Expression of the inhibitor of apoptosis protein family in multiple sclerosis reveals a potential immunomodulatory role during autoimmune mediated demyelination
Restricted accessResearch articleFirst published online June, 2008
Expression of the inhibitor of apoptosis protein family in multiple sclerosis reveals a potential immunomodulatory role during autoimmune mediated demyelination
A failure of autoreactive T cells to undergo apoptosis may contribute to the pathogenesis of multiple sclerosis (MS). The role of the inhibitor of apoptosis (IAP) family of anti-apoptotic proteins such as X-linked IAP (XIAP), human inhibitor of apoptosis-1 (HIAP-1), human inhibitor of apoptosis-2 (HIAP-2), neuronal apoptosis inhibitory protein (NAIP) and Survivin in relapsing–remitting, secondary-progressive, primary-progressive or benign forms of MS is unclear. We report here that expression of the IAP family of genes in peripheral blood samples and brain tissues from MS cases support a role for differential regulation of these potent anti-apoptotic proteins in the pathology of MS. XIAP mRNA and protein levels were elevated in peripheral blood mononuclear cells from patients with active disease relative to normal subjects. In patients with active MS, HIAP-1 and HIAP-2 mRNA levels were elevated in resting T cells while NAIP mRNA was increased in whole blood. In post-mortem MS brain tissue, XIAP and HIAP-1 in myelin lesions were co-localized with microglia and T cells, respectively. Only in primary-progressive patients was Survivin expression elevated suggestive of a distinct pathological basis for this subtype of MS. Taken together, these results suggest that patterns of inhibitor of apoptosis expression in immune cells may have value in distinguishing between MS subtypes and offer insight into the mechanisms responsible for their distinct clinical courses.
1 Noseworthy JH Lucchinetti C Rodriguez M Weinshenker BG . Medical progress: multiple sclerosis.New Engl J Med2000; 343: 938–952.
2.
2 McDonnell GV Hawkins SA . Primary progressive multiple sclerosis: increasing clarity but many unanswered questions.J Neurol Sci2002; 199: 1–15.
3.
3 Hawkins SA McDonnell GV . Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors.J Neurol Neurosurg Psychiatry1999; 67: 148–152.
4.
4 Pittock SJ Mayr WT McClelland RL . Disability profile of MS did not change over 10 years in a population-based prevalence cohort.Neurology2004; 62: 601–606.
5.
5 Sayao AL Devonshire V Tremlett H . Longitudinal follow-up of ‘benign’ multiple sclerosis at 20 years.Neurology2007; 68: 496–500.
6.
6 McDonnell GV Cabrera-Gomez J Calne DB Li DKB Oger J . Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions - the subclinical stage of primary progressive multiple sclerosis may last 10 years.Mult Scler2003; 9: 204–209.
7.
7 De Stefano N Battaglini M Stromillo ML . Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis.Brain2006; 129: 2008–2016.
8.
8 Rinaldi L Gallo P Calabrese M . Longitudinal analysis of immune cell phenotypes in early stage multiple sclerosis: distinctive patterns characterize MRI-active patients.Brain2006; 129: 1993–2007.
9.
9 Jensen J Langkilde AR Frederiksen JL Sellebjerg F . CD8(+) T cell activation correlates with disease activity in clinically isolated syndromes and is regulated by interferon-beta treatment.J Neuroimmunol2006; 179: 163–172.
10.
10 Siva A . The spectrum of multiple sclerosis and treatment decisions.Clin Neurol Neurosurg2006; 108: 333–338.
11.
11 Bernard CCA Derosbo NK . Multiple-sclerosis – an autoimmune-disease of multifactorial etiology.Curr Opin Immunol1992; 4: 760–765.
12.
12 Pender MP . Genetically determined failure of activation-induced apoptosis of autoreactive T cells as a cause of multiple sclerosis.Lancet1998; 351: 978–981.
13.
13 Pender MP Rist MJ . Apoptosis of inflammatory cells in immune control of the nervous system: Role of glia.Glia2001; 36: 137–144.
14.
14 Dsouza SD Bonetti B Balasingam V . Multiple sclerosis: Fas signaling in oligodendrocyte cell death.J Exp Med1996; 184: 2361–2370.
15.
15 Satoh J Nakanishi M Koike F . Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis.Neurobiol Dis2005; 18: 537–550.
16.
16 Holcik M Gibson H Korneluk RG . XIAP: apoptotic brake and promising therapeutic target.Apoptosis2001; 6: 253–261.
17.
17 Salvesen GS Duckett CS . IAP proteins: blocking the road to death’s door.Nature Rev Mol Cell Biol2002; 3: 401–410.
18.
18 Eckelman BP Salvesen GS . The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.J Biol Chem2006; 281: 3254–3260.
19.
19 Nachmias B Ashhab Y Ben Yehuda D . The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer.Semin Cancer Biol2004; 14: 231–243.
20.
20 Robertson GS Crocker SJ Nicholson DW Schulz JB . Neuroprotection by the inhibition of apoptosis.Brain Pathol2000; 10: 283–292.
21.
21 Damiano JS Newman RM Reed JC . Multiple roles of CLAN (caspase-associated recruitment domain, leucine-rich repeat, TPI-containing protein) in the and NAIP CIIA HET-E, and mammalian innate immune response.J Immunol2004; 173: 6338–6345.
22.
22 Segal BM Cross AH . Fas(t) track to apoptosis in MS - TNF receptors may suppress or potentiate CNS demyelination.Neurology2000; 55: 906–907.
23.
23 Sharief MK Noori MA Zoukos Y . Reduced expression of the inhibitor of apoptosis proteins in T cells from patients with multiple sclerosis following interferon-beta therapy.J Neuroimmunol2002; 129: 224–231.
24.
24 Sharief MK Semra YK . Upregulation of the inhibitor of apoptosis proteins in activated T lymphocytes from patients with multiple sclerosis.J Neuroimmunol2001; 119: 350–357.
25.
25 McDonald WI Compston A Edan G . Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis.Ann Neurol2001; 50: 121–127.
26.
26 Polman CH Reingold SC Edan G . Diagnostic criteria for multiple sclerosis: 2005 Revisions to the 'McDonald Criteria'.Ann Neurol2005; 58: 840–846.
27.
27 Lublin FD Reingold SC . Defining the clinical course of multiple sclerosis: results of an international survey.Neurology1996; 46: 907–911.
28.
28 Biswas P Mantelli B Sica A . Expression of CD4 on human peripheral blood neutrophils.Blood2003; 101: 4452–4456.
29.
29 Stroncek DF Clay ME Smith J Jaszcz WB Herr G McCullough J . Comparison of two blood cell separators in collecting peripheral blood stem cell components.Transfus Med1997; 7: 95–99.
30.
30 Livak KJ Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method.Methods2001; 25: 402–408.
31.
31 Feuer R Mena I Pagarigan RR Harkins S Hassett DE Whitton JL . Coxsackievirus B3 and the neonatal CNS – The roles of stem cells, developing neurons, and apoptosis in infection, viral dissemination, and disease.Am J Pathol2003; 163: 1379–1393.
32.
32 Kutzelnigg A Lucchinetti CF Stadelmann C . Cortical demyelination and diffuse white matter injury in multiple sclerosis.Brain2005; 128: 2705–2712.
33.
33 Chofflon M . Mechanisms of action for treatments in multiple sclerosis – does a heterogeneous disease demand a multi-targeted therapeutic approach?Biodrugs2005; 19: 299–308.
34.
34 Roy N Mahadevan MS McLean M . The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular-atrophy.Cell1995; 80: 167–178.
35.
35 Velasco E Valero C Valero A Moreno F Hernandez-Chico C . Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of (c)BCD541 and SNA phenotype (vol 5, pg 257, 1996).Hum Mol Genet1996; 5: 710.
36.
36 Martin Y Valero A Lopez-Terradas JM Marsal C Hernandez-Chico C . The X-linked IAP gene does not contribute to the clinical phenotype of spinal muscular atrophy.Clin Genets2000; 57: 154–156.
37.
37 Crocker SJ Wigle N Liston P . NAIP protects the nigrostriatal dopamine pathway in an intrastriatal rat model of Parkinson’s disease.Eur J Neurosci2001; 14: 391–400.
38.
38 Liston P Roy N Tamai K . Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes.Nature1996; 379: 349–353.
39.
39 Pari G Berrada F Verge G Karpati G Nalbantoglu J . Immunolocalization of NAIP in the human brain and spinal cord.Neuroreport2000; 11: 9–14.
40.
40 Greer JM Csurhes PA Pender MP McCombe PA . Effect of gender on T-cell proliferative responses to myelin proteolipid protein antigens in patients with multiple sclerosis and controls.J Autoimmun2004; 22: 345–352.
41.
41 Willard HF Riordan JR . Assignment of the gene for myelin proteolipid protein to the X-chromosome - implications for X-linked myelin disorders.Science1985; 230: 940–942.
42.
42 Damiano JS Oliveira V Welsh K Reed JC . Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses.Biochem J2004; 381: 213–219.
43.
43 Killestein J Den Drijver BF Van der Graaff WL Uitdehaag BMJ Polman CH Van Lier RAW . Intracellular cytokine profile in T-cell subsets of multiple sclerosis patients: different features in primary progressive disease.Mult Scler2001; 7: 145–150.
44.
44 Greer JM Csurhes PA Cameron KD McCombe PA Good MF Pender MP . Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis.Brain1997; 120: 1447–1460.
45.
45 Acarin N Rio J Fernandez AL . Different antiganglioside antibody pattern between relapsing-remitting and progressive multiple sclerosis.Acta Neurol Scand1996; 93: 99–103.
46.
46 Pender MP Csurhes PA Wolfe NP . Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis.J Clin Neurosci2003; 10: 63–66.
47.
47 Yuo A Kitagawa S Motoyoshi K Azuma E Saito M Takaku F . Rapid priming of human monocytes by human hematopoietic growth-factors – granulocyte-macrophage colony-stimulating factor (Csf), macrophage-Csf, and interleukin-3 selectively enhance superoxide release triggered by receptor-mediated agonists.Blood1992; 79: 1553–1557.
48.
48 Zehntner SP Brickman C Bourbonniere L Remington L Caruso M Owens T . Neutrophils that infiltrate the central nervous system regulate T cell responses.J Immunol2005; 174: 5124–5131.
49.
49 Todaro M Zeuner A Stassi G . Role of apoptosis in autoimmunity.J Clin Immunol2004; 24: 1–11.
50.
50 O’Neill AJ Doyle BT Molloy E . Gene expression profile of inflammatory neutrophils: alterations in the inhibitors of apoptosis proteins during spontaneous and delayed apoptosis.Shock2004; 21: 512–518.
51.
51 Ishikawa F Miyazaki S . New biodefense strategies by neutrophils.Arch Immunol Ther Exp (Warsz)2005; 53: 226–233.
52.
52 Diez E Yaraghi Z MacKenzie A Gros P . The neuronal apoptosis inhibitory protein (Naip) is expressed in macrophages and is modulated after phagocytosis and during intracellular infection with Legionella pneumophila.J Immunol2000; 164: 1470–1477.
53.
53 Libbey JE McCoy LL Fujinami RS . Molecular mimicry in multiple sclerosis. In: M Alireza, (ed.) International Review of Neurobiology The Neurobiology of Multiple Sclerosis.New York: Academic Press, 2007: 127–147.
54.
54 Tamm I Kornblau SM Segall H . Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias.Clin Cancer Res2000; 6: 1796–1803.
55.
55 van der Goes A Boorsma W Hoekstra K Montagne L de Groot CJA Dijkstra CD . Determination of the sequential degradation of myelin proteins by macrophages.J Neuroimmunol2005; 161: 12–20.
56.
56 Raivich G Banati R . Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease.Brain Res Rev2004; 46: 261–281.
57.
57 Djukic M Mildner A Schmidt H . Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice.Brain2006; 129: 2394–2403.
58.
58 Leone C Le Pavec G Meme W . Characterization of human monocyte-derived microglia-like cells.Glia2006; 54: 183–192.
59.
59 Bechmann I Goldmann J Kovac AD . Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia.FASEB J2005; 19: 647.
60.
60 Mezey E Chandross KJ Harta G Maki RA McKercher SR . Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow.Science2000; 290: 1779–1782.
61.
61 Ponomarev E Shriver L Maresz K Dittel B . Microglial cell activation and proliferation precedes the onset of CNS autoimmunity.J Neurosci Res2005; 81: 389.
62.
62 Miranda MB Dyer KF Grandis JR Johnson DE . Differential activation of apoptosis regulatory pathways during monocytic vs granulocytic differentiation: a requirement for Bcl-X-L and XIAP in the prolonged survival of monocytic cells.Leukemia2003; 17: 390–400.
63.
63 Liston P Fong WG Korneluk RG . The inhibitors of apoptosis: there is more to life than Bcl2.Oncogene2003; 22: 8568–8580.
64.
64 Vischioni B van der Valk P Ing SWS Kruyt FAE Rodriguez JA Giaccone G . Expression and localization of inhibitor of apoptosis proteins in normal human tissues.Hum Pathol2006; 37: 78–86.
65.
65 Reed JC Doctor K Rojas A . Comparative analysis of apoptosis and inflammation genes of mice and humans.Genome Research2003; 13: 1376–1388.
66.
66 Skulina C Schmitt S Dornmair K Babbe H Roers A Rajewsky K . Multiple sclerosis: Brain-infiltrating CD8(+) T cells persist as clonal expansions in the cerebrospinal fluid and blood.PNAS2004; 101: 2428–2433.
67.
67 Barnett MH Henderson APD Prineas JW . The macrophage in MS: just a scavenger after all? Pathology and pathogenesis of the acute MS lesion.Mult Scler2006; 12: 121–132.
68.
68 Lassmann H Bruck W Lucchinetti CF . The immunopathology of multiple sclerosis: an overview.Brain Pathol2007; 17: 210–218.
69.
69 Nyland H Mork S Matre R . Insitu characterization of mononuclear cell infiltrates in lesions of multiple-sclerosis.Neuropathol Appl Neurobiol1982; 8: 403–411.
70.
70 Khoury SJ Guttmann CRG Orav EJ Kikinis R Jolesz FA Weiner HL . Changes in activated T cells in the blood correlate with disease activity in multiple sclerosis.Arch Neurol2000; 57: 1183–1189.
71.
71 Ambrosini G Adida C Altieri DC . A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma.Nature Med1997; 3: 917–921.
72.
72 Fukuda S Pelus LM . Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis.Blood2001; 98: 2091–2100.
73.
73 Ouhtit A . Survivin is not only a death encounter but also a survival protein for invading tumor cells.Front Biosci2007; 1: 1260–1270.
74.
74 Kornacker M Verneris MR Kornacker B Scheffold C Negrin RS . Survivin expression correlates with apoptosis resistance after lymphocyte activation and is found preferentially in memory T cells.Immunol Lett2001; 76: 169–173.
75.
75 Maurer M Loserth S Kolb-Maurer A . A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1+49) alters T-cell activation.Immunogenetics2002; 54: 1–8.
76.
76 de Graaf AO van Krieken JH Tonnissen E . Expression of C-IAP1, C-IAP2 and SURVIVIN discriminates different types of lymphoid malignancies.Br J Haematol2005; 130: 852–859.
77.
77 Zehntner SP; Bourbonniere L; Moore CS; . X-linked inhibitor of apoptosis (XIAP) regulates T cell effector function. J Immunol 2007; 179: 7553–7560.
78.
78 Zehntner SP Bourbonniere L Morris SJ . Apoptosis induction as a therapeutic intervention to eliminate encephallitogenic T cells; Antisense XIAP (AEG35169) in murine models of EAE.Clin Immunol2005; 115: S36–S37.
