PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
 
Curr Mol Med. 2011 April; 11(3): 246–254.
PMCID: PMC3182412

The Role of Immune and Inflammatory Mechanisms in ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease. The cause is unknown, but genetic abnormalities have been identified in subjects with familial ALS and also in subjects with sporadic ALS. Environmental factors such as occupational exposure have been shown to be risk factors for the development of ALS. Patients differ in their clinical features and differ in the clinical course of disease. Immune abnormalities have been found in the central nervous system by pathological studies and also in the blood and CSF of subjects with ALS. Inflammation and immune abnormalities are also found in animals with a model of ALS due to mutations in the SOD1 gene. Previously it has been considered that immune abnormalities might contribute to the pathogenesis of disease. However more recently it has become apparent that an immune response can occur as a response to damage to the nervous system and this can be protective.

Keywords: Amyotrophic lateral sclerosis, biomarkers, immunity, inflammation, lymphocytes, protective immunity, T cells.

INTRODUCTION

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) lack the prominent infiltrates of blood-derived mononuclear cells that characterize primary autoimmune diseases. However, there is abundant evidence many substances involved in the promotion of inflammatory processes are present in the CNS of patients with such neurodegenerative diseases and there are also modest numbers of inflammatory cells present in the tissue in ALS. There have been previous reviews of the role of inflammation in ALS and the possibility of treating ALS by immune modulation [1-3]. We now review the evidence of immune abnormalities in ALS and whether this is helpful or harmful.

There have been suggestions that immune modulation could be used to modify the course of ALS. However, before such therapy is attempted, it is important to know if the immune response is harmful or beneficial. The presence of antibody and T cells at a site of pathology can occur as part of a harmful autoimmune process although there are a number of other criteria that must be met for a disease to be considered autoimmune [4]. Immune abnormalities at the site of disease could also be a response to damage [5] through activation of the innate immune system. This occurs as a response to so-called “danger signals” that are molecules released from damaged tissue [6]. Release of mitochondria is known to be important in provoking a systemic response to tissue injury [7]. In the brain the cells that respond to damage are microglia [8]. After an initial innate immune response due to microglia there can be further adaptive immune response to injury.

Once it has been provoked, an immune response could modulate the rate of progression of disease. One possibility is that an immune response could make disease more severe. However, an immune response can also be protective [9] and indeed strategies that enhance protective immunity are possible options for therapy of neurological diseases [10]. We will review the clinical features and pathogenesis if ALS, then provide evidence of immune abnormalities in ALS and the evidence for a role of these in pathogenesis and disease progression, including studies in experimental animal models of ALS.

BACKGROUND TO ALS

Clinical Features

ALS is a progressive disorder causing weakness of the limbs, and leading to death, usually within 3 –5 years. The incidence of ALS is around 2 per 100,000 [11-15]. ALS is slightly more common in men than in women [16]. For the diagnosis of ALS, there are strict clinical definitions [17] that involve the finding of a combination of upper and lower motor neurone signs. At first presentation, some patients do not fulfil these strict criteria but as time goes by they develop additional signs that confirm the diagnosis [18]. Although predominantly a motor disorder, ALS is commonly associated with dementia [19]. Although not clinically apparent, testing had found that there can also be subtle sensory abnormalities [20] and autonomic dysfunction [21].

Sub-Types of Disease

Patients with ALS vary in their clinical features such as the site of onset, and whether the subject has features of both upper and lower motor neurone weakness, or has solely upper or lower motor neurone signs. Patients with ALS may be placed into further subgroups (phenotypes) by combining information about both the site of onset (bulbar; upper or lower limb) and the type of weakness (predominantly affecting the upper or lower motor neurons). This type of analysis identifies groups such as the flail-arm presentation, which involves lower motor neuron weakness of the upper limbs [22, 23]. Cluster analysis has also found distinct subgroups of patients [23]. Furthermore the gender of the subject influences the site of onset of ALS, with women being more likely to have bulbar onset disease [16]. It is possible that the different sub-types of ALS have different pathogenesis. In one of the genome-wide association studies in ALS, the investigators found that the association with different SNPs was different according to gender [24]. It is important to understand the causes of heterogeneity in ALS, because sub-types of disease with different pathogenesis could confound clinical trials [25]. It is possible that the immune response could be important in the disease process, and this could vary among individuals, leading to further heterogeneity.

Prognostic Factors

In addition to different clinical features, patients also vary in the rate of progression of weakness and it may be that once the disease develops, there are factors that influence the rate of progression. The known prognostic factors in ALS are age and bulbar site of onset [26]. It is possible that gender also plays a role in prognosis [26] with women having a shorter survival on average, but this is controversial, and gender does not appear to be an independent risk factor in multivariate analysis [16]. It is important to look for modifiable factors that affect prognosis, because this could lead to possible therapies. This review will focus on the role of the immune system and whether immune responses alter the rate of progression of disease. Males and females have different immune responsiveness [27], so this could be another variable that could lead to differences between men and women in the clinical course of ALS.

Measuring Disease Progression in ALS

While prolonging survival of patients with ALS is the goal of therapy, survival time is not a good measure of the underlying rate of progression of disease, because survival is affected by other factors such as the use of mechanical ventilation [28], and also the site of onset of disease, so that subjects with early involvement of respiratory muscles have a shorter survival [29]. The underlying rate of death of upper and lower motor neurones is more difficult to measure. For this we need biomarkers which are “objective measurements that act as an indicator of normal biological processes, pathogenic processes or pharmacological response to therapeutic intervention” [30]. Any studies of the rate of disease progression in ALS need to measure the rate of cell death or surrogate markers of this. One measure of disease progression in ALS is motor unit number estimation, using neurophysiological techniques to determine the number of motor units in a muscle [30, 31]. We have developed a method of motor unit number estimation that uses measurement of the compound muscles action potential in response to increasing levels of electrical stimulation. This data is analyzed using Bayesian statistics to provide an estimate of the number of motor units in the muscle [32, 33]. This can be used repeatedly to measure the number of motor units in a muscle so that the rate of loss of motor units can be calculated [34]. Other possible biomarkers include serum levels of neurofilaments which are a measure of axonal degeneration and which are elevated in ALS [35].

BACKGROUND TO PATHOGENESIS OF ALS

The pathology of ALS includes loss of both upper and lower motor neurones, but the fundamental processes that lead to the death of neurones are also not fully understood [36] . Theories of the pathogenesis include the effects of abnormal proteins, such as TDP-43 [37, 38] , altered mitochondrial dysfunction [39], and glutamate toxicity [36]. Numerous studies have demonstrated biochemical abnormalities in autopsy tissue including AMPA receptor medicated toxicity [40], increased cytosolic phospholipase A(2) [41] and activation of apoptosis inducing factor [42]. While ALS is primarily a disease of motor neurones, there is also damage that is dependent on factors external to the motor neurone. Astrocytes have been implicated in causing such damage [43]. This is known as non-cell autonomous damage [44, 45] and occurs in other neurodegenerative diseases as well as in ALS.

It is likely that genetic and environmental factors play a role in pathogenesis of ALS. Some cases are familial ALS (fALS) with a number of causative genes being identified. The first gene to be identified was Cu/Zn superoxide dismutase 1 (SOD1), which has numerous different mutations [46]. The exact means of toxicity of mutant SOD1 is not fully understood, but mutant SOD1 expression in astrocytes and microglia contributes to disease progression in ALS [45]. Other genes implicated in fALS are fused in sarcoma protein (FUS) [47] and tar-DNA binding protein of molecular weight 43kDa (TDP 43) [48].

In sporadic ALS, genetic factors are also important. Having even a single relative with ALS increases risk of disease for an individual [49]. The genes implicated in sporadic ALS (sALS) include TDP-43 [48], FUS [50] and the SMN gene [51]. There have been several genome wide association studies in ALS. These have found somewhat differing results [24, 52, 53] but have found associations with genes for neurotransmitter release, genes associated with familial spastic paraparesis and genes associated with frontotemporal dementia. Environmental factors linked to ALS include cigarette smoking [54], occupational exposures particularly to toxins and metals, exercise [55, 56] and education [57-60].

EVIDENCE OF THE PRESENCE OF IMMUNE AND INFLAMMATORY ABNORMALITIES IN ALS

Findings from Pathology and Imaging

Studies in Humans

There is considerable evidence of inflammation in ALS. Studies of human post-mortem pathology have shown immune abnormalities in ALS. However, these studies are necessarily studies done at the end stage of disease, and do not reveal the early changes. In studies of ALS pathology there is morphological evidence of microglial activation [61-63]. Microglial activation occurs after tissue injury and involves change in shape and expression of cell surface receptors [8, 64] and is part of an innate immune response. Microglial activation in ALS has been further demonstrated by the finding of the signal transducer and activator of transcription-3 (STAT3) in microglia in autopsy studies [65]. Gene expression studies have found upregulation of the TLR4 signalling genes in subjects with ALS [66] and the authors suggest that this indicates chronic monocyte/macrophage activations.

Nuclear medicine technology is able to demonstrate neuroinflammation [67] and microglial activation can be demonstrated by binding of the PK 11195 ligand to the peripheral benzodiazepine receptor [68, 69]. Using this ligand, microglial activation has been demonstrated in ALS with PET imaging [70]. In ALS it is not clear is whether this change occurs early in disease or is a reaction to disease. For example, microglia activation can occur after distant pathology such as after a dying-back axonopathy [71].

There are also infiltrating immune cells in the CNS in human ALS [72] . These include macrophages and mast cells [73] and also T cells in the areas of motor neuron destruction [63, 74, 75]. There is evidence of immunoglobulin deposition in the CNS in ALS [76] and also of complement deposition [63, 77].

Studies in Animal Models

The most commonly used animal models of ALS are rats or mice with mutant SOD1. In human ALS, SOD1 mutations only account for a small proportion of subjects and the mechanisms of disease may differ from other subjects in whom abnormalities of TDP-43 are found [78]. However, animals with SOD1 mutations show progressive weakness typical of ALS. In symptomatic SOD1 mutant animals, there is evidence of immune activation, although the timing of onset of inflammation is not clear. One study showed that in G93A SOD1 mutant mice, early disease is associated with astrogliosis and late disease with microglial activation [79] while another suggested that microglial activation was an early event [80]. T cells are also found in the nervous system of mice with the SOD1 mutation [81]. Inflammation in SOD1 mutant mice is associated with activation of caspase 1 and caspase 3 [82].

Immune Abnormalities in Blood and CSF in ALS

There have been numerous studies investigating peripheral immune abnormalities in ALS. These include studies of antibodies, T cells, chemokines and cytokines and other markers of inflammation. The first studies were concerned with the presence of antibodies in the blood of subject with ALS. There have been many reports of antibodies to voltage gated calcium channels [83, 84]. In addition there have been studies of non-specific changes in antibodies, as a recent study has shown an increase in IgG levels in subjects with ALS compared to controls [85].

With respect to T cell abnormalities, in the blood of subjects with ALS, there have been reports of increased numbers of CD4+ T helper cells and increased expression of HLA class II molecules on monocytes and macrophages, suggestive of systemic immune activation [86]. Another study also found increased CD4+ cells, reduced regulatory T cells (Treg) but reduced expression of HLA DR by monocytes [87]. T cell clones from CSF of ALS subjects can be induced to secrete IFN gamma [75]. IL-13 producing T cells have been found in the blood of subjects with ALS and correlate with the rate of disease progression [88, 89]. The co-stimulatory pathway activated through CD40 ligand is upregulated in some human subjects with ALS [90].

There are increased levels of circulating chemokines and cytokines in ALS. There are higher levels of the chemokine MCP-1 in patients with a shorter diagnostic delay, which is a marker of more severe rapidly progressing disease [91]. Expression of MCP-1 receptor (CCR2) is reduced on circulating monocytes in ALS [92]. Increased levels of IL17 are found in the serum of subjects with ALS [88]. Levels of IL-6 are elevated in ALS, but only in subjects with hypoxia, so are probably a response to hypoxia rather than to the disease itself [93].

Other markers of inflammation are also abnormal in ALS. Levels of lipopolysaccharide are elevated in patients with ALS suggesting systemic inflammation [94]. There are also abnormalities of complement in ALS. Two dimensional gel electrophoresis was used to study serum proteins in ALS subjects and found that components of complement C3 were increased compared to controls [95]. There is also evidence of low level systemic inflammation with increased levels of C reactive protein and ESR in subjects with ALS compared to controls, with the levels correlating the levels of disability as measured by the ALS functional rating scale [96]. All these studies demonstrate the presence of an immune response in subjects with ALS.

DOES INFLAMMATION PARTICIPATE IN PATHOGENESIS?

The Immune Response can be Helpful or Harmful

Having shown that there is local and systemic alteration in the immune system in ALS, it is necessary to determine if this primary or secondary, and whether it is harmful or beneficial. The immune and inflammatory changes in ALS could be primary and part of the cause of the disease. Alternatively neuroinflammation and T cell infiltration could also be secondary to the tissue damage that occurs in ALS, as it is in other nervous system injury. Once established, inflammation and immune changes could exacerbate damage [97] or be protective [98]. The protective aspects of inflammation include clearance of debris by microglia which is important in repair [99] and interaction with T cells [98]. Brain-specific T cells at the site of injury can play a role in the repair of damaged or inflamed tissues — this has been termed “protective immunity” [9, 100, 101]. This is likely to be due to the effects of cytokines and growth factors delivered by T cells to the site of injury [102-105]. Such protective immunity was appears to be a general phenomenon, that is homeostatic [106].

To determine whether the immune system contributes to disease it is necessary to look at the effects of passive transfer, experimental studies in animals and the effects of modifying the immune response in humans with ALS.

Tissue Culture and Passive Transfer of Disease

In older studies, immunoglobulins from patients with ALS were toxic to motor neurones in culture, and thought to act on calcium channels. Passive transfer to mice of ALS immunoglobulin caused some abnormalities at motor end-plates [107] and also caused degeneration of motor neurones after passive transfer to BalbC mice [108]. IgG from subjects with ALS caused apoptosis of neurones in primary spinal cord cultures [109]. This suggested that antibody could contribute to disease pathogenesis.

Experimental Studies in Animal Models

Much of this work has been done in mice that have abnormalities of SOD1. Mutations in this gene are found in a small percentage of subjects with human ALS, so whether these results can be generalized to all subjects with ALS in unclear. There is conflicting evidence about whether the immune system is beneficial or harmful in this model. It must be noted that most mice used with the SOD1 mutation are of the BL6 strain. Mouse strains vary in their immune response. The immune system of BL6 mice produces a predominant Th1 response, as demonstrated by the response to Leishmania infection [110]. The macrophages of BL6 mice are involved in this process [111].

Mice with different genetic background to the SOD1 mutation have a different clinical course of disease, with SJL/J mice that are very susceptible to autoimmune disease having a shorter survival than mice with the BL6 background [112] and mice with ALR, NOD.Rag1KO and C3H background also showing a more severe phenotype than BL6, B10, BALB/c and DBA strains [113]. This has implications. It means that the results in SOD1 mice cannot necessarily be generalized to humans with ALS for two reasons- firstly not all subjects have SOD1 mutations and secondly, like different mouse strains, human ALS suffers will have different immune system capability.

There is evidence that the immune system can exacerbate disease in SOD1 mutant mice. Non-specific inflammation seems to make disease worse. For example in SOD1 mice, endotoxemia can stimulate disease in mice [114]. The role of microglial activation appears to be complex, but there is evidence that activation of innate immunity through TLR4 activates microglia and leads to increased neurodegeneration [115]. In SOD1 mice there have been studies suggesting that treatment with minocycline, starting in the presymptomatic stage, with the intention of reducing micgroglial activation, is helpful in reducing progression [116]. However, a more recent study shows that when treatment starts in the late stages of disease, treatment with minocycline increases microglial activation [117]. In SOD1 mutant mice, treatment with bee venom led to reduction in microglial activation and with some reduction in severity of disease [118]. However, it must be noted that if microglial activation is secondary to degeneration, then any treatment that slowed degeneration would also slow microglial activation.

Inflammation in SOD1 mice is mediated through inflammasomes, which are activated by NOD-like receptors in response to danger signals [119] and which contribute to sterile inflammation. This type of inflammation is thought to characterize autoinflammatory disorders, which are a rather new class of disorders where the clinical features include recurrent inflammation [120]. This leads to activation of caspase 1, which leads to activation of IL-1β. In SOD1 transgenic mice, mutant SOD1 leads to activation of this pathway. SOD1 mice that are deficient in caspase 1 or in IL-1β or treated with IL-1 receptor antagonists have increased lifespan [121]. SOD1 mice given intraventricular injections of a caspase inhibitor also have reduced disease severity. Taken together, these studies indicate that this type of inflammation leads to more severe disease in SOD1 1. It is not known if this mechanism is active in human subjects with ALS who have normal SOD1 protein.

Other evidence that immune processes are harmful include the finding that inhibition of C5a ameliorates disease in SOD1 mice [122]. A monoclonal antibody to CD40 ligand, to block co-stimulation, also led to reduced weight loss in SOD1 mice [90].

However, while the immune system can worsen disease, it is not the primary cause of disease since SOD1 mice deficient in B cells still get disease [123] and SOD1 mice without microglia have the same disease as those with normal microglia [124].

There is also evidence that protective immunity can lessen the disease. Protective immunity can lessen the harmful effects of damage to the nervous system [9, 125]. Protective immunity is mediated by regulatory T cells (Treg) and transfer of wild type Treg cells delayed symptom onset in G93A SOD1 mice [126]. Vaccination with SOD1 protein induces protective immunity and lessens disease [127]. SOD1 mice that are deficient in T cells have greater progression of disease and lack the upregulation of IGF-1 and downregulation of IL-6 that are seen in control mice [128] or increased levels of pro-inflammatory cytokines and NOX2 [129] .

Effects of Immune Therapies in Human Subjects with ALS

It is attractive to consider that modulation of the immune response will be a useful therapy in ALS. If neuroinflammation enhances disease activity, then control of neuroinflammation should be helpful [130] possibly by enhancing protective immunity [131]. So far there is little evidence in human subjects regarding the effects of enhancing protective immunity. There have been trials of immune suppression in ALS. After treatment with minocycline, to reduce microglial activation, patients did worse [132]. This might suggest that microglial activation is beneficial in ALS. Total body irradiation and stem cell therapy were of no benefit in ALS [133]. Earlier attempts at immune therapy included treatment with intravenous immunoglobulin, which was of no benefit [134], with cyclophosphamide, which also was of no benefit [135] and with azathioprine and prednisone which was of no benefit [136].

Recently a trial of granulocyte colony stimulating factor led to a decrease in levels of MCP-1 and IL-17 in subjects with ALS [137]. It remains to be determined whether this will lead to clinical benefit.

Do Genes for Immunity Modulate Human ALS?

We speculate that if the immune response plays a role in ALS, then genetic differences in immune responsiveness could affect the outcome. So far, genetic studies in ALS have concentrated on genes that are risk factors for acquiring the disease, and one recent estimate from twin studies is that the hereditable component is 61% of the risk of acquiring ALS, and the environment component is 39% [138]. Less is known about genes that modify the course of disease, although it is likely that there are such genes. The variability in the clinical course among individuals in families with FALS is evidence of this. Disease modifying genes could include genes that are protective against neurodegeneration. However, if the immune response modifies the clinical course of ALS, then genes for immune function might also be important in modifying disease. In diseases of autoimmune etiology such as multiple sclerosis, genome wide association studies show strong association with the MHC region and other immune genes [139] but this is not the case in ALS, although as already mentioned such genes are likely to influence the clinical course of ALS, rather than to be risks for acquiring ALS. We suggest that this is a field worth further study.

SUMMARY AND FUTURE DIRECTIONS

Immune activation in the CNS can be detected in ALS and indeed in other neurodegenerative diseases such as Alzheimer’s disease [140] and Parkinson’s disease [141], where there is similar debate as to whether the immune response is helpful or harmful. Immune activation also occurs after brain injury, such as stroke, where there is also uncertainty as to whether the immune response contributes to damage or to recovery [142]. Previously it was thought that this inflammation may contribute to pathogenesis of ALS. However, it may also be a protective response. The difference in the overall effect of immune activation may be related to the timing of the response. It is possible that individual variability in immune responsiveness means that individual patients have different immune responses in ALS. What is needed now are studies that use robust measurements of disease progression to see if patients with evidence of immune activation have different prognosis from those who do not, and to explore whether disease modifying genes include genes with immune function. It is important to know whether inflammation and immune response are helpful or harmful in ALS, so that possible immunomodulatory therapies can be pursued.

ACKNOWLEDGEMENTS

The authors acknowledge the financial support of the National Health and Medical Research Council of Australia and the Motor Neurone Disease Research Institute of Australia.

REFERENCES

1. Holmoy T. T cells in amyotrophic lateral sclerosis. Eur J Neurol. 2008;15:360–6. [PubMed]
2. Calvo A, Moglia C, Balma M, Chio A. Involvement of immune response in the pathogenesis of amyotrophic lateral sclerosis: a therapeutic opportunity? CNS Neurol Disord Drug Targets. 2010;9:325–30. [PubMed]
3. Barbeito AG, Mesci P, Boillee S. Motor neuron-immune interactions: the vicious circle of ALS. J Neural Transm. 2010;117:981–1000. [PMC free article] [PubMed]
4. Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited) Immunol Today. 1993;14:426–30. [PubMed]
5. Papadimitriou D, Le V V, Jacquier A, Ikiz B, Przedborski S, Re DB. Inflammation in ALS and SMA: Sorting out the good from the evil. Neurobiol Dis. 2010;37:493–502. [PMC free article] [PubMed]
6. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045. [PubMed]
7. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7. [PMC free article] [PubMed]
8. Graeber MB. Changing face of microglia. Science. 2010;330:783–8. [PubMed]
9. Schwartz M, Cohen I, Lazarov-Spiegler O, Moalem G, Yoles E. The remedy may lie in ourselves: prospects for immune cell therapy in central nervous system protection and repair. J Mol Med. 1999;77:713–7. [PubMed]
10. Graber JJ, Dhib-Jalbut S. Protective autoimmunity in the nervous system. Pharmacol Ther. 2009;121:147–59. [PubMed]
11. Abhinav K, Stanton B, Johnston C, et al. Amyotrophic lateral sclerosis in South-East England: a population-based study. The South-East England register for amyotrophic lateral sclerosis (SEALS Registry) Neuroepidemiology. 2007;29:44–8. [PubMed]
12. Vazquez MC, Ketzoian C, Legnani C, et al. Incidence and prevalence of amyotrophic lateral sclerosis in Uruguay: a population-based study. Neuroepidemiology. 2008;30:105–11. [PubMed]
13. Chio A, Mora G, Calvo A, Mazzini L, Bottacchi E, Mutani R. Epidemiology of ALS in Italy: a 10-year prospective population-based study. Neurology. 2009;72:725–31. [PubMed]
14. Beghi E, Millul A, Micheli A, Vitelli E, Logroscino G. Incidence of ALS in Lombardy, Italy. Neurology. 2007;68:141–5. [PubMed]
15. McGuire V, Longstreth WT Jr, Koepsell TD, van BG. Incidence of amyotrophic lateral sclerosis in three counties in western Washington state. Neurology. 1996;47:571–3. [PubMed]
16. McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral sclerosis. Gend Med. 2010;7:557–70. [PubMed]
17. World Federation of Neurology Research Group on Neuromuscular Diseases Subcommittee on Motor Neuron Disease. Airlie House guidelines. Therapeutic trials in amyotrophic lateral sclerosis. Airlie House "Therapeutic Trials in ALS" Workshop Contributors. J Neurol Sci. 1995;(129 Suppl):1–10. [PubMed]
18. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman OM. Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: A population-based study. Arch Neurol. 2000;57:1171–6. [PubMed]
19. Geser F, Martinez-Lage M, Kwong LK, Lee VM, Trojanowski JQ. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol. 2009;256:1205–14. [PMC free article] [PubMed]
20. Heads T, Pollock M, Robertson A, Sutherland WHF, Allpress S. Sensory nerve pathology in amyotrophic lateral sclerosis. Acta Neuropathol Berl. 1991;82:316–20. [PubMed]
21. Chida K, Sakamaki S, Takasu T. Alteration in autonomic function and cardiovascular regulation in amyotrophic lateral sclerosis. J Neurol. 1989;236:127–30. [PubMed]
22. Talman P, Forbes A, Mathers S. Clinical phenotypes and natural progression for motor neuron disease: analysis from an Australian database. Amyotroph Lateral Scler. 2009;10:79–84. [PubMed]
23. Ganesalingam J, Stahl D, Wijesekera L, et al. Latent cluster analysis of ALS phenotypes identifies prognostically differing groups. PLoS ONE. 2009;4:e7107. [PMC free article] [PubMed]
24. Dunckley T, Huentelman MJ, Craig DW, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med. 2007;357:775–88. [PubMed]
25. Beghi E, Chio A, Couratier P, et al. The epidemiology and treatment of ALS: Focus on the heterogeneity of the disease and critical appraisal of therapeutic trials. Amyotroph Lateral Scler. 2011;12:1–10. [PMC free article] [PubMed]
26. del Aguila MA, Longstreth WT Jr, McGuire V, Koepsell TD, van Belle G. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology. 2003;60:813–9. [PubMed]
27. McCombe PA, Greer JM, Mackay IR. Sexual dimorphism in autoimmune disease. Curr Mol Med. 2009;9:1058–79. [PubMed]
28. Carratu P, Spicuzza L, Cassano A, et al. Early treatment with noninvasive positive pressure ventilation prolongs survival in Amyotrophic Lateral Sclerosis patients with nocturnal respiratory insufficiency. Orphanet J Rare Dis. 2009;4:10. [PMC free article] [PubMed]
29. Baumann F, Henderson RD, Morrison SC, et al. Use of respiratory function tests to predict survival in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2009:1–9. [PubMed]
30. Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 2009;8:94–109. [PubMed]
31. Daube JR. Motor unit number estimates--from A to Z. J Neurol Sci. 2006;242:23–35. [PubMed]
32. Ridall PG, Pettitt AN, Henderson RD, McCombe PA. Motor Unit Number Estimation—A Bayesian Approach. Biometrics. 2006;62:1235–50. [PubMed]
33. Ridall PG, Pettitt AN, Friel N, McCombe PA, Henderson RD. Motor unit number estimation using reversible jump Markov chain Monte Carlo. Journal Royal Statistical Society Series C - Applied Statistics. 2007;56:235–69.
34. Henderson RD, Ridall PG, Hutchinson NM, Pettitt AN, McCombe PA. Bayesian statistical MUNE method. Muscle Nerve. 2007;36:206–13. [PubMed]
35. Boylan K, Yang C, Crook J, et al. Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker. J Neurochem. 2009;111:1182–91. [PubMed]
36. Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009;65(Suppl 1):S3–S9. [PubMed]
37. Liscic RM, Grinberg LT, Zidar J, Gitcho MA, Cairns NJ. ALS and FTLD: two faces of TDP-43 proteinopathy. Eur J Neurol. 2008;15:772–80. [PMC free article] [PubMed]
38. Buratti E, Baralle FE. The molecular links between TDP-43 dysfunction and neurodegeneration. Adv Genet. 2009;66:1–34. [PubMed]
39. Shi P, Gal J, Kwinter DM, Liu X, Zhu H. Mitochondrial dysfunction in amyotrophic lateral sclerosis. Biochim Biophys Acta. 2010;1802:45–51. [PMC free article] [PubMed]
40. Kwak S, Hideyama T, Yamashita T, Aizawa H. AMPA receptor-mediated neuronal death in sporadic ALS. Neuropathology. 2010;30:182–8. [PubMed]
41. Shibata N, Kakita A, Takahashi H, et al. Increased expression and activation of cytosolic phospholipase A(2) in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. Acta Neuropathol Berl. 2010 [Epub ahead of print] [PubMed]
42. Shibata N, Kakita A, Takahashi H, et al. Persistent cleavage and nuclear translocation of apoptosis-inducing factor in motor neurons in the spinal cord of sporadic amyotrophic lateral sclerosis patients. Acta Neuropathol Berl. 2009 [Epub ahead of print] [PubMed]
43. Aebischer J, Cassina P, Otsmane B, et al. IFNgamma triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1. Cell Death Differ. 2010 [Epub ahead of print] [PMC free article] [PubMed]
44. Boillee S, Vande VC, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006;52:39–59. [PubMed]
45. Ilieva H, Polymenidou M, Cleveland DW. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol. 2009;187:761–72. [PMC free article] [PubMed]
46. Orrell RW, Habgood JJ, Malaspina A, et al. Clinical characteristics of SOD1 gene mutations in UK families with ALS. J Neurol Sci. 1999;169:56–60. [PubMed]
47. Blair IP, Williams KL, Warraich ST, et al. FUS mutations in amyotrophic lateral sclerosis: clinical, pathological., neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry. 2010;81(6):639–45. [PubMed]
48. Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40:572–4. [PubMed]
49. Fang F, Kamel F, Lichtenstein P, et al. Familial aggregation of amyotrophic lateral sclerosis. Ann Neurol. 2009;66:94–9. [PMC free article] [PubMed]
50. Lai SL, Abramzon Y, Schymick JC, et al. FUS mutations in sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2010 [Epub ahead of print] [PMC free article] [PubMed]
51. Corcia P, Camu W, Praline J, Gordon PH, Vourch P, Andres C. The importance of the SMN genes in the genetics of sporadic ALS. Amyotroph Lateral Scler. 2009;10:436–40. [PubMed]
52. Sha Q, Zhang Z, Schymick JC, Traynor BJ, Zhang S. Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis. BMC Med Genet. 2009;10:86. [PMC free article] [PubMed]
53. Blauw HM, Al-Chalabi A, Andersen PM, et al. A large genome scan for rare CNVs in amyotrophic lateral sclerosis. Hum Mol Genet. 2010;19:4091–9. [PubMed]
54. Armon C. Smoking may be considered an established risk factor for sporadic ALS. Neurology. 2009;73:1693–8. [PMC free article] [PubMed]
55. Chio A, Calvo A, Dossena M, Ghiglione P, Mutani R, Mora G. ALS in Italian professional soccer players: the risk is still present and could be soccer-specific. Amyotroph Lateral Scler. 2009;10:205–9. [PubMed]
56. Beghi E, Logroscino G, Chio A, et al. Amyotrophic lateral sclerosis, results of a population-based pilot case-control study. Amyotroph Lateral Scler. 2010;11:289–92. [PMC free article] [PubMed]
57. Sutedja NA, Veldink JH, Fischer K, et al. Lifetime occupation, education, smoking, and risk of ALS. Neurology. 2007;69:1508–14. [PubMed]
58. Fang F, Quinlan P, Ye W, et al. Workplace exposures and the risk of amyotrophic lateral sclerosis. Environ Health Perspect. 2009;117:1387–92. [PMC free article] [PubMed]
59. Furby J, Hayton T, Anderson V, et al. Magnetic resonance imaging measures of brain and spinal cord atrophy correlate with clinical impairment in secondary progressive multiple sclerosis. Mult Scler. 2008;14:1068–75. [PubMed]
60. Sutedja NA, Veldink JH, Fischer K, et al. Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review. Amyotroph Lateral Scler. 2009;10:302–9. [PubMed]
61. Engelhardt JI, Tajti J, Appel SH. Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch Neurol. 1993;50:30–6. [PubMed]
62. McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002;26:459–70. [PubMed]
63. McGeer PL, McGeer EG, Kawamata T, Yamada T, Akiyama H. Reactions of the immune system in chronic degenerative neurological diseases. Can J Neurol Sci. 1991;18:376–9. [PubMed]
64. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8. [PubMed]
65. Shibata N, Kakita A, Takahashi H, et al. Activation of signal transducer and activator of transcription-3 in the spinal cord of sporadic amyotrophic lateral sclerosis patients. Neurodegener Dis. 2009;6:118–26. [PubMed]
66. Zhang R, Hadlock KG, Do H, et al. Gene expression profiling in peripheral blood mononuclear cells from patients with sporadic amyotrophic lateral sclerosis (sALS) J Neuroimmunol. 2011;230:114–23. [PMC free article] [PubMed]
67. Winkeler A, Boisgard R, Martin A, Tavitian B. Radioisotopic imaging of neuroinflammation. J Nucl Med. 2010;51:1–4. [PubMed]
68. Le Fur G, Perrier ML, Vaucher N, et al. Peripheral benzodiazepine binding sites: effect of PK 11195. 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide. I. In vitro studies. Life Sci. 1983;32:1839–47. [PubMed]
69. Cagnin A, Kassiou M, Meikle SR, Banati RB. Positron emission tomography imaging of neuroinflammation. Neurotherapeutics. 2007;4:443–52. [PubMed]
70. Turner MR, Cagnin A, Turkheimer FE, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15:601–9. [PubMed]
71. Fischer LR, Culver DG, Tennant P, et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004;185:232–40. [PubMed]
72. Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992;140:691–707. [PubMed]
73. Graves MC, Fiala M, Dinglasan LA, et al. Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5:213–9. [PubMed]
74. Lawson JM, Tremble J, Dayan C, et al. Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin Exp Immunol. 2008;154:353–9. [PubMed]
75. Holmoy T, Roos PM, Kvale EO. ALS: cytokine profile in cerebrospinal fluid T-cell clones. Amyotroph Lateral Scler. 2006;7:183–6. [PubMed]
76. Engelhardt JI, Appel SH. IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch Neurol. 1990;47:1210–6. [PubMed]
77. Donnenfeld H, Kascsak RJ, Bartfeld H. Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients. J Neuroimmunol. 1984;6:51–7. [PubMed]
78. Mackenzie IR, Bigio EH, Ince PG, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007;61:427–34. [PubMed]
79. Yang WW, Sidman RL, Taksir TV, et al. Relationship between neuropathology and disease progression in the SOD1(G93A) ALS mouse. Exp Neurol. 2010 [PubMed]
80. Sanagi T, Yuasa S, Nakamura Y, et al. Appearance of phagocytic microglia adjacent to motoneurons in spinal cord tissue from a presymptomatic transgenic rat model of amyotrophic lateral sclerosis. J Neurosci Res. 2010;88:2736–46. [PubMed]
81. Alexianu ME, Kozovska M, Appel SH. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology. 2001;57:1282–9. [PubMed]
82. Pasinelli P, Houseweart MK, Brown RH Jr, Cleveland DW. Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2000;97:13901–6. [PubMed]
83. Engelhardt JI, Siklos L, Komuves L, Smith RG, Appel SH. Antibodies to calcium channels from ALS patients passively transferred to mice selectively increase intracellular calcium and induce ultrastructural changes in motoneurons. Synapse. 1995;20:185–99. [PubMed]
84. Kimura F, Smith RG, Delbono O, et al. Amyotrophic lateral sclerosis patient antibodies label Ca2+ channel alpha 1 subunit. Ann Neurol. 1994;35:164–71. [PubMed]
85. Saleh IA, Zesiewicz T, Xie Y, et al. Evaluation of humoral immune response in adaptive immunity in ALS patients during disease progression. J Neuroimmunol. 2009;215:96–101. [PubMed]
86. Zhang R, Gascon R, Miller RG, et al. Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS) J Neuroimmunol. 2005;159:215–24. [PubMed]
87. Mantovani S, Garbelli S, Pasini A, et al. Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol. 2009;210:73–9. [PubMed]
88. Fiala M, Chattopadhay M, La CA, et al. IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients. J Neuroinflammation. 2010;7:76. [PMC free article] [PubMed]
89. Shi N, Kawano Y, Tateishi T, et al. Increased IL-13-producing T cells in ALS: positive correlations with disease severity and progression rate. J Neuroimmunol. 2007;182:232–5. [PubMed]
90. Lincecum JM, Vieira FG, Wang MZ, et al. From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis. Nat Genet. 2010;42:392–9. [PubMed]
91. Kuhle J, Lindberg RL, Regeniter A, et al. Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur J Neurol. 2009;16:771–4. [PubMed]
92. Zhang R, Gascon R, Miller RG, et al. MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS) J Neuroimmunol. 2006;179:87–93. [PubMed]
93. Moreau C, Devos D, Brunaud-Danel V, et al. Elevated IL-6 and TNF-alpha levels in patients with ALS: inflammation or hypoxia? Neurology. 2005;65:1958–60. [PubMed]
94. Zhang R, Miller RG, Gascon R, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS) J Neuroimmunol. 2009;206:121–4. [PMC free article] [PubMed]
95. Goldknopf IL, Sheta EA, Bryson J, et al. Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson's disease. Biochem Biophys Res Commun. 2006;342:1034–9. [PubMed]
96. Keizman D, Rogowski O, Berliner S, et al. Low-grade systemic inflammation in patients with amyotrophic lateral sclerosis. Acta Neurol Scand. 2009;119:383–9. [PubMed]
97. Wills AM, Cronin S, Slowik A, et al. A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS. Neurology. 2009;73:16–24. [PMC free article] [PubMed]
98. Appel SH, Beers DR, Henkel JS. T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol. 2010;31:7–17. [PubMed]
99. Neumann H, Kotter MR, Franklin RJ. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain. 2009;132:288–95. [PMC free article] [PubMed]
100. Schwartz M, Moalem G. Beneficial immune activity after CNS injury: prospects for vaccination. J Neuroimmunol. 2001;113:185–92. [PubMed]
101. Cohen IR, Schwartz M. Autoimmune maintenance and neuroprotection of the central nervous system. J Neuroimmunol. 1999;100:111–4. [PubMed]
102. Stoll G, Jander S, Schroeter M. Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. Adv Exp Med Biol. 2002;513:87–113. [PubMed]
103. Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H. The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis. Neurol Sci. 2006;27(Suppl 1):S1–S7. [PubMed]
104. Hohlfeld R. Does inflammation stimulate remyelination? J Neurol. 2007;254(Suppl 1):I47–I54.
105. Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H. The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis. J Neuroimmunol. 2000;107:161–6. [PubMed]
106. Schwartz M, Kipnis J. Protective autoimmunity: regulation and prospects for vaccination after brain and spinal cord injuries. Trends Mol Med. 2001;7:252–8. [PubMed]
107. Appel SH, Engelhardt JI, Garcia J, Stefani E. Immunoglobulins from animal models of motor neuron disease and from human amyotrophic lateral sclerosis patients passively transfer physiological abnormalities to the neuromuscular junction. Proc Natl Acad Sci USA. 1991;88:647–51. [PubMed]
108. Pullen AH, Demestre M, Howard RS, Orrell RW. Passive transfer of purified IgG from patients with amyotrophic lateral sclerosis to mice results in degeneration of motor neurons accompanied by Ca2+ enhancement. Acta Neuropathol Berl. 2004;107:35–46. [PubMed]
109. Demestre M, Pullen A, Orrell RW, Orth M. ALS-IgG-induced selective motor neurone apoptosis in rat mixed primary spinal cord cultures. J Neurochem. 2005;94:268–75. [PubMed]
110. Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989;169:59–72. [PMC free article] [PubMed]
111. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166–73. [PubMed]
112. Heiman-Patterson TD, Deitch JS, Blankenhorn EP, et al. Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS. J Neurol Sci. 2005;236:1–7. [PubMed]
113. Heiman-Patterson TD, Sher RB, Blankenhorn EA, et al. Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: A window of opportunity in the search for genetic modifiers. Amyotroph Lateral Scler. 2011 [PubMed]
114. Nguyen MD, D'Aigle T, Gowing G, Julien JP, Rivest S. Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. J Neurosci. 2004;24:1340–9. [PubMed]
115. Lehnardt S, Massillon L, Follett P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA. 2003;100:8514–9. [PubMed]
116. Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2002;10:268–78. [PubMed]
117. Keller AF, Gravel M, Kriz J. Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice. Exp Neurol. 2010 [PubMed]
118. Yang EJ, Jiang JH, Lee SM, et al. Bee venom attenuates neuroinflammatory events and extends survival in amyotrophic lateral sclerosis models. J Neuroinflammation. 2010;7:69. [PMC free article] [PubMed]
119. Cassel SL, Sutterwala FS. Sterile inflammatory responses mediated by the NLRP3 inflammasome. Eur J Immunol. 2010;40:607–11. [PMC free article] [PubMed]
120. Conforti-Andreoni C, Ricciardi-Castagnoli P, Mortellaro A. The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond. Cell Mol Immunol. 2011 [PubMed]
121. Meissner F, Molawi K, Zychlinsky A. Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci USA. 2010;107:13046–50. [PubMed]
122. Woodruff TM, Costantini KJ, Crane JW, et al. The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis. J Immunol. 2008;181:8727–34. [PubMed]
123. Naor S, Keren Z, Bronshtein T, Goren E, Machluf M, Melamed D. Development of ALS-like disease in SOD-1 mice deficient of B lymphocytes. J Neurol. 2009;256:1228–35. [PubMed]
124. Gowing G, Philips T, Van WB, et al. Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci. 2008;28:10234–44. [PubMed]
125. Schwartz M, Moalem G, Leibowitz-Amit R, Cohen IR. Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci. 1999;22:295–9. [PubMed]
126. Banerjee R, Mosley RL, Reynolds AD, et al. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS ONE. 2008;3:e2740. [PMC free article] [PubMed]
127. Takeuchi S, Fujiwara N, Ido A, et al. Induction of protective immunity by vaccination with wild-type apo superoxide dismutase 1 in mutant SOD1 transgenic mice. J Neuropathol Exp Neurol. 2010;69:1044–56. [PubMed]
128. Chiu IM, Chen A, Zheng Y, et al. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci USA. 2008;105:17913–8. [PubMed]
129. Beers DR, Henkel JS, Zhao W, Wang J, Appel SH. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci U S A. 2008;105:15558–63. [PubMed]
130. Mosley RL, Gendelman HE. Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders. Exp Neurol. 2010;222:1–5. [PMC free article] [PubMed]
131. Kosloski LM, Ha DM, Hutter JA, et al. Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases. J Neurochem. 2010;114:1261–76. [PMC free article] [PubMed]
132. Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007;6:1045–53. [PubMed]
133. Appel SH, Engelhardt JI, Henkel JS, et al. Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis. Neurology. 2008;71:1326–34. [PubMed]
134. Meucci N, Nobile-Orazio E, Scarlato G. Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis. J Neurol. 1996;243:117–20. [PubMed]
135. Smith SA, Miller RG, Murphy JR, Ringel SP. Treatment of ALS with high dose pulse cyclophosphamide. J Neurol Sci. 1994;124(Suppl):84–7. [PubMed]
136. Werdelin L, Boysen G, Jensen TS, Mogensen P. Immunosuppressive treatment of patients with amyotrophic lateral sclerosis. Acta Neurol Scand. 1990;82:132–4. [PubMed]
137. Chio A, Mora G, Bella VL, et al. Repeated courses of granulocyte colony-stimulating factor in amyotrophic lateral sclerosis: Clinical and biological results from a prospective multicenter study. Muscle Nerve. 2011;43:189–95. [PubMed]
138. Al-Chalabi A, Fang F, Hanby MF, Leigh PN, Shaw CE, Ye W, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry. 2010;81:1324–6. [PMC free article] [PubMed]
139. Wang JH, Pappas D, De Jager PL, et al. Modeling the Cumulative Genetic Risk for Multiple Sclerosis from Genome Wide Association Data. Genome Med. 2011;3:3. [PMC free article] [PubMed]
140. Galimberti D, Scarpini E. Inflammation and oxidative damage in Alzheimer's disease: friend or foe? Front Biosci (Schol Ed) 2011;3:252–66. [PubMed]
141. Barnum CJ, Tansey MG. Modeling neuroinflammatory pathogenesis of Parkinson's disease. Prog Brain Res. 2010;184:113–32. [PubMed]
142. McCombe PA, Read SJ. Immune and inflammatory responses to stroke: good or bad? Int J Stroke. 2008;3:254–65. [PubMed]

Articles from Bentham Open Access are provided here courtesy of Bentham Science Publishers