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
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

Innate Immunity in multiple sclerosis white matter lesions: expression of natural cytotoxicity triggering receptor 1 (NCR1)

Authors: Pascal F Durrenberger, Anna Ettorre, Fatemah Kamel, Louise V Webb, Malcolm Sim, Richard S Nicholas, Omar Malik, Richard Reynolds, Rosemary J Boyton, Daniel M Altmann

Published in: Journal of Neuroinflammation | Issue 1/2012

Login to get access

Abstract

Background

Pathogenic or regulatory effects of natural killer (NK) cells are implicated in many autoimmune diseases, but evidence in multiple sclerosis (MS) and its murine models remains equivocal. In an effort to illuminate this, we have here analysed expression of the prototypic NK cell marker, NCR1 (natural cytotoxicity triggering receptor; NKp46; CD335), an activating receptor expressed by virtually all NK cells and therefore considered a pan-marker for NK cells. The only definitive ligand of NCR1 is influenza haemagglutinin, though there are believed to be others. In this study, we investigated whether there were differences in NCR1+ cells in the peripheral blood of MS patients and whether NCR1+ cells are present in white matter lesions.

Results

We first investigated the expression of NCR1 on peripheral blood mononuclear cells and found no significant difference between healthy controls and MS patients. We then investigated mRNA levels in central nervous system (CNS) tissue from MS patients: NCR1 transcripts were increased more than 5 times in active disease lesions. However when we performed immunohistochemical staining of this tissue, few NCR1+ NK cells were identified. Rather, the major part of NCR1 expression was localised to astrocytes, and was considerably more pronounced in MS patients than controls. In order to further validate de novo expression of NCR1 in astrocytes, we used an in vitro staining of the human astrocytoma U251 cell line grown to model whether cell stress could be associated with expression of NCR1. We found up-regulation of NCR1 expression in U251 cells at both the mRNA and protein levels.

Conclusions

The data presented here show very limited expression of NCR1+ NK cells in MS lesions, the majority of NCR1 expression being accounted for by expression on astrocytes. This is compatible with a role of this cell-type and NCR1 ligand/receptor interactions in the innate immune response in the CNS in MS patients. This is the first report of NCR1 expression on astrocytes in MS tissue: it will now be important to unravel the nature of cellular interactions and signalling mediated through innate receptor expression on astrocytes.
Appendix
Available only for authorised users
Literature
1.
Mandelboim O, Lieberman N, Lev M, Paul L, Arnon TI, Bushkin Y, Davis DM, Strominger JL, Yewdell JW, Porgador A: Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 2001, 409:1055–1060.CrossRefPubMed
2.
Walzer T, Blery M, Chaix J, Fuseri N, Chasson L, Robbins SH, Jaeger S, Andre P, Gauthier L, Daniel L, Chemin K, Morel Y, Dalod M, Imbert J, Pierres M, Moretta A, Romagné F, Vivier E: Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc Natl Acad Sci USA 2007, 104:3384–3389.CrossRefPubMedPubMedCentral
3.
Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L: Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001, 19:197–223.CrossRefPubMed
4.
Sivori S, Vitale M, Morelli L, Sanseverino L, Augugliaro R, Bottino C, Moretta L, Moretta A: p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J Exp Med 1997, 186:1129–1136.CrossRefPubMedPubMedCentral
5.
Pessino A, Sivori S, Bottino C, Malaspina A, Morelli L, Moretta L, Biassoni R, Moretta A: Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J Exp Med 1998, 188:953–960.CrossRefPubMedPubMedCentral
6.
Arnon TI, Lev M, Katz G, Chernobrov Y, Porgador A, Mandelboim O: Recognition of viral hemagglutinins by NKp44 but not by NKp30. Eur J Immunol 2001, 31:2680–2689.CrossRefPubMed
7.
Foster CE, Colonna M, Sun PD: Crystal structure of the human natural killer (NK) cell activating receptor NKp46 reveals structural relationship to other leukocyte receptor complex immunoreceptors. J Biol Chem 2003, 278:46081–46086.CrossRefPubMed
8.
Sivori S, Pende D, Bottino C, Marcenaro E, Pessino A, Biassoni R, Moretta L, Moretta A: NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. Eur J Immunol 1999, 29:1656–1666.CrossRefPubMed
9.
Almeida-Oliveira A, Smith-Carvalho M, Porto LC, Cardoso-Oliveira J, Ribeiro Ados S, Falcao RR, Abdelhay E, Bouzas LF, Thuler LC, Ornellas MH, Diamond HR: Age-related changes in natural killer cell receptors from childhood through old age. Hum Immunol 2011, 72:319–329.CrossRefPubMed
10.
Arnon TI, Achdout H, Lieberman N, Gazit R, Gonen-Gross T, Katz G, Bar-Ilan A, Bloushtain N, Lev M, Joseph A, Kedar E, Porgador A, Mandelboim O: The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46. Blood 2004, 103:664–672.CrossRefPubMed
11.
Achdout H, Manaster I, Mandelboim O: Influenza virus infection augments NK cell inhibition through reorganization of major histocompatibility complex class I proteins. J Virol 2008, 82:8030–8037.CrossRefPubMedPubMedCentral
12.
Takayama T, Kamada N, Chinen H, Okamoto S, Kitazume MT, Chang J, Matuzaki Y, Suzuki S, Sugita A, Koganei K, Hisamatsu T, Kanai T, Hibi T: Imbalance of NKp44(+)NKp46(-) and NKp44(-)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease. Gastroenterology 2010, 139:882–892.CrossRefPubMed
13.
Gur C, Porgador A, Elboim M, Gazit R, Mizrahi S, Stern-Ginossar N, Achdout H, Ghadially H, Dor Y, Nir T, Doviner V, Hershkovitz O, Mendelson M, Naparstek Y, Mandelboim O: The activating receptor NKp46 is essential for the development of type 1 diabetes. Nat Immunol 2010, 11:121–128.CrossRefPubMed
14.
Lunemann JD, Munz C: Do natural killer cells accelerate or prevent autoimmunity in multiple sclerosis? Brain 2008, 131:1681–1683.CrossRefPubMed
15.
Zhang B, Yamamura T, Kondo T, Fujiwara M, Tabira T: Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. J Exp Med 1997, 186:1677–1687.CrossRefPubMedPubMedCentral
16.
Winkler-Pickett R, Young HA, Cherry JM, Diehl J, Wine J, Back T, Bere WE, Mason AT, Ortaldo JR: In vivo regulation of experimental autoimmune encephalomyelitis by NK cells: alteration of primary adaptive responses. J Immunol 2008, 180:4495–4506.CrossRefPubMed
17.
Saikali P, Antel JP, Newcombe J, Chen Z, Freedman M, Blain M, Cayrol R, Prat A, Hall JA, Arbour N: NKG2D-mediated cytotoxicity toward oligodendrocytes suggests a mechanism for tissue injury in multiple sclerosis. J Neurosci 2007, 27:1220–1228.CrossRefPubMed
18.
Lunemann A, Lunemann JD, Roberts S, Messmer B, Barreira da Silva R, Raine CS, Munz C: Human NK cells kill resting but not activated microglia via NKG2D- and NKp46-mediated recognition. J Immunol 2008, 181:6170–6177.CrossRefPubMedPubMedCentral
19.
Hammarberg H, Lidman O, Lundberg C, Eltayeb SY, Gielen AW, Muhallab S, Svenningsson A, Linda H, van Der Meide PH, Cullheim S, Olsson T, Piehl F: Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J Neurosci 2000, 20:5283–5291.PubMed
20.
Saraste M, Irjala H, Airas L: Expansion of CD56 Bright natural killer cells in the peripheral blood of multiple sclerosis patients treated with interferon-beta. Neurol Sci 2007, 28:121–126.CrossRefPubMed
21.
Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, Waldmann TA, McFarland H, Henkart PA, Martin R: Regulatory CD56 bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci USA 2006, 103:5941–5946.CrossRefPubMedPubMedCentral
22.
Airas L, Saraste M, Rinta S, Elovaara I, Huang YH, Wiendl H, The Finnish Multiple Sclerosis and Pregnancy Study Group: Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells. Clin Exp Immunol 2008, 151:235–243.CrossRefPubMedPubMedCentral
23.
Takahashi K, Aranami T, Endoh M, Miyake S, Yamamura T: The regulatory role of natural killer cells in multiple sclerosis. Brain 2004, 127:1917–1927.CrossRefPubMed
24.
De Jager PL, Rossin E, Pyne S, Tamayo P, Ottoboni L, Viglietta V, Weiner M, Soler D, Izmailova E, Faron-Yowe L, O'Brien C, Freeman S, Granados S, Parker A, Roubenoff R, Mesirov JP, Khoury SJ, Hafler DA, Weiner HL: Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8 low cells. Brain 2008, 131:1701–1711.CrossRefPubMedPubMedCentral
25.
Cooper MA, Fehniger TA, Caligiuri MA: The biology of human natural killer-cell subsets. Trends Immunol 2001, 22:633–640.CrossRefPubMed
26.
Lunemann A, Tackenberg B, DeAngelis T, da Silva RB, Messmer B, Vanoaica LD, Miller A, Apatoff B, Lublin FD, Lunemann JD, Munz C: Impaired IFN-γ production and proliferation of NK cells in multiple sclerosis. Int Immunol 2011, 23:139–148.CrossRefPubMedPubMedCentral
27.
Bell JE, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Budka H, Dexter DT, Falkai P, Ferrer I, Gelpi E, Gentleman SM, Giaccone G, Huitinga I, Ironside JW, Klioueva N, Kovacs GG, Meyronet D, Palkovits M, Parchi P, Patsouris E, Reynolds R, Riederer P, Roggendorf W, Seilhean D, Schmitt A, Schmitz P, Streichenberger N, Schwalber A, Kretzschmar H: Management of a twenty-first century brain bank: experience in the BrainNet Europe consortium. Acta Neuropathol 2008, 115:497–507.CrossRefPubMed
28.
Abramoff MD, Magalhaes PJ, Ram SJ: Image Processing with ImageJ. Biophotonics International 2004, 11:36–42.
29.
Durrenberger PF, Fernando S, Kashefi SN, Ferrer I, Hauw JJ, Seilhean D, Smith C, Walker R, Al-Sarraj S, Troakes C, Palkovits M, Kasztner M, Huitinga I, Arzberger T, Dexter DT, Kretzschmar H, Reynolds R: Effects of antemortem and postmortem variables on human brain mRNA quality: a BrainNet Europe study. J Neuropathol Exp Neurol 2010, 69:70–81.CrossRefPubMed
30.
Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B, Aloisi F, Reynolds R: A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010, 68:477–493.CrossRefPubMed
31.
Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F: Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007, 130:1089–1104.CrossRefPubMed
32.
Ponten J, Westermark B: Properties of human malignant glioma cells in vitro. Med Biol 1978, 56:184–193.PubMed
33.
Young NT, Waller EC, Patel R, Roghanian A, Austyn JM, Trowsdale J: The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells. Blood 2008, 111:3090–3096.CrossRefPubMed
34.
Anderson KJ, Allen RL: Regulation of T-cell immunity by leucocyte immunoglobulin-like receptors: innate immune receptors for self on antigen-presenting cells. Immunology 2009, 127:8–17.CrossRefPubMedPubMedCentral
35.
Bensussan A, Remtoula N, Sivori S, Bagot M, Moretta A, Marie-Cardine A: Expression and function of the natural cytotoxicity receptor NKp46 on circulating malignant CD4+ T lymphocytes of Sézary syndrome patients. J Invest Dermatol 2011, 131:969–976.CrossRefPubMed
36.
Yu J, Mitsui T, Wei M, Mao H, Butchar JP, Shah MV, Zhang J, Mishra A, Alvarez-Breckenridge C, Liu X, Liu S, Yokohama A, Trotta R, Marcucci G Jr, Benson DM, Loughran TP Jr, Tridandapani S, Caligiuri MA: NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human. J Clin Invest 2011, 121:1456–1470.CrossRefPubMedPubMedCentral
37.
Spits H, Di Santo JP: The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol 2011, 12:21–27.CrossRefPubMed
38.
39.
Saikali P, Antel JP, Pittet CL, Newcombe J, Arbour N: Contribution of astrocyte-derived IL-15 to CD8 T cell effector functions in multiple sclerosis. J Immunol 2010, 185:5693–5703.CrossRefPubMed
40.
Alvarez-Buylla A, Garcia-Verdugo JM, Tramontin AD: A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2001, 2:287–293.CrossRefPubMed
41.
Yonezawa T, Ohtsuka A, Yoshitaka T, Hirano S, Nomoto H, Yamamoto K, Ninomiya Y: Limitrin, a novel immunoglobulin superfamily protein localized to glia limitans formed by astrocyte endfeet. Glia 2003, 44:190–204.CrossRefPubMed
42.
Shapiro L, Love J, Colman DR: Adhesion molecules in the nervous system: structural insights into function and diversity. Annu Rev Neurosci 2007, 30:451–474.CrossRefPubMed
43.
Crossin KL, Krushel LA: Cellular signaling by neural cell adhesion molecules of the immunoglobulin superfamily. Dev Dyn 2000, 218:260–279.CrossRefPubMed
44.
Charles P, Reynolds R, Seilhean D, Rougon G, Aigrot MS, Niezgoda A, Zalc B, Lubetzki C: Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis? Brain 2002, 125:1972–1979.CrossRefPubMed
45.
Bonfanti L: PSA-NCAM in mammalian structural plasticity and neurogenesis. Prog Neurobiol 2006, 80:129–164.CrossRefPubMed
46.
Trotter J, Bitter-Suermann D, Schachner M: Differentiation-regulated loss of the polysialylated embryonic form and expression of the different polypeptides of the neural cell adhesion molecule by cultured oligodendrocytes and myelin. J Neurosci Res 1989, 22:369–383.CrossRefPubMed
47.
Nomura T, Yabe T, Rosenthal ES, Krzan M, Schwartz JP: PSA-NCAM distinguishes reactive astrocytes in 6-OHDA-lesioned substantia nigra from those in the striatal terminal fields. J Neurosci Res 2000, 61:588–596.CrossRefPubMed
48.
Ricard CS, Kobayashi S, Pena JD, Salvador-Silva M, Agapova O, Hernandez MR: Selective expression of neural cell adhesion molecule (NCAM)-180 in optic nerve head astrocytes exposed to elevated hydrostatic pressure in vitro. Brain Res Mol Brain Res 2000, 81:62–79.CrossRefPubMed
49.
Singhrao SK, Neal JW, Newman GR: Corpora amylacea could be an indicator of neurodegeneration. Neuropathol Appl Neurobiol 1993, 19:269–276.CrossRefPubMed
50.
51.
Kimura T, Fujise N, Ono T, Shono M, Yuzuriha T, Katsuragi S, Takamatsu J, Miyakawa T, Kitamura T: Identification of an aging-related spherical inclusion in the human brain. Pathol Int 2002, 52:636–642.CrossRefPubMed
52.
Mrak RE, Griffin ST, Graham DI: Aging-associated changes in human brain. J Neuropathol Exp Neurol 1997, 56:1269–1275.CrossRefPubMed
53.
Selmaj K, Pawlowska Z, Walczak A, Koziolkiewicz W, Raine CS, Cierniewski CS: Corpora amylacea from multiple sclerosis brain tissue consists of aggregated neuronal cells. Acta Biochim Pol 2008, 55:43–49.PubMed
Metadata
Title
Innate Immunity in multiple sclerosis white matter lesions: expression of natural cytotoxicity triggering receptor 1 (NCR1)
Authors
Pascal F Durrenberger
Anna Ettorre
Fatemah Kamel
Louise V Webb
Malcolm Sim
Richard S Nicholas
Omar Malik
Richard Reynolds
Rosemary J Boyton
Daniel M Altmann
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-1

Other articles of this Issue 1/2012

Journal of Neuroinflammation 1/2012 Go to the issue

Research

Post-ischemic estradiol treatment reduced glial response and triggers distinct cortical and hippocampal signaling in a rat model of cerebral ischemia

Research

Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells

Research

Increase of arginase activity in old apolipoprotein-E deficient mice under Western diet associated with changes in neurovascular unit

Research

Evaluation of age-related changes in translocator protein (TSPO) in human brain using 11C-[R]-PK11195 PET

Research

Prenatal stress causes alterations in the morphology of microglia and the inflammatory response of the hippocampus of adult female mice

Research

Peroxisome proliferator-activated receptors γ/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus