive immune system into the focus of interest. These data underline an increasing interest in the peripheral immune system for pathomechanisms of HD. It is still unclear if neuroinflammation is a reactive process or if there is an active influence on disease progression. Further understanding the influence of inflammation in HD using mouse models may open various avenues for promising therapeutic approaches aiming at slowing disease progression or forestalling onset of disease.

1. Introduction

Huntington’s disease (HD) is an autosomal dominantly inherited disorder with a trinucleotide CAG repeat expansion ≥36 in the exon 1 of the HD gene located on chromosome 4 [1]. The unstable CAG repeat is translated into a polyglutamine (polyQ) stretch in the huntingtin (htt) protein, which is ubiquitously expressed, including wide expression in neurons and glial cells [2–7]. The number of CAG repeats negatively correlates with the age of onset of the disease [8, 9].

The mutation leads to involuntary movement disturbances, psychiatric symptoms, and cognitive decline. The degenerative process primarily involves medium spiny striatal neurons and cortical neurons leading to dysfunction and subsequently neuronal loss.

Since the identification of the HD mutation in 1993, the understanding of the pathophysiology and molecular biology of the disease has significantly improved. Beside others, mechanisms of tissue damage in HD comprise excitotoxicity, mitochondrial damage, free radicals, and possibly also inflammatory mechanisms including microglia activation. New therapeutic strategies aim at slowing disease progression or forestalling the onset of disease. However, it is still unclear if neuroinflammation in HD is only a reactive process or if there is an active influence on disease progression.

Common transgenic murine models of HD are divided into three classes. First, there are fragment models with a human exon 1 N-terminal fragment with about 144 CAG-repeats, for example, the widely used R6/2 model [10]. Second, knock-in mouse models have been generated by introduction of a pathological CAG-repeat into the mouse htt gene [11]. Hdh^Q150/Q150 mice exemplarily belong to this group [12]. Third, full-length transgenic mouse models express mutant huntingtin (mhtt) on a yeast artificial chromosome (YAC) or bacterial artificial chromosome (BAC). YAC128 mice represent this category [13, 14].

The R6/2 and YAC128 mouse strains are well-characterized animal models mimicking many histopathological aspects of HD [10, 15]. In R6/2 mice, motor symptoms start at the age of about 6 weeks. Continuous weight loss leads to death between 11–14 weeks of age. In YAC128 mice with its full-length mhtt spanning about 120 CAG repeats [14, 16], hypoactivity is first seen at the age of 8 months. Additionally, progressive gait abnormalities, ataxia, hind limb clasping, and a progressive decline in the forced motor function occur over time [14, 17].

This review summarizes the current knowledge about the relation between the immune system and HD as well as the putative role of the adaptive and innate immune system in HD.

2. Huntington’s Disease and the Immune System

In neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), or amyotrophic lateral sclerosis (ALS), there are many studies demonstrating an involvement of neuroinflammation [18–21]. Yet, in HD, much fewer information is available on these processes to date.

Inflammation both in the CNS or in the periphery is typically initiated by aberration of the normal healthy state due to, for example, pathological injury, trauma, infection, abnormal folding of proteins, or aggregation of other triggers. Neuroinflammation may be mediated by soluble factors including cytokines, prostaglandins, and nitric oxide (NO) finally resulting in neuronal degeneration. A cellular characteristic of neuroinflammation is the presence of microglial cells, a typical marker for immune activation in the CNS [22].

A number of studies indicate that activation of the immune system and an altered immune response in HD is evident even in the premanifest stage of the disease [23]. Thus, striatal and cortical neurodegeneration may be triggered by inflammation. Conversely, increased inflammation in HD might be the response to neuronal death induced by mhtt toxicity. Probably, even mhtt itself may trigger inflammation in HD (Figure 1).

Figure 1

Neuroinflammation in the center of HD pathophysiology. Immune activation, induced by mutant huntingtin (mhtt), is found ubiquitously: in the central nervous system (central), the blood circulation (peripheral), and at molecular level (cellular). In the CNS, mhtt may not only influence migration of cells, for example, myeloid cells, but also induces microglia activation. Cytokines and chemokines (e.g., IL-6, TNFα) are secreted, and reactive oxygen species (ROS) are activated. Furthermore, glutamate-induced excitotoxicity, that is, in close interaction with oxidative stress, may contribute to degeneration. Migration deficits are discussed to influence innate immune response in the periphery very early in HD. Once again, cytokines, chemokines, and ROS in concert may trigger neuroinflammation. On a cellular level, mhtt upregulates the NF-kappa B (NF-κB) signaling pathway that triggers IL-6 expression. Finally, mitochondrial dysfunction generated by mhtt seems to be a key player leading to neuroinflammation in HD. The complement system is a connection between the innate and adaptive immune response. There are two ways that activate the complement system: first, inflammation with all its resulting effects targets factors of the complement system. Second, antibody response and T-cell response follow in secretion of complement factors. Various cell types may be affected, among these monocytes, astrocytes, and T and B cells.

In addition, inflammatory processes may also be caused via an involvement of mitochondrial dysfunction which is a well-known part in the pathophysiology of HD [24–27] (Figure 1). This hypothesis is supported by recent findings in Candida albicans, demonstrating a reduced recognition by macrophage receptors and decreased expression of cytokines such as interleukin-(IL-) 6, IL-10, and interferon-(IFN-) γ with changes in mitochondrial complex I structure [28]. Moreover, oxidative stress is discussed to induce an assembly of multiprotein inflammatory complexes called “inflammasomes” in normal aging [29], and mitochondrial dynamics influence T-cell function [30]. A link between inflammatory processes and mitochondrial function is also supported by the observation of severe ultrastructural mitochondrial changes in lymphoblasts from patients carrying a homozygous mutation for HD [31]. Glutamate-induced excitotoxicity stands in close relation to mitochondrial damage and also oxidative stress [32, 33]. N-Methyl-D-aspartate (NMDA) receptors are mainly activated by glutamate and are known to be linked to nitric oxide synthases (NOS). This results in increased nitric oxide (NO) levels in toxic amounts [34] leading once again to mitochondrial dysfunction and, in the end, cell death [35]. mhtt may enhance NMDA receptor-mediated toxicity strengthening the vicious circle of neurodegeneration [36] (Figure 1).

Another hypothesis aims at migration deficits of immune cells in HD. An impaired migration may negatively influence cytokines and chemokines resulting in chronically increased levels of proinflammatory cytokines and chemokines in the CNS. In turn, this may lead to microglial activation, neuroinflammation, and finally neurodegeneration in HD [37].

In contrast to inflammatory neurological diseases, for example, multiple sclerosis, there is a marginal influx of peripheral immune cells (lymphocytes, neutrophils) in HD. Based on the fact that T cells are numerically rare in HD pathology [38], major culprits in HD associated with neuroinflammation seem to be microglia, neurons, and macroglia.

3. Role of the Innate Immune System in Huntington’s Disease

3.1. Microglia

Microglia are primary mediators of neuroinflammation [39, 40] and seem to be key players in the pathogenesis of neurodegenerative diseases [20].

In HD, the main neuropathological changes take place in the nuclei of the basal ganglia and are characterized by degeneration and neuronal loss. Consequently and in line with the neurodegenerative process, astrocytes and microglia appear in the affected regions. Under physiological conditions, microglia are in a resting state and contribute to innate immune responses by producing anti-inflammatory and neurotrophic factors [41] (Figure 2). In brains of mhtt carriers, microglia are activated even before onset of symptoms [42]. Based on ferritin accumulation and Iba1 immunostaining, an increased microglial activation was also shown in the R6/2 mouse model [43].

Figure 2

Neuronal glia interactions in Huntington’s disease. Microglia/macrophages are essential for host defense and can trigger M1 or M2 responses. The dichotomous M1/M2 concept implies that M1 cells induce Th1 cells that produce proinflammatory cytokines like IFN-γ, while M2 cells induce Th2 cells that are associated with IL-4, IL-5, and IL-10 supporting anti-inflammatory effects or antibody production. Aggregates of mutant huntingtin (mhtt) are found in neurons, astrocytes, and microglia. With a decreased protective function due to fewer glutamate transporters, mhtt-containing astrocytes may contribute to excitotoxicity. Consequently, there is glutamate excitotoxicity and glutamate-induced apoptosis causing neurodegeneration. At the same time, mhtt enhances microglia function and leads to microglia activation. Migrating microglia secrete proinflammatory cytokines (e.g., TNFα) and nitric oxide thus contributing to neurotoxicity. Yet, simultaneously, phagocytic microglia may also produce neuroprotective factors.

In this paradigm, microglial activation correlates with the severity of disease progression and with loss of dopamine D2 receptor binding sites [44, 45]. This could be proven by PET studies using a ligand for the peripheral benzodiazepine receptor (PBR), PK-11195, visualizing activated microglia [46]. The presence of activated microglia induces a cascade of proinflammatory cytokines [47]. Among these are IL-6, IL-12, and tumor necrosis factor alpha (TNFα). As downstream effects, an increase of caspase activity, intracellular calcium levels, and the production of reactive oxygen species and nitric oxide could be detected [48].

Yet, microglia do not generally exert negative effects. They may release neurotrophic factors that are able to induce neuroprotection and they support clearing cell debris as well as toxic proteins that may worsen degeneration upon accumulation. However, concurrently, microglia with their proinflammatory functions may also damage and remove healthy neurons thus supporting a “bystander” pathogenic process [49] (Figure 2).

3.2. Mutant Huntingtin (mhtt) and Inflammation

To add another level of complexity, mhtt itself is also expressed in microglia [50]. Therefore, in HD, mhtt effects may directly cause inflammation in the CNS and peripheral tissues. Secreted immunomodulatory messengers may then cross the blood brain barrier (BBB) in both directions with inflammation starting in the periphery and spreading into the CNS or vice versa. Studies of Björkqvist et al. confirmed an interaction of both the CNS (“central”) and the peripheral immune system in HD by detecting increased IL-6 and IL-8 levels in plasma and striatum [23]. Since there are no direct alterations at the BBB [51], one might assume that mhtt probably induces ubiquitous changes peripherally as well as in the CNS.

In addition, R6/2 mice show expression of mhtt in other glial cells, mainly in astrocytes, thus reducing the neuroprotective function of these cells. This further underlines the concept of a functional role of inflammation in HD [50, 52].

3.3. Macrophages

Macrophages are critical effectors and regulators of inflammation and the innate immune response. In lymphoid and nonlymphoid tissues, their main function consists of phagocytosis and production of growth factor as well as inflammatory cytokines [53]. Macrophage-like cells are part of a diverse group of cell types mediating immune responses. Among these are patrolling monocytes, monocyte/dendritic cells, and CNS infiltrating macrophages. Monocytes circulate and produce inflammatory cytokines. They can differentiate into proinflammatory DCs or macrophages. Classical DCs are antigen-processing and presenting migrating cells that regulate T-cell responses [54, 55].

More recent findings further refined this concept and indicate that macrophages can be differentiated into M1 and M2 subtypes [53, 56]. Activating stimuli of M1 macrophages include IFN-γ and IL-4. Consequently, a Th1 response mediated by IL-12 is initiated. In contrast, M2 macrophages rather support Th2 responses in the immune system which are associated with the expression of IL-4, IL-5, and IL-10. These cytokines inhibit macrophage activation but induce antibody production resulting in resolution of inflammation through endocytic clearance and trophic factor synthesis [57]. In general, the concept of M1/M2 macrophages and the Th1/Th2 paradigm postulates that M1 macrophages are assumed to have proinflammatory functions and M2 macrophages may have anti-inflammatory and wound-healing functions. Thus, further studies on M1/M2 macrophages in HD are of great interest.

Most studies on macrophages in HD and its models investigate migratory capacities. In the BACHD mouse model of HD, an impaired migration of macrophages to an inflammatory stimulus was shown [37]. To demonstrate whether mhtt was necessary for deficits in migration, mice with conditionally deleted mhtt expression in macrophages were generated (BACHD^Tg/+; CD11b-Cre mice). In these mice, migration of macrophages was not affected which strengthens the hypothesis that migration deficits of macrophages in BACHD mice are governed by mhtt expression in these cells.

In further studies in humans, blood monocytes from HD patients were isolated to study migration defects. As expected, migration of isolated monocytes and macrophages to chemoattractants was severely impaired [37]. Based on these data, a lack in cytokine and chemokine signaling mechanisms is assumed in HD. This may lead to a chronic increase in proinflammatory cytokines and chemokines in the CNS and consequently microglia activation as well as augmented inflammation.

Comparing the results of isolated primary microglia culture assays, microglial cell lines with overexpression of mhtt, isolated human HD myeloid cells, and in vivo studies in HD mouse models, all studies demonstrate and underline the deficits in migration of myeloid cells with mhtt expression. Therefore, the transfer of experiences in HD mouse models into humans seems to be legitimate and helpful in this case. However, despite these detailed studies, the exact nature of mhtt pathogenicity in the immune system, for example, via interacting with the ubiquitin-proteasome system and a capacity for modulating immune and inflammatory responses, is still not completely clarified [58].

3.4. The Complement System

One of the most important systems in the innate immune system is the complement system [59], which is often regarded as a connection between the innate and adaptive immune response. Most complement components and receptors are expressed by astrocytes, microglia, and neurons [60, 61]. Thus, the system may be a key factor in several neurodegenerative diseases [59]. In HD, the complement system is activated by peptides such as mhtt. Activation of the complement systems triggers a cascade of processes including cytokine release, enhancing phagocytosis of antigens, attracting macrophages and neutrophils, cell lysis, and, amongst others, production of anaphylatoxins with its central component C3 [62]. In HD, several complement factors, notably C1q, C4, and C3, are expressed in the striatum comprising neurons, astrocytes, and myelin [63]. Yet, it is still unclear which factors initiate this deleterious activation of the complement system.

3.5. Cytokines: IL-6

Increased cytokine production may be caused by dysfunction of microglia and related cell types (monocytes/macrophages). Monocytes of HD patients express mhtt [23]. In turn, mhtt may upregulate NF-kappa B dependent pathways which are crucially involved in IL-6 expression [64]. IL-6 triggers the acute phase response and crosses the BBB [65]. It is primarily produced by monocytes and lymphocytes. On one hand, the function of both of these cells may be directly modified by mhtt. On the other hand, external processes that evoke inflammation, such as tissue damage, may result in IL-6 production. It is even discussed that mhtt itself acts as an antigen and is presented by antigen-presenting cells thus activating inflammation [23].

IL-6 is upregulated in plasma of HD patients [23, 66]. An excessive IL-6 release was also detected in R6/2 and YAC128 mice. To test the hypothesis that IL-6 may actively influence the disease course in HD, Bouchard et al. administered an IL-6 neutralizing antibody into R6/2 mice. As compared to IgG as control, treatment with the specific antibody diminished weight loss at late stages in R6/2 mice and partially rescued motor deficits on the rotarod () [67].

In further studies, Bouchard and coworkers sought to determine whether cannabinoid receptor 2 (CB₂) controls IL-6 levels that again contribute to the disease phenotype in the R6/2 model. CB₂ regulates the production of the proinflammatory cytokines IL-6 and TNFα [68–70]. Upon genetical deletion of CB₂ receptors, which are mainly expressed in peripheral immune cells, IL-6 blood levels were increased [67]. In line, adding the CB₂ receptor agonist GW405833 significantly reduced plasma levels of IL-6, while levels of TNFα were not altered [67]. These studies confirm the hypothesis that IL-6 produced by peripheral immune cells may contribute to pathogenesis in R6/2 mice.

Yet, not only IL-6 but also other inflammatory proteins may be involved in innate immune responses in HD. IL-6 stimulates the expression of another acute phase protein: -macroglobulin (M). M is upregulated in plasma of HD patients, mainly in reactive astrocytes, and therefore influences immune proteins and cytokines. Based on this pathway, M takes part in both the local CNS and peripheral immune system in HD and might contribute to progression of neurodegeneration HD [66, 71].

In concert, these factors may influence astrocytes which are able to amplify inflammatory responses [72].

3.6. Cytokines: IL-1β

IL-1β is not only secreted by microglia and macrophages but also typically expressed in dendritic cells (DC) [72, 73] and is verifiably increased in several mouse models of HD and in the serum of HD patients. Notably, brain lysates of R6/2 HD mice display significantly higher levels of IL-1β than wild-type control [23, 74–76]. Amongst other cytokines, IL-1β may augment inflammatory signals in the CNS. Knockout mice with a deletion of the chemokine receptor type 2 (Ccr2) show impaired migration of monocytes and macrophages. In these mice, serum levels of IL-1β and IL-6 were elevated [77, 78], and the mice were unable to induce an effective adaptive immune response [79, 80]. Thus, the reason for elevated IL-1β and IL-6 levels in premanifest and manifest HD patients as well as in mouse models may be due to migration deficits in immune cells. These deficits may induce a dysregulated signaling pathway leading to aggregation and elevation of, for example, IL-1β levels [37]. In turn, this may directly cause neuronal dysfunction: IL-1β itself is able to directly induce neurotoxicity via activation of tyrosine kinases and phosphorylation of NMDA receptors involving the NF-kappa(κ)B pathway [81].

Further transferring these results to HD, elevated IL-1β levels may additionally lead to deficits in clearing bacterial and viral infections probably further advancing degenerative processes in the CNS and the periphery [37].

3.7. Genes/Toll-Like Receptors/Inflammasomes

Inflammatory responses are initiated by different receptors, among others including the Toll-like receptors (TLRs). TLR activation generally promotes the expression of proinflammatory cytokines and may induce neuronal damage by changing the environmental conditions in the organisms [82]. TLRs are upregulated in many neurological disorders influencing not only microglia but also astrocytes, oligodendrocytes, and neurons [83].

These TLRs recognize pathogens and are highly expressed on macrophages and microglia. TLR activation evokes NF-κB activation resulting in increased transcription of proinflammatory cytokines [84]. Some TLRs, for example, TLR4, which recognizes lipopolysaccharide (LPS), activate microglia [85]. Hereby, DCs, normally not present under healthy conditions, secrete inflammatory mediators such as TNFα and IL-1β which may affect function of the blood brain barrier thus further contributing to a pathogenic role of DC (see above). The recent evaluation of HD-relevant genes in the HD research crossroads database [86] investigated several new pathways in HD especially pointing at the importance of TLR. There are, for example, 17 genes in TLRs pathways which were analyzed in different studies and which could be merged in the HD crossroads analysis [86].

TLRs are only one of multiple molecular mechanisms associated with the pathogenesis of HD that are up to now only marginally studied. Other factors of interest include proteins involved in cell cycle, RNA splicing, or novel genetic modifiers. Consequently, TLRs may trigger neuroinflammation in a different way. Inflammasomes recruit and activate caspase-1, thereby complementing TLR signaling to generate IL-1β and IL-18 and mediating neuroinflammation [84].

Activation of inflammasomes is discussed as central to the pathology of several neurodegenerative as well as autoinflammatory diseases. Inflammasomes are multiprotein complexes which activate immature forms of IL-1β and IL-18 into active mature cytokines. This process is caspase-1 dependent [87]. Inflammasomes are activated by the cytoplasmic presence of microbial components, tissue-injury products, or inflammation-associated substances [84]. Its activation is essential in triggering IL-1β-driven inflammation and in line also IL-1β-driven IL-17 production. In view of previous data on the role of IL-1β in HD (see above), inflammasome-derived activation of IL-1β may constitute an interesting new target in future research on the role of the immune system in HD.

In summary, the first line of inflammation in HD undoubtedly involves the innate immune system. Yet, in HD, not only changes in the innate immune system but also altered adaptive immune responses may occur.

4. Role of the Adaptive Immune System in Huntington’s Disease

In general, the immune response involves a balanced interaction between the innate and adaptive immune system. Yet, to date, it remains very difficult to exactly determine the initiation point of an adaptive immune response in HD or its animal models.

4.1. Dendritic Cells

Dendritic cells (DCs) are antigen-processing and presenting cells. In the immature state, they harbor a high phagocytic activity in contrast to mature cells with a high cytokine producing capacity [54, 55]. DCs have a high migratory capacity and are only short living [88, 89]. Conversely, brain microglia, the macrophage/DC of the CNS, are self-renewing and arise from fetal myeloid progenitors. They prime T-cell responses as a main arm of the adaptive immune system and secrete inflammatory mediators such as TNFα and IL-1β.

In 1994, a subset of CD11c⁻ immature DCs, with low MHC class II expression were identified. Called plasmacytoid DCs (pDCs), they induce Th2 cell differentiation in response to certain stimuli and are specialized to respond to viral infections with production of type I interferons [90, 91].

Both, myeloid DCs and pDCs may support neuroinflammation. Chronic neuroinflammation includes not only extended activation and proliferation of microglia, as mentioned previously, but also increased levels of proinflammatory cytokines. This prolonged inflammation affects the BBB and impairs its integrity. Normally, the BBB protects the brain from circulating immune cells such as DCs. In HD, the chronic neuroinflammation may weaken the BBB thus leading to infiltration of DCs that may additionally contain mhtt and further foster pathogenic immune responses [23, 92].

In summary, the influence of myeloid DCs and pDCs in pathology of HD is critically discussed. There is still a lack of good markers to distinguish between monocytes and bona fide DCs. Thus, a specific effect of DCs in HD cannot be delineated to date.

4.2. T Cells

Elevated T-cell responses and a shift in CD4⁺ and CD8⁺ cell populations were observed in different neurodegenerative disorders. For example, CD4⁺ T cells were found in the substantia nigra in PD patients and there was an alteration of CD4⁺ and CD8⁺ T cells in AD [93, 94].

In contrast, T cells were not numerically increased in postmortem human HD tissue [38]. Silvestroni and coworkers analyzed the striatum, cortex, and cerebellum from postmortem HD patients using quantitative real-time PCR. As a result, they assumed that neuroinflammation in HD is solely based on interaction of microglia, neurons, and macroglia. In contrast, some evidence for a role of T cells in HD has emerged from studies that measured elevated T-cell responses to specific antigens as well as shifts in CD4⁺ and CD8⁺ cell populations in the CNS [93]. However, functional studies and comprehensive immunological analysis on T cells in HD have not been largely performed to date. In summary, the involvement of T cells as a causative factor in disease pathology is still difficult to verify, and further studies are needed to decipher the exact role of different T-cell subsets in HD, especially with a focus on regulatory T cells (see also what follows for Th2 cells).

4.3. IL-4

IL-4 is an anti-inflammatory cytokine, which is involved in the adaptive immune system and is regarded as a signature factor of “Th2” T helper cells. Moreover, IL-4 induces B-cell class switching, upregulates MHC II class production and is also involved in tolerance and induction of regulatory T cells. Consequently, IL-4 decreases the production of Th1 cells, macrophages, IFN-γ, and IL-12. In line, IL-4 increases the production of M2 macrophages under conditions of IL-10 and TGF-β secretion while inhibiting classical activation of macrophages into M1 cells [95]. In concert with the repair function of M2 macrophages, IL-4 actions result in diminished neuroinflammation. Thus, IL-4 may be an interesting regulatory factor in HD.

Yet, the exact role of regulatory cytokines T cells and Th2 cells in neurodegenerative diseases is not exactly known. There may be beneficial effects on regeneration involving BDNF or IL-4, but detailed mechanisms are still not completely understood [96]. In plasma samples from HD mutation carriers, IL-4 levels were significantly increased compared to control subjects [23]. This fact emphasizes the hypothesis that the adaptive immune system does play a role in HD. The increase of IL-4 and in line IL-10 both in HD patients and in the CNS as well as peripherally also in HD mouse models was mainly seen in late stages of the disease [23]. This may implicate an adaptive response to chronic immune activation, possibly involving monocytes/macrophages and “Th2” cells.

In summary, the data mentioned previously support meaningful interactions between immune cells and neurodegeneration in HD. Of note, migration deficits seen in immune cells in both, HD patients and mouse models, may be an initial step in early immunological changes and may lead to elevation of proinflammatory cytokines and chemokines in HD.

5. Conclusions

In summary, there is a large body of evidence for a pivotal role of neuroinflammation in the development of several neurodegenerative diseases. Yet, the exact underlying inflammatory pathomechanisms and the definite impact of the innate and adaptive immune system in HD pathology are still not fully understood. It is not verified yet if changes in the immune system which may trigger or may be triggered by, for example, neuronal death are the cause or the consequence of HD pathology. However, an activation of the immune system in HD is not doubted and was clearly proven by the elevated expression of cytokines such as IL-6 in mouse models and symptomatic as well as presymptomatic patients. Furthermore, activation of CNS innate immune cells in HD, such as microglia and astrocytes, is one of the universal components of neuroinflammation, and these cell types are directly implicated in the pathogenesis of several neurodegenerative diseases. Therefore, the contribution of inflammation to neurodegeneration in HD is strongly suggested but not definitely demonstrated.

6. Outlook

In view of an aging community and a growing incidence of neurodegenerative diseases, the need for effective therapies rapidly increases. Changes in microglial properties are not yet well understood and thus remain in the center of ongoing investigations. Still these cells constitute an interesting new therapeutic target in HD.

A first idea to reduce neuronal damage via interfering with the immune system was the use of minocycline. As a caspase inhibitor, minocycline aims at the reduction of TNFα, IL-1β, and inducible nitric oxide synthase (iNOS). In the R6/2 mouse model of HD, the compound led to a significant delay in disease progression. A small study in HD patients has also shown positive effects with this well-tolerated, and safe drug [97].

Assuming inflammatory mechanisms as a key player in HD pathogenesis, anti-inflammatory treatments with Cox2 inhibitors were analyzed. Yet, there was no neuroprotective effect in the R6/2 and N171-82Q transgenic mouse models of HD although in theory folding of mhtt should be improved, inflammatory pathways should be less activated and pro-apoptotic signaling mediated by NF-κB should be reduced [98].

Administering a compound that inhibits the proinflammatory cytokine TNFα may also reduce neuroinflammation hereby delaying disease progression in HD. TNFα inhibitors, for example, etanercept, are biologic drugs. However, etanercept is a large molecule and therefore does not cross the BBB [99]. This may be the reason why this approach displayed no convincing therapeutic effect in mouse models of neurodegenerative diseases [100].

Another hypothesis-driven anticytokine approach may be the treatment of HD with antibodies against the IL-6 receptor (IL-6R, tocilizumab). IL-6R antibodies are a widely used therapy for rheumatoid arthritis. While this disease is not directly comparable to HD, it shows that this approach is very well tolerated, and first data on longer-term treatment in CNS disease-like neuromyelitis optica were recently published [101]. In view of the pivotal role of IL-6 in HD, further studies with treatment options targeting IL-6 mediated pathways are clearly warranted.

Finally, an auspicious approach in the therapy of HD may be the application of the fumaric acid ester dimethylfumarate (DMF) as a modern immunomodulator with pronounced effects on macrophages [102]. The compound was recently approved for the treatment of relapsing remitting multiple sclerosis in the USA. Own studies further revealed that DMF potentially exerts neuroprotective effects via induction of the transcription factor “nuclear factor E2-related factor 2” (Nrf2) and detoxification pathways [103]. Since oxidative stress and free radicals are, amongst macrophages, known to support neurodegeneration, we thus investigated the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice [104]. After DMF treatment, there were significant differences in survival, motor impairment, weight loss, and parameters of neuronal degeneration in favor of DMF therapy. Initiating a phase II study with DMF in HD patients would be a promising next step in treating HD probably targeting both, immune cells and detoxification pathways.

In summary, there is no doubt that the importance of the immune system in neurodegenerative diseases is increasingly recognized. The near future will certainly see further studies targeting immune responses in HD as a therapeutic approach.

Acknowledgments

Carsten Saft received honoraria from Temmler Pharma GmbH & Co. KG for scientific talks, compensation in the context of the Registry-Study of the Euro-HD-Network, in the context of the ACR16-Study (Neurosearch), the AFQ-Study (Novartis), and the Selisistat-Studies (Siena Biotech), and received research support for a research project with Teva Pharma GmbH and the Cure Huntington’s Disease Initiative (CHDI). The other authors declare no conflict of interests.

References

M. E. MacDonald, C. M. Ambrose, M. P. Duyao et al., “A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes,” Cell, vol. 72, no. 6, pp. 971–983, 1993.
View at: Publisher Site | Google Scholar
M. J. Buraczynska, M. L. Van Keuren, K. M. Buraczynska, Y. S. Chang, E. Crombez, and D. M. Kurnit, “Construction of human embryonic cDNA libraries: HD, PKD1 and BRCA1 are transcribed widely during embryogenesis,” Cytogenetics and Cell Genetics, vol. 71, no. 2, pp. 197–202, 1995.
View at: Google Scholar
E. Cattaneo, C. Zuccato, and M. Tartari, “Normal huntingtin function: an alternative approach to Huntington's disease,” Nature Reviews Neuroscience, vol. 6, no. 12, pp. 919–930, 2005.
View at: Publisher Site | Google Scholar
J. F. Gusella and M. E. MacDonald, “Huntington's disease: seeing the pathogenic process through a genetic lens,” Trends in Biochemical Sciences, vol. 31, no. 9, pp. 533–540, 2006.
View at: Publisher Site | Google Scholar
S.-H. Li and X.-J. Li, “Huntingtin-protein interactions and the pathogenesis of Huntington's disease,” Trends in Genetics, vol. 20, no. 3, pp. 146–154, 2004.
View at: Publisher Site | Google Scholar
S.-H. Li, G. Schilling, W. S. Young III et al., “Huntington's disease gene (IT15) is widely expressed in human and rat tissues,” Neuron, vol. 11, no. 5, pp. 985–993, 1993.
View at: Publisher Site | Google Scholar
Y. Trottier, D. Devys, G. Imbert et al., “Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form,” Nature Genetics, vol. 10, no. 1, pp. 104–110, 1995.
View at: Google Scholar
S. E. Andrew, Y. P. Goldberg, B. Kremer et al., “The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease,” Nature Genetics, vol. 4, no. 4, pp. 398–403, 1993.
View at: Publisher Site | Google Scholar
R. G. Snell, J. C. MacMillan, J. P. Cheadle et al., “Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease,” Nature Genetics, vol. 4, no. 4, pp. 393–397, 1993.
View at: Publisher Site | Google Scholar
L. Mangiarini, K. Sathasivam, M. Seller et al., “Exon I of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice,” Cell, vol. 87, no. 3, pp. 493–506, 1996.
View at: Publisher Site | Google Scholar
L. B. Menalled, J. D. Sison, I. Dragatsis, S. Zeitlin, and M.-F. Chesselet, “Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats,” Journal of Comparative Neurology, vol. 465, no. 1, pp. 11–26, 2003.
View at: Publisher Site | Google Scholar
C.-H. Lin, S. Tallaksen-Greene, W.-M. Chien et al., “Neurological abnormalities in a knock-in mouse model of Huntington's disease,” Human Molecular Genetics, vol. 10, no. 2, pp. 137–144, 2001.
View at: Google Scholar
M. Gray, D. I. Shirasaki, C. Cepeda et al., “Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice,” Journal of Neuroscience, vol. 28, no. 24, pp. 6182–6195, 2008.
View at: Publisher Site | Google Scholar
E. J. Slow, J. van Raamsdonk, D. Rogers et al., “Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease,” Human Molecular Genetics, vol. 12, no. 13, pp. 1555–1567, 2003.
View at: Publisher Site | Google Scholar
E. C. Stack, J. K. Kubilus, K. Smith et al., “Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice,” Journal of Comparative Neurology, vol. 490, no. 4, pp. 354–370, 2005.
View at: Publisher Site | Google Scholar
J. G. Hodgson, N. Agopyan, C.-A. Gutekunst et al., “A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration,” Neuron, vol. 23, no. 1, pp. 181–192, 1999.
View at: Publisher Site | Google Scholar
J. M. Van Raamsdonk, Z. Murphy, E. J. Slow, B. R. Leavitt, and M. R. Hayden, “Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease,” Human Molecular Genetics, vol. 14, no. 24, pp. 3823–3835, 2005.
View at: Publisher Site | Google Scholar
G. J. Harry and A. D. Kraft, “Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment,” Expert Opinion on Drug Metabolism and Toxicology, vol. 4, no. 10, pp. 1265–1277, 2008.
View at: Publisher Site | Google Scholar
E. C. Hirsch and S. Hunot, “Neuroinflammation in Parkinson's disease: a target for neuroprotection?” The Lancet Neurology, vol. 8, no. 4, pp. 382–397, 2009.
View at: Publisher Site | Google Scholar
C. S. Lobsiger and D. W. Cleveland, “Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease,” Nature Neuroscience, vol. 10, no. 11, pp. 1355–1360, 2007.
View at: Publisher Site | Google Scholar
J. Rogers, “The inflammatory response in Alzheimer's disease,” Journal of Periodontology, vol. 79, no. 8, pp. 1535–1543, 2008.
View at: Publisher Site | Google Scholar
T. Möller, “Neuroinflammation in Huntington's disease,” Journal of Neural Transmission, vol. 117, no. 8, pp. 1001–1008, 2010.
View at: Publisher Site | Google Scholar
M. Björkqvist, E. J. Wild, J. Thiele et al., “A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease,” Journal of Experimental Medicine, vol. 205, no. 8, pp. 1869–1877, 2008.
View at: Publisher Site | Google Scholar
E. Bossy-Wetzel, A. Petrilli, and A. B. Knott, “Mutant huntingtin and mitochondrial dysfunction,” Trends in Neurosciences, vol. 31, no. 12, pp. 609–616, 2008.
View at: Publisher Site | Google Scholar
C. Saft, J. Zange, J. Andrich et al., “Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease,” Movement Disorders, vol. 20, no. 6, pp. 674–679, 2005.
View at: Publisher Site | Google Scholar
S. H. Stuwe, O. Goetze, C. Lukas et al., “Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease,” Neurology, vol. 80, pp. 743–746, 2013.
View at: Publisher Site | Google Scholar
E. Taherzadeh-Fard, C. Saft, D. A. Akkad et al., “PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease,” Molecular Neurodegeneration, vol. 6, no. 1, article 32, 2011.
View at: Publisher Site | Google Scholar
X. She, L. Zhang, H. Chen, R. Calderone, and D. Li, “Cell surface changes in the Candida albicans mitochondrial mutant goa1Δ are associated with reduced recognition by innate immune cells,” Cellular Microbiology, 2013.
View at: Publisher Site | Google Scholar
A. Salminen, J. Ojala, K. Kaarniranta, and A. Kauppinen, “Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases,” Cellular and Molecular Life Sciences, vol. 69, pp. 2999–3013, 2013.
View at: Publisher Site | Google Scholar
A. Quintana and M. Hoth, “Mitochondrial dynamics and their impact on T cell function,” Cell Calcium, vol. 52, pp. 57–63, 2012.
View at: Publisher Site | Google Scholar
F. Squitieri, M. Cannella, G. Sgarbi et al., “Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation,” Mechanisms of Ageing and Development, vol. 127, no. 2, pp. 217–220, 2006.
View at: Publisher Site | Google Scholar
A. Lau and M. Tymianski, “Glutamate receptors, neurotoxicity and neurodegeneration,” Pflugers Archiv European Journal of Physiology, vol. 460, no. 2, pp. 525–542, 2010.
View at: Publisher Site | Google Scholar
A. Novelli, J. A. Reilly, P. G. Lysko, and R. C. Henneberry, “Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced,” Brain Research, vol. 451, no. 1-2, pp. 205–212, 1988.
View at: Google Scholar
R. Sattler, Z. Xiong, W.-Y. Lu, M. Hafner, J. F. MacDonald, and M. Tymianski, “Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein,” Science, vol. 284, no. 5421, pp. 1845–1848, 1999.
View at: Publisher Site | Google Scholar
F. Ichas and J.-P. Mazat, “From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state,” Biochimica et Biophysica Acta, vol. 1366, no. 1-2, pp. 33–50, 1998.
View at: Publisher Site | Google Scholar
Y. Sun, A. Savanenin, P. H. Reddy, and Y. F. Liu, “Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95,” Journal of Biological Chemistry, vol. 276, no. 27, pp. 24713–24718, 2001.
View at: Publisher Site | Google Scholar
W. Kwan, U. Trager, D. Davalos et al., “Mutant huntingtin impairs immune cell migration in Huntington disease,” Journal of Clinical Investigation, vol. 122, no. 12, pp. 4737–4747, 2012.
View at: Publisher Site | Google Scholar
A. Silvestroni, R. L. M. Faull, A. D. Strand, and T. Möllera, “Distinct neuroinflammatory profile in post-mortem human Huntington's disease,” NeuroReport, vol. 20, no. 12, pp. 1098–1103, 2009.
View at: Publisher Site | Google Scholar
R. M. Ransohoff and V. H. Perry, “Microglial physiology: unique stimuli, specialized responses,” Annual Review of Immunology, vol. 27, pp. 119–145, 2009.
View at: Publisher Site | Google Scholar
D. van Rossum and U.-K. Hanisch, “Microglia,” Metabolic Brain Disease, vol. 19, no. 3-4, pp. 393–411, 2004.
View at: Publisher Site | Google Scholar
W. J. Streit, “Microglia as neuroprotective, immunocompetent cells of the CNS,” Glia, vol. 40, no. 2, pp. 133–139, 2002.
View at: Publisher Site | Google Scholar
Y. F. Tai, N. Pavese, A. Gerhard et al., “Microglial activation in presymptomatic Huntington's disease gene carriers,” Brain, vol. 130, no. 7, pp. 1759–1766, 2007.
View at: Publisher Site | Google Scholar
D. A. Simmons, M. Casale, B. Alcon, N. Pham, N. Narayan, and G. Lynch, “Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's Disease,” Glia, vol. 55, no. 10, pp. 1074–1084, 2007.
View at: Publisher Site | Google Scholar
N. Pavese, A. Gerhard, Y. F. Tai et al., “Microglial activation correlates with severity in Huntington disease: a clinical and PET study,” Neurology, vol. 66, no. 11, pp. 1638–1643, 2006.
View at: Publisher Site | Google Scholar
Y. F. Tai, N. Pavese, A. Gerhard et al., “Imaging microglial activation in Huntington's disease,” Brain Research Bulletin, vol. 72, no. 2-3, pp. 148–151, 2007.
View at: Publisher Site | Google Scholar
L. Hertz, Z. Zhao, and Y. Chen, “The astrocytic GABA(A)/benzodiazepine-like receptor: the Joker receptor for benzodiazepine-mimetic drugs?” Recent Patents on CNS Drug Discovery, vol. 1, no. 1, pp. 93–103, 2006.
View at: Publisher Site | Google Scholar
R. B. Banati, “Brain plasticity and microglia: is transsynaptic glial activation in the thalamus after limb denervation linked to cortical plasticity and central sensitisation?” Journal of Physiology Paris, vol. 96, no. 3-4, pp. 289–299, 2002.
View at: Publisher Site | Google Scholar
U.-K. Hanisch, “Microglia as a source and target of cytokines,” Glia, vol. 40, no. 2, pp. 140–155, 2002.
View at: Publisher Site | Google Scholar
G. C. Brown and J. J. Neher, “Inflammatory neurodegeneration and mechanisms of microglial killing of neurons,” Molecular Neurobiology, vol. 41, no. 2-3, pp. 242–247, 2010.
View at: Publisher Site | Google Scholar
J.-Y. Shin, Z.-H. Fang, Z.-X. Yu, C.-E. Wang, S.-H. Li, and X.-J. Li, “Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity,” Journal of Cell Biology, vol. 171, no. 6, pp. 1001–1012, 2005.
View at: Publisher Site | Google Scholar
S. M. Hersch, S. Gevorkian, K. Marder et al., “Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG,” Neurology, vol. 66, no. 2, pp. 250–252, 2006.
View at: Publisher Site | Google Scholar
J. Bradford, J.-Y. Shin, M. Roberts et al., “Mutant huntingtin in glial cells exacerbates neurological symptoms of huntington disease mice,” Journal of Biological Chemistry, vol. 285, no. 14, pp. 10653–10661, 2010.
View at: Publisher Site | Google Scholar
F. Geissmann, M. G. Manz, S. Jung, M. H. Sieweke, M. Merad, and K. Ley, “Development of monocytes, macrophages, and dendritic cells,” Science, vol. 327, no. 5966, pp. 656–661, 2010.
View at: Publisher Site | Google Scholar
J. Banchereau and R. M. Steinman, “Dendritic cells and the control of immunity,” Nature, vol. 392, no. 6673, pp. 245–252, 1998.
View at: Publisher Site | Google Scholar
I. Mellman and R. M. Steinman, “Dendritic cells: specialized and regulated antigen processing machines,” Cell, vol. 106, no. 3, pp. 255–258, 2001.
View at: Publisher Site | Google Scholar
C. D. Mills, K. Kincaid, J. M. Alt, M. J. Heilman, and A. M. Hill, “M-1/M-2 macrophages and the Th1/Th2 paradigm,” Journal of Immunology, vol. 164, no. 12, pp. 6166–6173, 2000.
View at: Google Scholar
F. O. Martinez, L. Helming, and S. Gordon, “Alternative activation of macrophages: an immunologic functional perspective,” Annual Review of Immunology, vol. 27, pp. 451–483, 2009.
View at: Publisher Site | Google Scholar
D. Soulet and F. Cicchetti, “The role of immunity in Huntington's disease,” Molecular Psychiatry, vol. 16, no. 9, pp. 889–902, 2011.
View at: Publisher Site | Google Scholar
H. Rus, C. Cudrici, S. David, and F. Niculescu, “The complement system in central nervous system diseases,” Autoimmunity, vol. 39, no. 5, pp. 395–402, 2006.
View at: Publisher Site | Google Scholar
D. M. Bonifati and U. Kishore, “Role of complement in neurodegeneration and neuroinflammation,” Molecular Immunology, vol. 44, no. 5, pp. 999–1010, 2007.
View at: Publisher Site | Google Scholar
P. Gasque, Y. D. Dean, E. P. McGreal, J. Vanbeek, and B. P. Morgan, “Complement components of the innate immune system in health and disease in the CNS,” Immunopharmacology, vol. 49, no. 1-2, pp. 171–186, 2000.
View at: Google Scholar
B. J. C. Janssen, E. G. Huizinga, H. C. A. Raaijmakers et al., “Structures of complement component C3 provide insights into the function and evolution of immunity,” Nature, vol. 437, no. 7058, pp. 505–511, 2005.
View at: Publisher Site | Google Scholar
S. K. Singhrao, J. W. Neal, B. P. Morgan, and P. Gasque, “Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease,” Experimental Neurology, vol. 159, no. 2, pp. 362–376, 1999.
View at: Publisher Site | Google Scholar
A. Khoshnan, J. Ko, E. E. Watkin, L. A. Paige, P. H. Reinhart, and P. H. Patterson, “Activation of the IκB kinase complex and nuclear factor-κB contributes to mutant huntingtin neurotoxicity,” Journal of Neuroscience, vol. 24, no. 37, pp. 7999–8008, 2004.
View at: Publisher Site | Google Scholar
W. A. Banks, A. J. Kastin, and E. G. Gutierrez, “Penetration of interleukin-6 across the murine blood-brain barrier,” Neuroscience Letters, vol. 179, no. 1-2, pp. 53–56, 1994.
View at: Publisher Site | Google Scholar
A. Dalrymple, E. J. Wild, R. Joubert et al., “Proteomic profiling of plasma in Huntington's disease reveals neuroinflammatory activation and biomarker candidates,” Journal of Proteome Research, vol. 6, no. 7, pp. 2833–2840, 2007.
View at: Publisher Site | Google Scholar
J. Bouchard, J. Truong, K. Bouchard et al., “Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington's disease,” The Journal of Neuroscience, vol. 32, pp. 9–6, 2012.
View at: Publisher Site | Google Scholar
A. Klegeris, C. J. Bissonnette, and P. L. McGeer, “Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor,” British Journal of Pharmacology, vol. 139, no. 4, pp. 775–786, 2003.
View at: Publisher Site | Google Scholar
M. Rajesh, P. Mukhopadhyay, G. Haskó, J. W. Huffman, K. Mackie, and P. Pacher, “CB2 cannabinoid receptor agonists attenuate TNF-α-induced human vascular smooth muscle cell proliferation and migration,” British Journal of Pharmacology, vol. 153, no. 2, pp. 347–357, 2008.
View at: Publisher Site | Google Scholar
T. F. Su, Y. Q. Zhao, L. H. Zhang et al., “Electroacupuncture reduces the expression of proinflammatory cytokines in inflamed skin tissues through activation of cannabinoid CB2 receptors,” European Journal of Pain, vol. 16, pp. 624–635, 2012.
View at: Publisher Site | Google Scholar
Y. Du, K. R. Bales, R. C. Dodel et al., “α2-macroglobulin attenuates β-amyloid peptide 1-40 fibril formation and associated neurotoxicity of cultured fetal rat cortical neurons,” Journal of Neurochemistry, vol. 70, no. 3, pp. 1182–1188, 1998.
View at: Google Scholar
K. Saijo, B. Winner, C. T. Carson et al., “A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death,” Cell, vol. 137, no. 1, pp. 47–59, 2009.
View at: Publisher Site | Google Scholar
P. J. Khandelwal, A. M. Herman, and C. E.-H. Moussa, “Inflammation in the early stages of neurodegenerative pathology,” Journal of Neuroimmunology, vol. 238, no. 1-2, pp. 1–11, 2011.
View at: Publisher Site | Google Scholar
E. Wild, A. Magnusson, N. Lahiri et al., “Abnormal peripheral chemokine profile in Huntington's disease,” PLOS Currents, vol. 3, Article ID RRN1231, 2011.
View at: Publisher Site | Google Scholar
A. E. Cardona, E. P. Pioro, M. E. Sasse et al., “Control of microglial neurotoxicity by the fractalkine receptor,” Nature Neuroscience, vol. 9, no. 7, pp. 917–924, 2006.
View at: Publisher Site | Google Scholar
V. Chaparro-Huerta, M. C. Rivera-Cervantes, M. E. Flores-Soto, U. Gómez-Pinedo, and C. Beas-Zárate, “Proinflammatory cytokines and apoptosis following glutamate-induced excitotoxicity mediated by p38 MAPK in the hippocampus of neonatal rats,” Journal of Neuroimmunology, vol. 165, no. 1-2, pp. 53–62, 2005.
View at: Publisher Site | Google Scholar
T. Kurihara, G. Warr, J. Loy, and R. Bravo, “Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor,” Journal of Experimental Medicine, vol. 186, no. 10, pp. 1757–1762, 1997.
View at: Publisher Site | Google Scholar
R. R. Rampersad, T. K. Tarrant, C. T. Vallanat et al., “Enhanced Th17-cell responses render CCR2-deficient mice more susceptible for autoimmune arthritis,” PLoS ONE, vol. 6, no. 10, Article ID e25833, 2011.
View at: Publisher Site | Google Scholar
L. Boring, J. Gosling, S. W. Chensue et al., “Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice,” Journal of Clinical Investigation, vol. 100, no. 10, pp. 2552–2561, 1997.
View at: Google Scholar
J. E. Christensen, A. Nansen, T. Moos et al., “Efficient T-cell surveillance of the CNS requires expression of the CXC chemokine receptor 3,” Journal of Neuroscience, vol. 24, no. 20, pp. 4849–4858, 2004.
View at: Publisher Site | Google Scholar
V. O. Ona, M. Li, J. P. G. Vonsattel et al., “Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease,” Nature, vol. 399, no. 6733, pp. 263–267, 1999.
View at: Publisher Site | Google Scholar
E. Okun, K. J. Griffioen, J. D. Lathia, S.-C. Tang, M. P. Mattson, and T. V. Arumugam, “Toll-like receptors in neurodegeneration,” Brain Research Reviews, vol. 59, no. 2, pp. 278–292, 2009.
View at: Publisher Site | Google Scholar
M. Bsibsi, R. Ravid, D. Gveric, and J. M. Van Noort, “Broad expression of Toll-like receptors in the human central nervous system,” Journal of Neuropathology and Experimental Neurology, vol. 61, no. 11, pp. 1013–1021, 2002.
View at: Google Scholar
R. M. Ransohoff and M. A. Brown, “Innate immunity in the central nervous system,” Journal of Clinical Investigation, vol. 122, no. 4, pp. 1164–1171, 2012.
View at: Publisher Site | Google Scholar
U. Koedel, U. M. Merbt, C. Schmidt et al., “Acute brain injury triggers MyD88-dependent, TLR2/4-independent inflammatory responses,” American Journal of Pathology, vol. 171, no. 1, pp. 200–213, 2007.
View at: Publisher Site | Google Scholar
R. K. Kalathur, M. A. Hernandez-Prieto, and M. E. Futschik, “Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database,” BMC Neurology, vol. 12, p. 47, 2012.
View at: Publisher Site | Google Scholar
K. H. Milld, L. S. Dungan, S. A. Jones, and J. Harris, “The role of inflammasome-derived IL-1 in driving IL-17 responses,” Journal of Leukocyte Biology, vol. 93, no. 4, pp. 489–497, 2013.
View at: Google Scholar
K. Liu, G. D. Victora, T. A. Schwickert et al., “In vivo analysis of dendritic cell development and homeostasis,” Science, vol. 324, no. 5925, pp. 392–397, 2009.
View at: Google Scholar
C. Waskow, K. Liu, G. Darrasse-Jèze et al., “The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues,” Nature Immunology, vol. 9, no. 6, pp. 676–683, 2008.
View at: Publisher Site | Google Scholar
U. O'Doherty, M. Peng, S. Gezelter et al., “Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature,” Immunology, vol. 82, no. 3, pp. 487–493, 1994.
View at: Google Scholar
G. Grouard, M.-C. Rissoan, L. Filgueira, I. Durand, J. Banchereau, and Y.-J. Liu, “The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand,” Journal of Experimental Medicine, vol. 185, no. 6, pp. 1101–1111, 1997.
View at: Publisher Site | Google Scholar
A. Nayak, R. Ansar, S. K. Verma, D. M. Bonifati, and U. Kishore, “Huntington's disease: an immune perspective,” Neurology Research International, vol. 2011, Article ID 563784, 7 pages, 2011.
View at: Publisher Site | Google Scholar
R. Huizinga, R. Q. Hintzen, K. Assink, M. Van Meurs, and S. Amor, “T-cell responses to neurofilament light protein are part of the normal immune repertoire,” International Immunology, vol. 21, no. 4, pp. 433–441, 2009.
View at: Publisher Site | Google Scholar
A. Larbi, G. Pawelec, J. M. Witkowski et al., “Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild alzheimer's disease,” Journal of Alzheimer's Disease, vol. 17, no. 1, pp. 91–103, 2009.
View at: Publisher Site | Google Scholar
S. J. Van Dyken and R. M. Locksley, “Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease,” Annual Review of Immunology, vol. 31, pp. 317–343, 2013.
View at: Google Scholar
M. Schwartz, A. London, and R. Shechter, “Boosting T-cell immunity as a therapeutic approach for neurodegenerative conditions: the role of innate immunity,” Neuroscience, vol. 158, no. 3, pp. 1133–1142, 2009.
View at: Publisher Site | Google Scholar
M. Thomas, T. Ashizawa, and J. Jankovic, “Minocycline in Huntington's disease: a pilot study,” Movement Disorders, vol. 19, no. 6, pp. 692–695, 2004.
View at: Publisher Site | Google Scholar
F. Norflus, A. Nanje, C.-A. Gutekunst et al., “Anti-inflammatory treatment with acetylsalicylate or rofecoxib is not neuroprotective in Huntington's disease transgenic mice,” Neurobiology of Disease, vol. 17, no. 2, pp. 319–325, 2004.
View at: Publisher Site | Google Scholar
R. J. Boado, E. K.-W. Hui, J. Zhiqiang Lu, and W. M. Pardridge, “Drug targeting of erythropoietin across the primate blood-brain barrier with an IgG molecular trojan horse,” Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 3, pp. 961–969, 2010.
View at: Publisher Site | Google Scholar
Q.-H. Zhou, R. Sumbria, E. K.-W. Hui, J. Z. Lu, R. J. Boado, and W. M. Pardridge, “Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor,” Journal of Pharmacology and Experimental Therapeutics, vol. 339, no. 2, pp. 618–623, 2011.
View at: Publisher Site | Google Scholar
I. Ayzenberg, I. Kleiter, A. Schroder et al., “Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy,” JAMA Neurology, vol. 70, no. 3, pp. 394–397, 2013.
View at: Publisher Site | Google Scholar
S. Schilling, S. Goelz, R. Linker, F. Luehder, and R. Gold, “Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration,” Clinical and Experimental Immunology, vol. 145, no. 1, pp. 101–107, 2006.
View at: Publisher Site | Google Scholar
R. A. Linker, D.-H. Lee, S. Ryan et al., “Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway,” Brain, vol. 134, no. 3, pp. 678–692, 2011.
View at: Publisher Site | Google Scholar
G. Ellrichmann, E. Petrasch-Parwez, D.-H. Lee et al., “Efficacy of fumaric acid esters in the R6/2 and YAC128 models of huntington's disease,” PLoS ONE, vol. 6, no. 1, Article ID e16172, 2011.
View at: Publisher Site | Google Scholar

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Copyright © 2013 Gisa Ellrichmann et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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