Skip to main content

Advertisement

SpringerLink
Log in

Immune-mediated Mechanisms in the Pathoprogression of Amyotrophic Lateral Sclerosis

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with selective loss of upper and lower motor neurons. At sites of motor neuron injury, neuroinflammation is a prominent pathological finding and is characterized by microglial activation, astrogliosis, and infiltration of monocytes and T-cells. Both innate and adaptive immune responses actively influence disease progression in animal models and in ALS patients, and promote neuroprotection or neurotoxicity at different stages of disease. The early immune reaction to signals from injured motor neurons is to rescue and repair damaged tissue. As disease accelerates, a shift occurs from beneficial immune responses (involving M2 microglia and regulatory T-cells) to deleterious immune responses (involving M1 microglia and Th1 cells). In this review, we underscore the importance of immune-mediated mechanisms in the pathogenesis of ALS and discuss the alterations and distinct phenotypes of immune cells at the different stages of disease. The better we understand the dynamic changes that occur within the immune system over the course of disease, the better we will be able to develop effective therapeutic regimens in ALS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57:1282–1289

    Article  PubMed  CAS  Google Scholar 

  • Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31:7–17

    Article  PubMed  CAS  Google Scholar 

  • Baloh RH (2011) TDP-43: the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. FEBS J 278:3539–3549

    Article  PubMed  CAS  Google Scholar 

  • Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE (2008) Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One 3:e2740

    Article  PubMed  Google Scholar 

  • Barrette B, Hébert MA, Filali M, Lafortune K, Vallières N, Gowing G, Julien JP, Lacroix S (2008) Requirement of myeloid cells for axon regeneration. J Neurosci 28:9363–9376

    Article  PubMed  CAS  Google Scholar 

  • Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklós L, McKercher SR, Appel SH (2006) Wild-type microglia extends survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 103:16021–16026

    Article  PubMed  CAS  Google Scholar 

  • Beers DR, Henkel JS, Zhao W, Wang J, Appel SH (2008) 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 105:15558–15563

    Article  PubMed  CAS  Google Scholar 

  • Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH (2011a) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134:1293–1314

    Article  PubMed  Google Scholar 

  • Beers DR, Zhao W, Liao B, Kano O, Wang J, Huang A, Appel SH, Henkel JS (2011b) Neuroinflammation modulates distinct regional and temporal clinical responses in ALS mice. Brain Behav Immun 25:1025–1035

    Article  PubMed  CAS  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  PubMed  CAS  Google Scholar 

  • Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392

    Article  PubMed  Google Scholar 

  • Bosco DA, Morfini G, Karabacak NM, Song Y, Gros-Louis F, Pasinelli P, Goolsby H, Fontaine BA, Lemay N, McKenna-Yasek D, Frosch MP, Agar JN, Julien JP, Brady ST, Brown RH Jr (2010) Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci 13:1396–1403

    Article  PubMed  CAS  Google Scholar 

  • Buechler C, Ritter M, Orsó E, Langmann T, Klucken J, Schmitz G (2000) Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 67:97–103

    PubMed  CAS  Google Scholar 

  • Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, Doykan CE, Wu PM, Gali RR, Iyer LK, Lawson R, Berry J, Krichevsky AM, Cudkowicz ME, Weiner HL (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122:3063–3087

    Article  PubMed  CAS  Google Scholar 

  • Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TH, Brown RH Jr, Carroll MC (2008) T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci USA 105:17913–17918

    Article  PubMed  CAS  Google Scholar 

  • Chiu IM, Phatnani H, Kuligowski M, Tapia JC, Carrasco MA, Zhang M, Maniatis T, Carroll MC (2009) Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A 106:20960–20965

    Article  PubMed  CAS  Google Scholar 

  • Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH, Julien J-P, Goldstein LSB, Cleveland DW (2003) Wild-type noneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117

    Article  PubMed  CAS  Google Scholar 

  • Corcia P, Tauber C, Vercoullie J et al (2012) Molecular imaging of microglial activation in amyotrophic lateral sclerosis. PLoS One 7:e52941

    Article  PubMed  CAS  Google Scholar 

  • Da Cruz S, Cleveland DW (2011) Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol 21:904–919

    Article  PubMed  Google Scholar 

  • DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256

    Article  PubMed  CAS  Google Scholar 

  • Dodge JC, Haidet AM, Yang W, Passini MA, Hester M, Clarke J, Roskelley EM, Treleaven CM, Rizo L, Martin H, Kim SH, Kaspar R, Taksir TV, Griffiths DA, Cheng SH, Shihabuddin LS, Kaspar BK (2008) Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Mol Ther 16:1056–1064

    Article  PubMed  CAS  Google Scholar 

  • Dringen R, Pfeiffer B, Hamprecht B (1999) Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci 19:562–569

    PubMed  CAS  Google Scholar 

  • Ezzi SA, Urushitani M, Julien JP (2007) Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. J Neurochem 102:170–178

    Article  PubMed  Google Scholar 

  • Finkelstein A, Kunis G, Seksenyan A, Ronen A, Berkutzki T, Azoulay D, Koronyo-Hamaoui M, Schwartz M (2011) Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS. PLoS One 6:e22374

    Article  PubMed  CAS  Google Scholar 

  • Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240

    Article  PubMed  Google Scholar 

  • Gao Z,Tsirka SE (2011) Animal models of MS reveal multiple roles of microglia in disease pathogenesis. Neurol Res Int. doi:10.1155/2011/383087

  • Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604

    Article  PubMed  CAS  Google Scholar 

  • Guareschi S, Cova E, Cereda C, Ceroni M, Donetti E, Bosco DA, Trotti D, Pasinelli P (2012) An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1. Proc Natl Acad Sci U S A 109:5074–5079

    Article  PubMed  CAS  Google Scholar 

  • Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammesheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828

    Article  PubMed  CAS  Google Scholar 

  • Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH (2004) Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 55:221–235

    Article  PubMed  CAS  Google Scholar 

  • Henkel JH, Beers DR, Siklós L, Appel SH (2006) The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS. Mol Cell Neurosci 31:427–437

    Article  PubMed  CAS  Google Scholar 

  • Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, Zhao W, Moore DH, Powell SZ, Appel SH (2013) Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med 5:64–79

    Article  PubMed  CAS  Google Scholar 

  • Holmøy T (2008) T cells in amyotrophic lateral sclerosis. Eur J Neurol 15:360–366

    Article  PubMed  Google Scholar 

  • Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, Strong MJ, Shaw PJ (2011) Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol 122:657–671

    Article  PubMed  CAS  Google Scholar 

  • Jaarsma D, Teuling E, Haasdijk ED, De Zeeuw CI, Hoogenraad CC (2008) Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J Neurosci 28:2075–2088

    Article  PubMed  CAS  Google Scholar 

  • Kang J, Rivest S (2007) MyD88-deficient bone marrow cells accelerate onset and reduce survival in a mouse model of amyotrophic lateral sclerosis. J Cell Biol 179:1219–1230

    Article  PubMed  CAS  Google Scholar 

  • Kano O, Beers DR, Henkel JS, Appel SH (2012) Peripheral nerve inflammation in ALS mice: cause or consequence. Neurology 78:833–835

    Article  PubMed  Google Scholar 

  • Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH (2003) Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Sciencen 301:839–842

    Article  CAS  Google Scholar 

  • Lepore AC, Haenggeli C, Gasmi M, Bishop KM, Bartus RT, Maragakis NJ, Rothstein JD (2007) Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS. Brain Res 1185:256–265

    Article  PubMed  CAS  Google Scholar 

  • Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, Maragakis NJ (2008) Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci 11:1294–1301

    Article  PubMed  CAS  Google Scholar 

  • Li L, Kim J, Boussiotis VA (2010) IL-1β-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells. J Immunol 185:4148–4153

    Article  PubMed  CAS  Google Scholar 

  • Liao B, Zhao W, Beers DR, Henkel JS, Appel SH (2012) Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 237:147–152

    Article  PubMed  CAS  Google Scholar 

  • Lino MM, Schneider C, Caroni P (2002) Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J Neurosci 22:4825–4832

    PubMed  CAS  Google Scholar 

  • Liu W, Tang Y, Feng J (2011) Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 89:141–146

    Article  PubMed  CAS  Google Scholar 

  • Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:649–657

    Article  PubMed  CAS  Google Scholar 

  • Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, Min SW, Gan L, Finkbeiner S, Huang EJ, Farese RV Jr (2012) Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest 122:3955–3959

    Article  PubMed  CAS  Google Scholar 

  • Meissner F, Molawi K, Zychlinsky A (2010) Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci U S A 107:13046–13050

    Article  PubMed  CAS  Google Scholar 

  • Nagano I, Ilieva H, Shiote M, Murakami T, Yokoyama M, Shoji M, Abe K (2005a) Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of Amyotrophic Lateral Sclerosis. J Neurol Sci 235:61–68

    Article  PubMed  CAS  Google Scholar 

  • Nagano I, Shiote M, Murakami T, Kamada H, Hamakawa Y, Matsubara E, Yokoyama M, Moritaz K, Shoji M, Abe K (2005b) Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis. Neurol Res 27:768–772

    Article  PubMed  CAS  Google Scholar 

  • Naor S, Keren Z, Bronshtein T, Goren E, Machluf M, Melamed D (2009) Development of ALS-like disease in SOD-1 mice deficient of B lymphocytes. J Neurol 256:1228–1235

    Article  PubMed  CAS  Google Scholar 

  • Neumann H (2001) Control of glial immune function by neurons. Glia 36:191–199

    Article  PubMed  CAS  Google Scholar 

  • Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, Liu X, Xiao L, Chen X, Wan B, Chin YE, Zhang JZ (2013) Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med 19:322–328

    Article  PubMed  CAS  Google Scholar 

  • Niebroj-Dobosz I, Dziewulska D, Janik P (2006) Auto-antibodies against proteins of spinal cord cells in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Folia Neuropathol 44:191–196

    PubMed  CAS  Google Scholar 

  • Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 10:253–263

    Article  PubMed  CAS  Google Scholar 

  • Philips T, De Muynck L, Thu HN, Weynants B, Vanacker P, Dhondt J, Sleegers K, Schelhaas HJ, Verbeek M, Vandenberghe R, Sciot R, Van Broeckhoven C, Lambrechts D, Van Leuven F, Van Den Bosch L, Robberecht W, Van Damme P (2010) Microglial upregulation of progranulin as a marker of motor neuron degeneration. J Neuropathol Exp Neurol 69:1191–1200

    Article  PubMed  CAS  Google Scholar 

  • Pramatarova A, Laganiere J, Roussel J, Brisebois K, Rouleau GA (2001) Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 21:3369–3374

    PubMed  CAS  Google Scholar 

  • Renton AE, Majounie E, Waite A et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268

    Article  PubMed  CAS  Google Scholar 

  • Rentzos M, Evangelopoulos E, Sereti E, Zouvelou V, Marmara S, Alexakis T, Evdokimidis I (2012) Alterations of T cell subsets in ALS: a systemic immune activation? Acta Neurol Scand 125:260–264

    Article  PubMed  CAS  Google Scholar 

  • Roberts K, Zeineddine R, Corcoran L, Li W, Campbell IL, Yerbury JJ (2013) Extracellular aggregated Cu/Zn superoxide dismutase activates microglia to give a cytotoxic phenotype. Glia 61:409–419

    Article  PubMed  Google Scholar 

  • Savage ND, de Boer T, Walburg KV, Joosten SA, van Meijgaarden K, Geluk A, Ottenhoff TH (2008) Human anti-inflammatory macrophages induce Foxp3+ GITR + CD25+ regulatory T cells, which suppress via membrane-bound TGFbeta-1. J Immunol 181:2220–2226

    PubMed  CAS  Google Scholar 

  • Schaefer AM, Sanes JR, Lichtman JW (2005) A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis. J Comp Neurol 490:209–219

    Article  PubMed  Google Scholar 

  • Tiemessen CT, Kuhn L (2007) CC chemokines and protective immunity: insights gained from mother-to-child transmission of HIV. Nat Immunol 8:219–222

    Article  PubMed  CAS  Google Scholar 

  • Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 5:601–609

    Article  Google Scholar 

  • Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R, Julien JP (2006) Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9:108–118

    Article  PubMed  CAS  Google Scholar 

  • Van Blitterswijk M, DeJesus-Hernandez M, Rademakers R (2012) How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders? Curr Opin Neurol 25:689–700

    Article  PubMed  Google Scholar 

  • Wang L, Sharma K, Grisotti G, Roos RP (2009) The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol Dis 35:234–240

    Article  PubMed  CAS  Google Scholar 

  • Weydt P, Yuen EC, Ransom BR, Moller T (2004) Increased cytotoxic potential of microglia from ALS-transgenic mice. Glia 48:179–182

    Article  PubMed  Google Scholar 

  • Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV (2013) Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol 125:111–120

    Article  PubMed  CAS  Google Scholar 

  • Xiao Q, Zhao W, Beers DR, Yen AA, Xie W, Henkel JS, Appel SH (2007) Mutant SOD1G93A microglia are more neurotoxic relative to wild-type microglia. J Neurochem 102:2008–2019

    Article  PubMed  CAS  Google Scholar 

  • Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251–253

    Article  PubMed  CAS  Google Scholar 

  • Zhao W, Xie W, Le W, Beers DR, He Y, Henkel JS, Simpson EP, Yen AA, Xiao Q, Appel SH (2004) Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism. J Neuropathol Exp Neurol 63:964–977

    PubMed  CAS  Google Scholar 

  • Zhao W, Xie W, Xiao Q, Beers DR, Appel SH (2006) Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. J Neurochem 99:1176–1187

    Article  PubMed  CAS  Google Scholar 

  • Zhao W, Beers DR, Henkel JS, Zhang W, Urushitani M, Julien JP, Appel SH (2010) Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia 58:231–243

    Article  PubMed  Google Scholar 

  • Zhao W, Beers DR, Liao B, Henkel JS, Appel SH (2012) Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol Dis 48:418–428

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by grants from the Muscular Dystrophy Association and the NIH (NS079943).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurology, Methodist Neurological Institute, Methodist Research Institute, The Methodist Hospital, Houston, TX, USA

    Weihua Zhao, David R. Beers & Stanley H. Appel

  2. Department of Neurology, Methodist Neurological Institute, 6560 Fannin Street, Suite 802, Houston, TX, 77030, USA

    Stanley H. Appel

Authors
  1. Weihua Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David R. Beers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stanley H. Appel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stanley H. Appel.

Additional information

This chapter is dedicated to the memory of the late Dr. Jenny S. Henkel and to the legacy of brilliant writings and people she touched. She is greatly missed.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, W., Beers, D.R. & Appel, S.H. Immune-mediated Mechanisms in the Pathoprogression of Amyotrophic Lateral Sclerosis. J Neuroimmune Pharmacol 8, 888–899 (2013). https://doi.org/10.1007/s11481-013-9489-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-013-9489-x

Keywords

Search

Navigation