Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2018

Open Access 01-12-2018 | Research article

Counteracting roles of MHCI and CD8+ T cells in the peripheral and central nervous system of ALS SOD1G93A mice

Authors: Giovanni Nardo, Maria Chiara Trolese, Mattia Verderio, Alessandro Mariani, Massimiliano de Paola, Nilo Riva, Giorgia Dina, Nicolò Panini, Eugenio Erba, Angelo Quattrini, Caterina Bendotti

Published in: Molecular Neurodegeneration | Issue 1/2018

Login to get access

Abstract

Background

The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8+T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1G93A mice.

Methods

To assess the role of MHCI in the disease, we examined transgenic SOD1G93A mice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8+ T cells.

Results

The lack of MHCI and CD8+ T cells in the sciatic nerve affects the motor axon stability, anticipating the muscle atrophy and the disease onset. In contrast, MHCI depletion in resident microglia and the lack of CD8+ T cell infiltration in the spinal cord protect the cervical motor neurons delaying the paralysis of forelimbs and prolonging the survival of SOD1G93A mice.

Conclusions

We provided straightforward evidence for a dual role of MHCI in the peripheral nervous system (PNS) compared to the CNS, pointing out regional and temporal differences in the clinical responses of ALS mice. These findings offer a possible explanation for the failure of systemic immunomodulatory treatments and suggest new potential strategies to prevent the progression of ALS.
Appendix
Available only for authorised users
Literature
1.
Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17085.CrossRefPubMed
2.
Zarei S, Carr K, Reiley L, Diaz K, Guerra O, Altamirano PF, Pagani W, Lodin D, Orozco G, Chinea A. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int. 2015;6:171.CrossRefPubMedPubMedCentral
3.
Chia R, Chio A, Traynor BJ. Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol. 2018;17:94–102.CrossRefPubMed
4.
Nardo G, Trolese MC, Tortarolo M, Vallarola A, Freschi M, Pasetto L, Bonetto V, Bendotti C. New insights on the mechanisms of disease course variability in ALS from mutant SOD1 mouse models. Brain Pathol. 2016;26:237–47.CrossRefPubMed
5.
Nardo G, Trolese MC, Bendotti C. Major histocompatibility complex I expression by motor neurons and its implication in amyotrophic lateral sclerosis. Front Neurol. 2016;7:89.CrossRefPubMedPubMedCentral
6.
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.CrossRefPubMed
7.
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.CrossRefPubMedPubMedCentral
8.
Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH Jr, Carroll MC. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A. 2008;105:17913–8.CrossRefPubMedPubMedCentral
9.
Zhao W, Beers DR, Appel SH. Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J NeuroImmune Pharmacol. 2013;8:888–99.CrossRefPubMedPubMedCentral
10.
11.
Nardo G, Trolese MC, de Vito G, Cecchi R, Riva N, Dina G, Heath PR, Quattrini A, Shaw PJ, Piazza V, Bendotti C. Immune response in peripheral axons delays disease progression in SOD1(G93A) mice. J Neuroinflammation. 2016;13:261.CrossRefPubMedPubMedCentral
12.
Chiu IM, Phatnani H, Kuligowski M, Tapia JC, Carrasco MA, Zhang M, Maniatis T, Carroll MC. Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A. 2009;106:20960–5.CrossRefPubMedPubMedCentral
13.
Khalid SI, Ampie L, Kelly R, Ladha SS, Dardis C. Immune modulation in the treatment of amyotrophic lateral sclerosis: a review of clinical trials. Front Neurol. 2017;8:486.CrossRefPubMedPubMedCentral
14.
15.
NBeers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011;134:1293–314.CrossRef
16.
Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O’Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013;4:385–401.CrossRefPubMedPubMedCentral
17.
Sta M, Sylva-Steenland RM, Casula M, de Jong JM, Troost D, Aronica E, Baas F. Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis. 2011;42:211–20.CrossRefPubMed
18.
Peter ME, Budd RC, Desbarats J, Hedrick SM, Hueber AO, Newell MK, Owen LB, Pope RM, Tschopp J, Wajant H, et al. The CD95 receptor: apoptosis revisited. Cell. 2007;129:447–50.CrossRefPubMed
19.
Raoul C, Buhler E, Sadeghi C, Jacquier A, Aebischer P, Pettmann B, Henderson CE, Haase G. Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL. Proc Natl Acad Sci U S A. 2006;103:6007–12.CrossRefPubMedPubMedCentral
20.
Raoul C, Estevez AG, Nishimune H, Cleveland DW, deLapeyriere O, Henderson CE, Haase G, Pettmann B. Motoneuron death triggered by a specific pathway downstream of Fas. Potentiation by ALS-linked SOD1 mutations. Neuron. 2002;35:1067–83.CrossRefPubMed
21.
Petri S, Kiaei M, Wille E, Calingasan NY, Flint Beal M. Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice. J Neurol Sci. 2006;251:44–9.CrossRefPubMed
22.
Nardo G, Iennaco R, Fusi N, Heath PR, Marino M, Trolese MC, Ferraiuolo L, Lawrence N, Shaw PJ, Bendotti C. Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis. Brain. 2013;136:3305–32.CrossRefPubMed
23.
Bendotti C, Marino M, Cheroni C, Fontana E, Crippa V, Poletti A, De Biasi S. Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Prog Neurobiol. 2012;97:101–26.CrossRefPubMed
24.
Cheroni C, Marino M, Tortarolo M, Veglianese P, De Biasi S, Fontana E, Zuccarello LV, Maynard CJ, Dantuma NP, Bendotti C. Functional alterations of the ubiquitin-proteasome system in motor neurons of a mouse model of familial amyotrophic lateral sclerosis. Hum Mol Genet. 2009;18:82–96.CrossRefPubMed
25.
Cheroni C, Peviani M, Cascio P, Debiasi S, Monti C, Bendotti C. Accumulation of human SOD1 and ubiquitinated deposits in the spinal cord of SOD1G93A mice during motor neuron disease progression correlates with a decrease of proteasome. Neurobiol Dis. 2005;18:509–22.CrossRefPubMed
26.
Chiarotto GB, Nardo G, Trolese MC, França MC Jr, Bendotti C, Rodrigues de Oliveira AL. The Emerging Role of the Major Histocompatibility Complex Class I in Amyotrophic Lateral Sclerosis. Int J Mol Sci. 2017;18(11).
27.
Song S, Miranda CJ, Braun L, Meyer K, Frakes AE, Ferraiuolo L, Likhite S, Bevan AK, Foust KD, McConnell MJ, et al. Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis. Nat Med. 2016;22:397–403.CrossRefPubMedPubMedCentral
28.
Marino M, Papa S, Crippa V, Nardo G, Peviani M, Cheroni C, Trolese MC, Lauranzano E, Bonetto V, Poletti A, et al. Differences in protein quality control correlate with phenotype variability in 2 mouse models of familial amyotrophic lateral sclerosis. Neurobiol Aging. 2015;36:492–504.CrossRefPubMed
29.
Geuna S, Tos P, Guglielmone R, Battiston B, Giacobini-Robecchi MG. Methodological issues in size estimation of myelinated nerve fibers in peripheral nerves. Anat Embryol (Berl). 2001;204:1–10.CrossRef
30.
De Paola M, Mariani A, Bigini P, Peviani M, Ferrara G, Molteni M, Gemma S, Veglianese P, Castellaneta V, Boldrin V, et al. Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration. Mol Med. 2012;18:971–81.PubMedPubMedCentral
31.
Koller BH, Marrack P, Kappler JW, Smithies O. Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science. 1990;248:1227–30.CrossRefPubMed
32.
Zijlstra M, Bix M, Simister NE, Loring JM, Raulet DH, Jaenisch R. Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature. 1990;344:742–6.CrossRefPubMed
33.
Clark JA, Southam KA, Blizzard CA, King AE, Dickson TC. Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. J Chem Neuroanat. 2016;76:35–47.CrossRefPubMed
34.
Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997;18:327–38.CrossRefPubMed
35.
Friese A, Kaltschmidt JA, Ladle DR, Sigrist M, Jessell TM, Arber S. Gamma and alpha motor neurons distinguished by expression of transcription factor Err3. Proc Natl Acad Sci U S A. 2009;106:13588–93.CrossRefPubMedPubMedCentral
36.
Gerber YN, Sabourin JC, Rabano M, Vivanco M, Perrin FE. Early functional deficit and microglial disturbances in a mouse model of amyotrophic lateral sclerosis. PLoS One. 2012;7:e36000.CrossRefPubMedPubMedCentral
37.
Weydt P, Yuen EC, Ransom BR, Moller T. Increased cytotoxic potential of microglia from ALS-transgenic mice. Glia. 2004;48:179–82.CrossRefPubMed
38.
Jarry U, Jeannin P, Pineau L, Donnou S, Delneste Y, Couez D. Efficiently stimulated adult microglia cross-prime naive CD8+ T cells injected in the brain. Eur J Immunol. 2013;43:1173–84.CrossRefPubMed
39.
Beauvillain C, Donnou S, Jarry U, Scotet M, Gascan H, Delneste Y, Guermonprez P, Jeannin P, Couez D. Neonatal and adult microglia cross-present exogenous antigens. Glia. 2008;56:69–77.CrossRefPubMed
40.
MacAry PA, Lindsay M, Scott MA, Craig JI, Luzio JP, Lehner PJ. Mobilization of MHC class I molecules from late endosomes to the cell surface following activation of CD34-derived human Langerhans cells. Proc Natl Acad Sci U S A. 2001;98:3982–7.CrossRefPubMedPubMedCentral
41.
Rangaraju S, Raza SA, Pennati A, Deng Q, Dammer EB, Duong D, Pennington MW, Tansey MG, Lah JJ, Betarbet R, et al. A systems pharmacology-based approach to identify novel Kv1.3 channel-dependent mechanisms in microglial activation. J Neuroinflammation. 2017;14:128.CrossRefPubMedPubMedCentral
42.
Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004;185:232–40.CrossRefPubMed
43.
Dobrowolny G, Aucello M, Musaro A. Muscle atrophy induced by SOD1G93A expression does not involve the activation of caspase in the absence of denervation. Skelet Muscle. 2011;1:3.CrossRefPubMedPubMedCentral
44.
Tsuneki H, Salas R, Dani JA. Mouse muscle denervation increases expression of an alpha7 nicotinic receptor with unusual pharmacology. J Physiol. 2003;547:169–79.CrossRefPubMed
45.
Covault J, Sanes JR. Neural cell adhesion molecule (N-CAM) accumulates in denervated and paralyzed skeletal muscles. Proc Natl Acad Sci U S A. 1985;82:4544–8.CrossRefPubMedPubMedCentral
46.
Fujiwara S, Hoshikawa S, Ueno T, Hirata M, Saito T, Ikeda T, Kawaguchi H, Nakamura K, Tanaka S, Ogata T. SOX10 transactivates S100B to suppress Schwann cell proliferation and to promote myelination. PLoS One. 2014;9:e115400.CrossRefPubMedPubMedCentral
47.
Song Y, Panzer JA, Wyatt RM, Balice-Gordon RJ. Formation and plasticity of neuromuscular synaptic connections. Int Anesthesiol Clin. 2006;44:145–78.CrossRefPubMed
48.
Thams S, Brodin P, Plantman S, Saxelin R, Karre K, Cullheim S. Classical major histocompatibility complex class I molecules in motoneurons: new actors at the neuromuscular junction. J Neurosci. 2009;29:13503–15.CrossRefPubMed
49.
Fuller HR, Mandefro B, Shirran SL, Gross AR, Kaus AS, Botting CH, Morris GE, Sareen D. Spinal muscular atrophy patient iPSC-derived motor neurons have reduced expression of proteins important in neuronal development. Front Cell Neurosci. 2015;9:506.PubMed
50.
Lee S, Shea TB. The high molecular weight neurofilament subunit plays an essential role in axonal outgrowth and stabilization. Biol Open. 2014;3:974–81.CrossRefPubMedPubMedCentral
51.
Perry RB, Doron-Mandel E, Iavnilovitch E, Rishal I, Dagan SY, Tsoory M, Coppola G, McDonald MK, Gomes C, Geschwind DH, et al. Subcellular knockout of importin beta1 perturbs axonal retrograde signaling. Neuron. 2012;75:294–305.CrossRefPubMedPubMedCentral
52.
Rossi F, Gianola S, Corvetti L. Regulation of intrinsic neuronal properties for axon growth and regeneration. Prog Neurobiol. 2007;81:1–28.CrossRefPubMed
53.
54.
Gaudet AD, Popovich PG, Ramer MS. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation. 2011;8:110.CrossRefPubMedPubMedCentral
55.
Berg A, Zelano J, Pekna M, Wilhelmsson U, Pekny M, Cullheim S. Axonal regeneration after sciatic nerve lesion is delayed but complete in GFAP- and vimentin-deficient mice. PLoS One. 2013;8:e79395.CrossRefPubMedPubMedCentral
56.
Tsuda Y, Kanje M, Dahlin LB. Axonal outgrowth is associated with increased ERK 1/2 activation but decreased caspase 3 linked cell death in Schwann cells after immediate nerve repair in rats. BMC Neurosci. 2011;12:12.CrossRefPubMedPubMedCentral
57.
Keller AF, Gravel M, Kriz J. Live imaging of amyotrophic lateral sclerosis pathogenesis: disease onset is characterized by marked induction of GFAP in Schwann cells. Glia. 2009;57:1130–42.CrossRefPubMed
58.
59.
Triolo D, Dina G, Lorenzetti I, Malaguti M, Morana P, Del Carro U, Comi G, Messing A, Quattrini A, Previtali SC. Loss of glial fibrillary acidic protein (GFAP) impairs Schwann cell proliferation and delays nerve regeneration after damage. J Cell Sci. 2006;119:3981–93.CrossRefPubMed
60.
Perlson E, Hanz S, Ben-Yaakov K, Segal-Ruder Y, Seger R, Fainzilber M. Vimentin-dependent spatial translocation of an activated MAP kinase in injured nerve. Neuron. 2005;45:715–26.CrossRefPubMed
61.
Cebrian C, Loike JD, Sulzer D. Neuronal MHC-I expression and its implications in synaptic function, axonal regeneration and Parkinson’s and other brain diseases. Front Neuroanat. 2014;8:114.CrossRefPubMedPubMedCentral
62.
Staats KA, Schonefeldt S, Van Rillaer M, Van Hoecke A, Van Damme P, Robberecht W, Liston A, Van Den Bosch L. Beta-2 microglobulin is important for disease progression in a murine model for amyotrophic lateral sclerosis. Front Cell Neurosci. 2013;7:249.CrossRefPubMedPubMedCentral
63.
Ludolph AC, Bendotti C, Blaugrund E, Chio A, Greensmith L, Loeffler JP, Mead R, Niessen HG, Petri S, Pradat PF, et al. Guidelines for preclinical animal research in ALS/MND: a consensus meeting. Amyotroph Lateral Scler. 2010;11:38–45.CrossRefPubMed
64.
McGoldrick P, Joyce PI, Fisher EM, Greensmith L. Rodent models of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2013;1832:1421–36.CrossRefPubMed
65.
Gillen C, Gleichmann M, Spreyer P, Muller HW. Differentially expressed genes after peripheral nerve injury. J Neurosci Res. 1995;42:159–71.CrossRefPubMed
66.
Thomson CE, Griffiths IR, McCulloch MC, Kyriakides E, Barrie JA, Montague P. In vitro studies of axonally-regulated Schwann cell genes during Wallerian degeneration. J Neurocytol. 1993;22:590–602.CrossRefPubMed
67.
Neuberger TJ, Cornbrooks CJ. Transient modulation of Schwann cell antigens after peripheral nerve transection and subsequent regeneration. J Neurocytol. 1989;18:695–710.CrossRefPubMed
68.
Franklin RJ, Kotter MR. The biology of CNS remyelination: the key to therapeutic advances. J Neurol. 2008;255(Suppl 1):19–25.CrossRefPubMed
69.
Bieber AJ, Kerr S, Rodriguez M. Efficient central nervous system remyelination requires T cells. Ann Neurol. 2003;53:680–4.CrossRefPubMed
70.
Begolka WS, Haynes LM, Olson JK, Padilla J, Neville KL, Dal Canto M, Palma J, Kim BS, Miller SD. CD8-deficient SJL mice display enhanced susceptibility to Theiler’s virus infection and increased demyelinating pathology. J Neuro-Oncol. 2001;7:409–20.
71.
Bombeiro AL, Santini JC, Thome R, Ferreira ER, Nunes SL, Moreira BM, Bonet IJ, Sartori CR, Verinaud L, Oliveira AL. Enhanced immune response in immunodeficient mice improves peripheral nerve regeneration following axotomy. Front Cell Neurosci. 2016;10:151.CrossRefPubMedPubMedCentral
72.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. Motor neuron degeneration in mice that express a human cu,Zn superoxide dismutase mutation. Science. 1994;264:1772–5.CrossRefPubMed
73.
Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995;14:1105–16.CrossRefPubMed
74.
Beers DR, Zhao W, Liao B, Kano O, Wang J, Huang A, Appel SH, Henkel JS. Neuroinflammation modulates distinct regional and temporal clinical responses in ALS mice. Brain Behav Immun. 2011;25:1025–35.CrossRefPubMed
75.
Capitanio D, Vasso M, Ratti A, Grignaschi G, Volta M, Moriggi M, Daleno C, Bendotti C, Silani V, Gelfi C. Molecular signatures of amyotrophic lateral sclerosis disease progression in hind and forelimb muscles of an SOD1(G93A) mouse model. Antioxid Redox Signal. 2012;17:1333–50.CrossRefPubMedPubMedCentral
76.
Rosser BW, Norris BJ, Nemeth PM. Metabolic capacity of individual muscle fibers from different anatomic locations. J Histochem Cytochem. 1992;40:819–25.CrossRefPubMed
77.
Komine O, Yamashita H, Fujimori-Tonou N, Koike M, Jin S, Moriwaki Y, Endo F, Watanabe S, Uematsu S, Akira S, et al. Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes. Cell Death Differ. 2018; [Epub ahead of print]
Metadata
Title
Counteracting roles of MHCI and CD8+ T cells in the peripheral and central nervous system of ALS SOD1G93A mice
Authors
Giovanni Nardo
Maria Chiara Trolese
Mattia Verderio
Alessandro Mariani
Massimiliano de Paola
Nilo Riva
Giorgia Dina
Nicolò Panini
Eugenio Erba
Angelo Quattrini
Caterina Bendotti
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2018
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-018-0271-7

Other articles of this Issue 1/2018

Molecular Neurodegeneration 1/2018 Go to the issue

Research article

Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease

Research article

Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins

Research article

Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain

Research article

Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse

Research article

Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration

Research article

Tolerogenic bone marrow-derived dendritic cells induce neuroprotective regulatory T cells in a model of Parkinson’s disease