Skip to main content
Top
Published in: Metabolic Brain Disease 3/2012

Open Access 01-09-2012 | Original Paper

The conundrum of iron in multiple sclerosis – time for an individualised approach

Authors: Susan J. van Rensburg, Maritha J. Kotze, Ronald van Toorn

Published in: Metabolic Brain Disease | Issue 3/2012

Login to get access

Abstract

Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome - some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations.
Literature
go back to reference Adams CW (1988) Perivascular iron deposition and other vascular damage in multiple sclerosis. J Neurol Neurosurg Psychiatry 51:260–265PubMedCrossRef Adams CW (1988) Perivascular iron deposition and other vascular damage in multiple sclerosis. J Neurol Neurosurg Psychiatry 51:260–265PubMedCrossRef
go back to reference Alcina A, Ramagopalan SV, Fernández O, Catalá-Rabasa A, Fedetz M, Ndagire D, Leyva L, Arnal C, Delgado C, Lucas M, Izquierdo G, Ebers GC, Matesanz F (2010) Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis. Eur J Hum Genet 18:618–620PubMedCrossRef Alcina A, Ramagopalan SV, Fernández O, Catalá-Rabasa A, Fedetz M, Ndagire D, Leyva L, Arnal C, Delgado C, Lucas M, Izquierdo G, Ebers GC, Matesanz F (2010) Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis. Eur J Hum Genet 18:618–620PubMedCrossRef
go back to reference Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122PubMedCrossRef Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122PubMedCrossRef
go back to reference Ates O, Kurt S, Bozkurt N, Karaer H (2010) NRAMP1 (SLC11A1) variants: genetic susceptibility to multiple Sclerosis. J Clin Immunol 30:583–586PubMedCrossRef Ates O, Kurt S, Bozkurt N, Karaer H (2010) NRAMP1 (SLC11A1) variants: genetic susceptibility to multiple Sclerosis. J Clin Immunol 30:583–586PubMedCrossRef
go back to reference Axtell RC, Raman C, Steinman L (2011) Interferon-β exacerbates Th17-mediated inflammatory disease. Trends Immunol 32:272–277PubMedCrossRef Axtell RC, Raman C, Steinman L (2011) Interferon-β exacerbates Th17-mediated inflammatory disease. Trends Immunol 32:272–277PubMedCrossRef
go back to reference Baas D, Prüfer K, Ittel ME, Kuchler-Bopp S, Labourdette G, Sarliève LL, Brachet P (2000) Rat oligodendrocytes express the vitamin D(3) receptor and respond to 1,25-dihydroxyvitamin D(3). Glia 31:59–68PubMedCrossRef Baas D, Prüfer K, Ittel ME, Kuchler-Bopp S, Labourdette G, Sarliève LL, Brachet P (2000) Rat oligodendrocytes express the vitamin D(3) receptor and respond to 1,25-dihydroxyvitamin D(3). Glia 31:59–68PubMedCrossRef
go back to reference Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ (1998) Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci 18:6241–6253PubMed Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ (1998) Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci 18:6241–6253PubMed
go back to reference Badaracco ME, Siri MV, Pasquini JM (2010) Oligodendrogenesis: the role of iron. Biofactors 36:98–102PubMed Badaracco ME, Siri MV, Pasquini JM (2010) Oligodendrogenesis: the role of iron. Biofactors 36:98–102PubMed
go back to reference Baldwin GS, Carnegie PR (1971) Specific enzymic methylation of an arginine in the experimental allergic encephalomyelitis protein from human myelin. Science 171:579–581PubMedCrossRef Baldwin GS, Carnegie PR (1971) Specific enzymic methylation of an arginine in the experimental allergic encephalomyelitis protein from human myelin. Science 171:579–581PubMedCrossRef
go back to reference Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA, Zhang L, Farmer AD, Bell CJ, Kim RW, May GD, Woodward JE, Caillier SJ, McElroy JP, Gomez R, Pando MJ, Clendenen LE, Ganusova EE, Schilkey FD, Ramaraj T, Khan OA, Huntley JJ, Luo S, Kwok PY, Wu TD, Schroth GP, Oksenberg JR, Hauser SL, Kingsmore SF (2010) Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464:1351–1356PubMedCrossRef Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA, Zhang L, Farmer AD, Bell CJ, Kim RW, May GD, Woodward JE, Caillier SJ, McElroy JP, Gomez R, Pando MJ, Clendenen LE, Ganusova EE, Schilkey FD, Ramaraj T, Khan OA, Huntley JJ, Luo S, Kwok PY, Wu TD, Schroth GP, Oksenberg JR, Hauser SL, Kingsmore SF (2010) Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464:1351–1356PubMedCrossRef
go back to reference Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468PubMedCrossRef Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468PubMedCrossRef
go back to reference Barnett MH, Henderson AP, Prineas JW (2006) The macrophage in MS: just a scavenger after all? Pathology and pathogenesis of the acute MS lesion. Mult Scler 12:121–132PubMedCrossRef Barnett MH, Henderson AP, Prineas JW (2006) The macrophage in MS: just a scavenger after all? Pathology and pathogenesis of the acute MS lesion. Mult Scler 12:121–132PubMedCrossRef
go back to reference Behan PO, Chaudhuri A (2010) The sad plight of multiple sclerosis research (low on fact, high on fiction): critical data to support it being a neurocristopathy. Inflammopharmacology 18:265–290PubMedCrossRef Behan PO, Chaudhuri A (2010) The sad plight of multiple sclerosis research (low on fact, high on fiction): critical data to support it being a neurocristopathy. Inflammopharmacology 18:265–290PubMedCrossRef
go back to reference Bettencourt A, Silva AM, Santos E, Gomes S, Mendonça D, Costa PP, Faustino P, Silva BM (2011) HFE gene polymorphisms and severity in Portuguese patients with multiple sclerosis. Eur J Neurol 18:663–666PubMedCrossRef Bettencourt A, Silva AM, Santos E, Gomes S, Mendonça D, Costa PP, Faustino P, Silva BM (2011) HFE gene polymorphisms and severity in Portuguese patients with multiple sclerosis. Eur J Neurol 18:663–666PubMedCrossRef
go back to reference Beutler E, Van Geet C, te Loo DM, Gelbart T, Crain K, Truksa J, Lee PL (2010) Polymorphisms and mutations of human TMPRSS6 in iron deficiency anaemia. Blood Cells Mol Dis 44:16–21PubMedCrossRef Beutler E, Van Geet C, te Loo DM, Gelbart T, Crain K, Truksa J, Lee PL (2010) Polymorphisms and mutations of human TMPRSS6 in iron deficiency anaemia. Blood Cells Mol Dis 44:16–21PubMedCrossRef
go back to reference Byun E, Caillier SJ, Montalban X, Villoslada P, Fernández O, Brassat D, Comabella M, Wang J, Barcellos LF, Baranzini SE, Oksenberg JR (2008) Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. Arch Neurol 65:337–344PubMedCrossRef Byun E, Caillier SJ, Montalban X, Villoslada P, Fernández O, Brassat D, Comabella M, Wang J, Barcellos LF, Baranzini SE, Oksenberg JR (2008) Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. Arch Neurol 65:337–344PubMedCrossRef
go back to reference Cable RG, Glynn SA, Kiss JE, Mast AE, Steele WR, Murphy EL, Wright DJ, Sacher RA, Gottschall JL, Vij V, Simon TL; for the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II) (2011) Iron deficiency in blood donors: analysis of enrollment data from the REDS-II Donor Iron Status Evaluation (RISE) study. Transfusion 51:511–522CrossRef Cable RG, Glynn SA, Kiss JE, Mast AE, Steele WR, Murphy EL, Wright DJ, Sacher RA, Gottschall JL, Vij V, Simon TL; for the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II) (2011) Iron deficiency in blood donors: analysis of enrollment data from the REDS-II Donor Iron Status Evaluation (RISE) study. Transfusion 51:511–522CrossRef
go back to reference Cammer W (2002) Protection of cultured oligodendrocytes against tumor necrosis factor-alpha by the antioxidants coenzyme Q(10) and N-acetyl cysteine. Brain Res Bull 58:587–592PubMedCrossRef Cammer W (2002) Protection of cultured oligodendrocytes against tumor necrosis factor-alpha by the antioxidants coenzyme Q(10) and N-acetyl cysteine. Brain Res Bull 58:587–592PubMedCrossRef
go back to reference Cau M, Melis MA, Congiu R, Galanello R (2010) Iron-deficiency anaemia secondary to mutations in genes controlling hepcidin. Expert Rev Hematol 3:205–216PubMedCrossRef Cau M, Melis MA, Congiu R, Galanello R (2010) Iron-deficiency anaemia secondary to mutations in genes controlling hepcidin. Expert Rev Hematol 3:205–216PubMedCrossRef
go back to reference Caplan LR (2011) Evidence and the effective clinical neurologist: the 2009 H. Houston Merritt Lecture. Arch Neurol 68:1252–1256PubMedCrossRef Caplan LR (2011) Evidence and the effective clinical neurologist: the 2009 H. Houston Merritt Lecture. Arch Neurol 68:1252–1256PubMedCrossRef
go back to reference Ceccarelli A, Filippi M, Neema M, Arora A, Valsasina P, Rocca MA, Healy BC, Bakshi R (2009) T2 hypointensity in the deep gray matter of patients with benign multiple sclerosis. Mult Scler 15:678–686PubMedCrossRef Ceccarelli A, Filippi M, Neema M, Arora A, Valsasina P, Rocca MA, Healy BC, Bakshi R (2009) T2 hypointensity in the deep gray matter of patients with benign multiple sclerosis. Mult Scler 15:678–686PubMedCrossRef
go back to reference Cepeda-Lopez AC, Osendarp SJ, Melse-Boonstra A, Aeberli I, Gonzalez-Salazar F, Feskens E, Villalpando S, Zimmermann MB (2011) Sharply higher rates of iron deficiency in obese Mexican women and children are predicted by obesity-related inflammation rather than by differences in dietary iron intake. Am J Clin Nutr 93:975–983PubMedCrossRef Cepeda-Lopez AC, Osendarp SJ, Melse-Boonstra A, Aeberli I, Gonzalez-Salazar F, Feskens E, Villalpando S, Zimmermann MB (2011) Sharply higher rates of iron deficiency in obese Mexican women and children are predicted by obesity-related inflammation rather than by differences in dietary iron intake. Am J Clin Nutr 93:975–983PubMedCrossRef
go back to reference Collins FS (2010) The language of life. DNA and the revolution in personalized medicine. Harper Perennial, New York Collins FS (2010) The language of life. DNA and the revolution in personalized medicine. Harper Perennial, New York
go back to reference Comabella M, Altet L, Peris F, Villoslada P, Sánchez A, Montalban X (2004) Genetic analysis of SLC11A1 polymorphisms in multiple sclerosis patients. Mult Scler 10:618–620PubMedCrossRef Comabella M, Altet L, Peris F, Villoslada P, Sánchez A, Montalban X (2004) Genetic analysis of SLC11A1 polymorphisms in multiple sclerosis patients. Mult Scler 10:618–620PubMedCrossRef
go back to reference Confavreux C, Vukusic S, Moreau T, Adeleine P (2000) Relapses and progression of disability in multiple sclerosis. N Engl J Med 343:1430–1438PubMedCrossRef Confavreux C, Vukusic S, Moreau T, Adeleine P (2000) Relapses and progression of disability in multiple sclerosis. N Engl J Med 343:1430–1438PubMedCrossRef
go back to reference Connor JR (1994) Iron acquisition and expression of iron regulatory proteins in the developing brain: manipulation by ethanol exposure, iron deprivation and cellular dysfunction. Dev Neurosci 16:233–247PubMedCrossRef Connor JR (1994) Iron acquisition and expression of iron regulatory proteins in the developing brain: manipulation by ethanol exposure, iron deprivation and cellular dysfunction. Dev Neurosci 16:233–247PubMedCrossRef
go back to reference Connor JR, Menzies SL (1996) Relationship of iron to oligodendrocytes and myelination. Glia 17:83–93PubMedCrossRef Connor JR, Menzies SL (1996) Relationship of iron to oligodendrocytes and myelination. Glia 17:83–93PubMedCrossRef
go back to reference Corthals AP (2011) Multiple sclerosis is not a disease of the immune system. The Q Rev Biol 86:287–321CrossRef Corthals AP (2011) Multiple sclerosis is not a disease of the immune system. The Q Rev Biol 86:287–321CrossRef
go back to reference Dale JC, Burritt MF, Zinsmeister AR (2002) Diurnal variation of serum iron, iron-binding capacity, transferrin saturation, and ferritin levels. Am J Clin Pathol 117:802–808PubMedCrossRef Dale JC, Burritt MF, Zinsmeister AR (2002) Diurnal variation of serum iron, iron-binding capacity, transferrin saturation, and ferritin levels. Am J Clin Pathol 117:802–808PubMedCrossRef
go back to reference DeLuca GC, Ramagopalan SV, Herrera BM, Dyment DA, Lincoln MR, Montpetit A, Pugliatti M, Barnardo MC, Risch NJ, Sadovnick AD, Chao M, Sotgiu S, Hudson TJ, Ebers GC (2007) An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus. Proc Natl Acad Sci U S A 104:20896–20901PubMedCrossRef DeLuca GC, Ramagopalan SV, Herrera BM, Dyment DA, Lincoln MR, Montpetit A, Pugliatti M, Barnardo MC, Risch NJ, Sadovnick AD, Chao M, Sotgiu S, Hudson TJ, Ebers GC (2007) An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus. Proc Natl Acad Sci U S A 104:20896–20901PubMedCrossRef
go back to reference Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC (2009) Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 50:1801–1807PubMedCrossRef Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC (2009) Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 50:1801–1807PubMedCrossRef
go back to reference Elolf E, Bockermann V, Gringel T, Knauth M, Dechent P, Helms G (2007) Improved visibility of the subthalamic nucleus on high-resolution stereotactic MR imaging by added susceptibility (T2*) contrast using multiple gradient echoes. AJNR Am J Neuroradiol 28:1093–1094PubMedCrossRef Elolf E, Bockermann V, Gringel T, Knauth M, Dechent P, Helms G (2007) Improved visibility of the subthalamic nucleus on high-resolution stereotactic MR imaging by added susceptibility (T2*) contrast using multiple gradient echoes. AJNR Am J Neuroradiol 28:1093–1094PubMedCrossRef
go back to reference Fassl S, Leisser C, Huettenbrenner S, Maier S, Rosenberger G, Strasser S, Grusch M, Fuhrmann G, Leuhuber K, Polgar D, Stani J, Tichy B, Nowotny C, Krupitza G (2003) Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFalpha, FasL, TRAIL, or Myc. Oncogene 22:8343–8355PubMedCrossRef Fassl S, Leisser C, Huettenbrenner S, Maier S, Rosenberger G, Strasser S, Grusch M, Fuhrmann G, Leuhuber K, Polgar D, Stani J, Tichy B, Nowotny C, Krupitza G (2003) Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFalpha, FasL, TRAIL, or Myc. Oncogene 22:8343–8355PubMedCrossRef
go back to reference Filippi M, Rocca MA, Barkhof F, Bakshi R, Fazekas F, Khan O, Pelletier D, Rovira A, Simon J (2011) Multiple sclerosis and chronic cerebrospinal venous insufficiency: the neuroimaging perspective. AJNR Am J Neuroradiol 32:424–427PubMedCrossRef Filippi M, Rocca MA, Barkhof F, Bakshi R, Fazekas F, Khan O, Pelletier D, Rovira A, Simon J (2011) Multiple sclerosis and chronic cerebrospinal venous insufficiency: the neuroimaging perspective. AJNR Am J Neuroradiol 32:424–427PubMedCrossRef
go back to reference Filippini G, Moja L, Liberati A, Gensini GF, Gusinu R, Conti AA (2008) When drug companies select what they want to publish patients are denied relevant therapeutic information. Intern Emerg Med 3:255–257PubMedCrossRef Filippini G, Moja L, Liberati A, Gensini GF, Gusinu R, Conti AA (2008) When drug companies select what they want to publish patients are denied relevant therapeutic information. Intern Emerg Med 3:255–257PubMedCrossRef
go back to reference Fink F, Rischkau E, Butt M, Klein J, Eling P, Hildebrandt H (2010) Efficacy of an executive function intervention programme in MS: a placebo-controlled and pseudo-randomised trial. Mult Scler 16:1148–1151PubMedCrossRef Fink F, Rischkau E, Butt M, Klein J, Eling P, Hildebrandt H (2010) Efficacy of an executive function intervention programme in MS: a placebo-controlled and pseudo-randomised trial. Mult Scler 16:1148–1151PubMedCrossRef
go back to reference Fisher J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, Klinger M, Simpson IA, Connor JR (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol 293:C641–C649PubMedCrossRef Fisher J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, Klinger M, Simpson IA, Connor JR (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol 293:C641–C649PubMedCrossRef
go back to reference French HM, Reid M, Mamontov P, Simmons RA, Grinspan JB (2009) Oxidative stress disrupts oligodendrocyte maturation. J Neurosci Res 87:3076–87PubMedCrossRef French HM, Reid M, Mamontov P, Simmons RA, Grinspan JB (2009) Oxidative stress disrupts oligodendrocyte maturation. J Neurosci Res 87:3076–87PubMedCrossRef
go back to reference Gazouli M, Sechi L, Paccagnini D, Sotgiu S, Arru G, Nasioulas G, Vassilopoulos D (2008) NRAMP1 polymorphism and viral factors in Sardinian multiple sclerosis patients. Can J Neurol Sci 35:491–494PubMed Gazouli M, Sechi L, Paccagnini D, Sotgiu S, Arru G, Nasioulas G, Vassilopoulos D (2008) NRAMP1 polymorphism and viral factors in Sardinian multiple sclerosis patients. Can J Neurol Sci 35:491–494PubMed
go back to reference Gerber MR, Connor JR (1989) Do oligodendrocytes mediate iron regulation in the human brain? Ann Neurol 26:95–98PubMedCrossRef Gerber MR, Connor JR (1989) Do oligodendrocytes mediate iron regulation in the human brain? Ann Neurol 26:95–98PubMedCrossRef
go back to reference Grant SM, Wiesinger JA, Beard JL, Cantorna MT (2003) Iron-deficient mice fail to develop autoimmune encephalomyelitis. J Nutr 133:2635–2638PubMed Grant SM, Wiesinger JA, Beard JL, Cantorna MT (2003) Iron-deficient mice fail to develop autoimmune encephalomyelitis. J Nutr 133:2635–2638PubMed
go back to reference Gray E, Thomas TL, Betmouni S, Scolding N, Love S (2008) Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol 18:86–95PubMedCrossRef Gray E, Thomas TL, Betmouni S, Scolding N, Love S (2008) Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol 18:86–95PubMedCrossRef
go back to reference Haacke EM, Makki M, Ge Y, Maheshwari M, Sehgal V, Hu J, Selvan M, Wu Z, Latif Z, Xuan Y, Khan O, Garbern J, Grossman RI (2009) Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J Magn Reson Imaging 29:537–544PubMedCrossRef Haacke EM, Makki M, Ge Y, Maheshwari M, Sehgal V, Hu J, Selvan M, Wu Z, Latif Z, Xuan Y, Khan O, Garbern J, Grossman RI (2009) Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J Magn Reson Imaging 29:537–544PubMedCrossRef
go back to reference Haacke EM, Garbern J, Miao Y, Habib C, Liu M (2010) Iron stores and cerebral veins in MS studied by susceptibility weighted imaging. Int Angiol 29:149–157PubMed Haacke EM, Garbern J, Miao Y, Habib C, Liu M (2010) Iron stores and cerebral veins in MS studied by susceptibility weighted imaging. Int Angiol 29:149–157PubMed
go back to reference Hancock LM, Bruce JM, Lynch SG (2011) Exacerbation history is associated with medication and appointment adherence in MS. J Behav Med 34:330–338PubMedCrossRef Hancock LM, Bruce JM, Lynch SG (2011) Exacerbation history is associated with medication and appointment adherence in MS. J Behav Med 34:330–338PubMedCrossRef
go back to reference Hiremath MM, Chen VS, Suzuki K, Ting JP, Matsushima GK (2008) MHC class II exacerbates demyelination in vivo independently of T cells. J Neuroimmunol 203:23–32PubMedCrossRef Hiremath MM, Chen VS, Suzuki K, Ting JP, Matsushima GK (2008) MHC class II exacerbates demyelination in vivo independently of T cells. J Neuroimmunol 203:23–32PubMedCrossRef
go back to reference Hohlfeld R (2010) ‘Gimme five’: future challenges in multiple sclerosis. ECTRIMS Lecture 2009. Mult Scler 16:3–14PubMedCrossRef Hohlfeld R (2010) ‘Gimme five’: future challenges in multiple sclerosis. ECTRIMS Lecture 2009. Mult Scler 16:3–14PubMedCrossRef
go back to reference Healy BC, Ali EN, Guttmann CR, Chitnis T, Glanz BI, Buckle G, Houtchens M, Stazzone L, Moodie J, Berger AM, Duan Y, Bakshi R, Khoury S, Weiner H, Ascherio A (2009) Smoking and disease progression in multiple sclerosis. Arch Neurol 66:858–864PubMedCrossRef Healy BC, Ali EN, Guttmann CR, Chitnis T, Glanz BI, Buckle G, Houtchens M, Stazzone L, Moodie J, Berger AM, Duan Y, Bakshi R, Khoury S, Weiner H, Ascherio A (2009) Smoking and disease progression in multiple sclerosis. Arch Neurol 66:858–864PubMedCrossRef
go back to reference Hulet SW, Powers S, Connor JR (1999) Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains. J Neurol Sci 165:48–55PubMedCrossRef Hulet SW, Powers S, Connor JR (1999) Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains. J Neurol Sci 165:48–55PubMedCrossRef
go back to reference Ilniczky S, Jelencsik I, Kenéz J, Szirmai I (2002) MR findings in subacute combined degeneration of the spinal cord caused by nitrous oxide anaesthesia - two cases. Eur J Neurol 9:101–104PubMedCrossRef Ilniczky S, Jelencsik I, Kenéz J, Szirmai I (2002) MR findings in subacute combined degeneration of the spinal cord caused by nitrous oxide anaesthesia - two cases. Eur J Neurol 9:101–104PubMedCrossRef
go back to reference Jana A, Pahan K (2007) Oxidative stress kills human primary oligodendrocytes via neutral sphingomyelinase: implications for multiple sclerosis. J Neuroimmune Pharmacol 2:184–193PubMedCrossRef Jana A, Pahan K (2007) Oxidative stress kills human primary oligodendrocytes via neutral sphingomyelinase: implications for multiple sclerosis. J Neuroimmune Pharmacol 2:184–193PubMedCrossRef
go back to reference Kamen DL, Tangpricha V (2010) Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med (Berl) 88:441–450 Kamen DL, Tangpricha V (2010) Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med (Berl) 88:441–450
go back to reference Kaur C, Wu CH, Wen CY, Ling EA (1994) The effects of subcutaneous injections of glucocorticoids on amoeboid microglia in postnatal rats. Arch Histol Cytol 57:449–459PubMedCrossRef Kaur C, Wu CH, Wen CY, Ling EA (1994) The effects of subcutaneous injections of glucocorticoids on amoeboid microglia in postnatal rats. Arch Histol Cytol 57:449–459PubMedCrossRef
go back to reference Kell DB (2009) Iron behaving badly: inappropriate iron chelation as a major contributor to the aaetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med Genomics 2:2PubMedCrossRef Kell DB (2009) Iron behaving badly: inappropriate iron chelation as a major contributor to the aaetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med Genomics 2:2PubMedCrossRef
go back to reference Khalil M, Enzinger C, Langkammer C, Tscherner M, Wallner-Blazek M, Jehna M, Ropele S, Fuchs S, Fazekas F (2009) Quantitative assessment of brain iron by R(2)* relaxometry in patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis. Mult Scler 15:1048–1054PubMedCrossRef Khalil M, Enzinger C, Langkammer C, Tscherner M, Wallner-Blazek M, Jehna M, Ropele S, Fuchs S, Fazekas F (2009) Quantitative assessment of brain iron by R(2)* relaxometry in patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis. Mult Scler 15:1048–1054PubMedCrossRef
go back to reference Kim YS, Kim SU (1991) Oligodendroglial cell death induced by oxygen radicals and its protection by catalase. J Neurosci Res 29:100–106PubMedCrossRef Kim YS, Kim SU (1991) Oligodendroglial cell death induced by oxygen radicals and its protection by catalase. J Neurosci Res 29:100–106PubMedCrossRef
go back to reference Kimball S, Vieth R, Dosch HM, Bar-Or A, Cheung R, Gagne D, O’Connor P, D’Souza C, Ursell M, Burton JM (2011) Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis. J Clin Endocrinol Metab 96:2826–2834PubMedCrossRef Kimball S, Vieth R, Dosch HM, Bar-Or A, Cheung R, Gagne D, O’Connor P, D’Souza C, Ursell M, Burton JM (2011) Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis. J Clin Endocrinol Metab 96:2826–2834PubMedCrossRef
go back to reference Kirkman HN, Gaetani GF (2007) Mammalian catalase: a venerable enzyme with new mysteries. Trends Biochem Sci 32:44–50PubMedCrossRef Kirkman HN, Gaetani GF (2007) Mammalian catalase: a venerable enzyme with new mysteries. Trends Biochem Sci 32:44–50PubMedCrossRef
go back to reference Koc M, Nad’ová Z, Truksa J, Ehrlichová M, Kovár J (2005) Iron deprivation induces apoptosis via mitochondrial changes related to Bax translocation. Apoptosis 10:381–393PubMedCrossRef Koc M, Nad’ová Z, Truksa J, Ehrlichová M, Kovár J (2005) Iron deprivation induces apoptosis via mitochondrial changes related to Bax translocation. Apoptosis 10:381–393PubMedCrossRef
go back to reference Koning N, Uitdehaag BM, Huitinga I, Hoek RM (2009) Restoring immune suppression in the multiple sclerosis brain. Prog Neurobiol 89:359–368PubMedCrossRef Koning N, Uitdehaag BM, Huitinga I, Hoek RM (2009) Restoring immune suppression in the multiple sclerosis brain. Prog Neurobiol 89:359–368PubMedCrossRef
go back to reference Kotze MJ, Rooney RN (1997) Hereditary biochemical multiple sclerosis: a new subtype of multiple sclerosis characterized by porphyria-like symptoms? Am J Hum Genet 61(Suppl):A255 Kotze MJ, Rooney RN (1997) Hereditary biochemical multiple sclerosis: a new subtype of multiple sclerosis characterized by porphyria-like symptoms? Am J Hum Genet 61(Suppl):A255
go back to reference Kotze MJ, de Villiers JN, Rooney RN, Grobbelaar JJ, Mansvelt EP, Bouwens CS, Carr J, Stander I, du Plessis L (2001) Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects. Blood Cells Mol Dis 27:44–53PubMedCrossRef Kotze MJ, de Villiers JN, Rooney RN, Grobbelaar JJ, Mansvelt EP, Bouwens CS, Carr J, Stander I, du Plessis L (2001) Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects. Blood Cells Mol Dis 27:44–53PubMedCrossRef
go back to reference Kotze MJ, de Villiers JNP, Zaahl MG, Robson K (2003) The role of iron metabolism in multiple sclerosis. In: Zatta P (ed) Metal ions and neurodegenerative disorders. World Sci, Singapore, London, pp 399–414CrossRef Kotze MJ, de Villiers JNP, Zaahl MG, Robson K (2003) The role of iron metabolism in multiple sclerosis. In: Zatta P (ed) Metal ions and neurodegenerative disorders. World Sci, Singapore, London, pp 399–414CrossRef
go back to reference Kotze MJ, de Villiers JN, Warnich L, Schmidt S, Carr J, Mansvelt E, Fourie E, van Rensburg SJ (2006) Lack of clinical manifestation of hereditary haemochromatosis in South African patients with multiple sclerosis. Metab Brain Dis 21:109–120PubMedCrossRef Kotze MJ, de Villiers JN, Warnich L, Schmidt S, Carr J, Mansvelt E, Fourie E, van Rensburg SJ (2006) Lack of clinical manifestation of hereditary haemochromatosis in South African patients with multiple sclerosis. Metab Brain Dis 21:109–120PubMedCrossRef
go back to reference Kotze MJ, van Rensburg SJ, Rooney R, Haug PD (2010) In vitro method of diagnosis of a demyelinating disease subtype. Patent 01 04 - P1982ZA00 Kotze MJ, van Rensburg SJ, Rooney R, Haug PD (2010) In vitro method of diagnosis of a demyelinating disease subtype. Patent 01 04 - P1982ZA00
go back to reference Krayenbuehl PA, Maly FE, Hersberger M, Wiesli P, Himmelmann A, Eid K, Greminger P, Vetter W, Schulthess G (2006) Tumor necrosis factor-alpha -308 G > A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis. Clin Chem 52:1552–1558PubMedCrossRef Krayenbuehl PA, Maly FE, Hersberger M, Wiesli P, Himmelmann A, Eid K, Greminger P, Vetter W, Schulthess G (2006) Tumor necrosis factor-alpha -308 G > A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis. Clin Chem 52:1552–1558PubMedCrossRef
go back to reference Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452PubMedCrossRef Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452PubMedCrossRef
go back to reference Lefebvre d'Hellencourt C, Montero-Menei CN, Bernard R, Couez D (2003) Vitamin D3 inhibits proinflammatory cytokines and nitric oxide production by the EOC13 microglial cell line. J Neurosci Res 71:575–582PubMedCrossRef Lefebvre d'Hellencourt C, Montero-Menei CN, Bernard R, Couez D (2003) Vitamin D3 inhibits proinflammatory cytokines and nitric oxide production by the EOC13 microglial cell line. J Neurosci Res 71:575–582PubMedCrossRef
go back to reference Levenson CW, Cutler RG, Ladenheim B, Cadet JL, Hare J, Mattson MP (2004) Role of dietary iron restriction in a mouse model of Parkinson’s disease. Exp Neurol 190:506–514PubMedCrossRef Levenson CW, Cutler RG, Ladenheim B, Cadet JL, Hare J, Mattson MP (2004) Role of dietary iron restriction in a mouse model of Parkinson’s disease. Exp Neurol 190:506–514PubMedCrossRef
go back to reference Levin LI, Munger KL, O’Reilly EJ, Falk KI, Ascherio A (2010) Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol 67:824–830PubMed Levin LI, Munger KL, O’Reilly EJ, Falk KI, Ascherio A (2010) Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol 67:824–830PubMed
go back to reference LeVine SM, Chakrabarty A (2004) The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci 1012:252–266PubMedCrossRef LeVine SM, Chakrabarty A (2004) The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci 1012:252–266PubMedCrossRef
go back to reference Liuzzi GM, Latronico T, Rossano R, Viggiani S, Fasano A, Riccio P (2007) Inhibitory effect of polyunsaturated fatty acids on MMP-9 release from microglial cells–implications for complementary multiple sclerosis treatment. Neurochem Res 32:2184–2193PubMedCrossRef Liuzzi GM, Latronico T, Rossano R, Viggiani S, Fasano A, Riccio P (2007) Inhibitory effect of polyunsaturated fatty acids on MMP-9 release from microglial cells–implications for complementary multiple sclerosis treatment. Neurochem Res 32:2184–2193PubMedCrossRef
go back to reference Logroscino G, Marder K, Graziano J, Freyer G, Slavkovich V, LoIacono N, Cote L, Mayeux R (1997) Altered systemic iron metabolism in Parkinson’s disease. Neurology 49:714–717PubMedCrossRef Logroscino G, Marder K, Graziano J, Freyer G, Slavkovich V, LoIacono N, Cote L, Mayeux R (1997) Altered systemic iron metabolism in Parkinson’s disease. Neurology 49:714–717PubMedCrossRef
go back to reference Logroscino G, Chen H, Wing A, Ascherio A (2006) Blood donations, iron stores, and risk of Parkinson’s disease. Mov Disord 21:835–838PubMedCrossRef Logroscino G, Chen H, Wing A, Ascherio A (2006) Blood donations, iron stores, and risk of Parkinson’s disease. Mov Disord 21:835–838PubMedCrossRef
go back to reference Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911PubMedCrossRef Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911PubMedCrossRef
go back to reference Ly JD, Grubb DR, Lawen A (2003) The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8:115–128PubMedCrossRef Ly JD, Grubb DR, Lawen A (2003) The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8:115–128PubMedCrossRef
go back to reference Lynch SG, Fonseca T, LeVine SM (2000) A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell Mol Biol (Noisy-le-grand) 46:865–869 Lynch SG, Fonseca T, LeVine SM (2000) A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell Mol Biol (Noisy-le-grand) 46:865–869
go back to reference Marder K, Logroscino G, Tang MX, Graziano J, Cote L, Louis E, Alfaro B, Mejia H, Slavkovich V, Mayeux R (1998) Systemic iron metabolism and mortality from Parkinson’s disease. Neurology 50:1138–1140PubMedCrossRef Marder K, Logroscino G, Tang MX, Graziano J, Cote L, Louis E, Alfaro B, Mejia H, Slavkovich V, Mayeux R (1998) Systemic iron metabolism and mortality from Parkinson’s disease. Neurology 50:1138–1140PubMedCrossRef
go back to reference Mastorodemos V, Nikolakaki H, Tzagournissakis M, Kotzamani D, Panou T, Spanaki C, Klados G, Maris T, Kontolaimaki E, Psaroudaki K, Chlouverakis G, Georgakakis G, Plaitakis A (2010) Benign multiple sclerosis in Crete. Mult Scler 16:701–706PubMedCrossRef Mastorodemos V, Nikolakaki H, Tzagournissakis M, Kotzamani D, Panou T, Spanaki C, Klados G, Maris T, Kontolaimaki E, Psaroudaki K, Chlouverakis G, Georgakakis G, Plaitakis A (2010) Benign multiple sclerosis in Crete. Mult Scler 16:701–706PubMedCrossRef
go back to reference Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116PubMedCrossRef Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116PubMedCrossRef
go back to reference Michaeli S, Oz G, Sorce DJ, Garwood M, Ugurbil K, Majestic S, Tuite P (2007) Assessment of brain iron and neuronal integrity in patients with Parkinson’s disease using novel MRI contrasts. Mov Disord 22:334–340PubMedCrossRef Michaeli S, Oz G, Sorce DJ, Garwood M, Ugurbil K, Majestic S, Tuite P (2007) Assessment of brain iron and neuronal integrity in patients with Parkinson’s disease using novel MRI contrasts. Mov Disord 22:334–340PubMedCrossRef
go back to reference Miravalle A, Corboy JR (2010) Therapeutic options in multiple sclerosis: five new things. Neurology 75:S22–S27PubMedCrossRef Miravalle A, Corboy JR (2010) Therapeutic options in multiple sclerosis: five new things. Neurology 75:S22–S27PubMedCrossRef
go back to reference Morath DJ, Mayer-Pröschel M (2001) Iron modulates the differentiation of a distinct population of glial precursor cells into oligodendrocytes. Dev Biol 237:232–243PubMedCrossRef Morath DJ, Mayer-Pröschel M (2001) Iron modulates the differentiation of a distinct population of glial precursor cells into oligodendrocytes. Dev Biol 237:232–243PubMedCrossRef
go back to reference Morath DJ, Mayer-Pröschel M (2002) Iron deficiency during embryogenesis and consequences for oligodendrocyte generation in vivo. Dev Neurosci 24:197–207PubMedCrossRef Morath DJ, Mayer-Pröschel M (2002) Iron deficiency during embryogenesis and consequences for oligodendrocyte generation in vivo. Dev Neurosci 24:197–207PubMedCrossRef
go back to reference Munger KL, Chitnis T, Ascherio A (2009) Body size and risk of MS in two cohorts of US women. Neurology 73:1543–1550PubMedCrossRef Munger KL, Chitnis T, Ascherio A (2009) Body size and risk of MS in two cohorts of US women. Neurology 73:1543–1550PubMedCrossRef
go back to reference Neveu I, Naveilhan P, Menaa C, Wion D, Brachet P, Garabédian M (1994) Synthesis of 1,25-dihydroxyvitamin D3 by rat brain macrophages in vitro. J Neurosci Res 38:214–220PubMedCrossRef Neveu I, Naveilhan P, Menaa C, Wion D, Brachet P, Garabédian M (1994) Synthesis of 1,25-dihydroxyvitamin D3 by rat brain macrophages in vitro. J Neurosci Res 38:214–220PubMedCrossRef
go back to reference Newman B (2006) Iron depletion by whole-blood donation harms menstruating females: the current whole-blood-collection paradigm needs to be changed. Transfusion 46:1667–1681PubMedCrossRef Newman B (2006) Iron depletion by whole-blood donation harms menstruating females: the current whole-blood-collection paradigm needs to be changed. Transfusion 46:1667–1681PubMedCrossRef
go back to reference Nordvik I, Myhr KM, Nyland H, Bjerve KS (2000) Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta Neurol Scand 102:143–149PubMedCrossRef Nordvik I, Myhr KM, Nyland H, Bjerve KS (2000) Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta Neurol Scand 102:143–149PubMedCrossRef
go back to reference Owens GP, Bennett JL, Lassmann H, O’Connor KC, Ritchie AM, Shearer A, Lam C, Yu X, Birlea M, DuPree C, Williamson RA, Hafler DA, Burgoon MP, Gilden D (2009) Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann Neurol 65:639–649PubMedCrossRef Owens GP, Bennett JL, Lassmann H, O’Connor KC, Ritchie AM, Shearer A, Lam C, Yu X, Birlea M, DuPree C, Williamson RA, Hafler DA, Burgoon MP, Gilden D (2009) Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann Neurol 65:639–649PubMedCrossRef
go back to reference Perron H, Lang A (2010) The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clin Rev Allergy Immunol 39:51–61PubMedCrossRef Perron H, Lang A (2010) The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clin Rev Allergy Immunol 39:51–61PubMedCrossRef
go back to reference Pittock SJ, McClelland RL, Mayr WT, Jorgensen NW, Weinshenker BG, Noseworthy J, Rodriguez M (2004) Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 56:303–306PubMedCrossRef Pittock SJ, McClelland RL, Mayr WT, Jorgensen NW, Weinshenker BG, Noseworthy J, Rodriguez M (2004) Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 56:303–306PubMedCrossRef
go back to reference Pittock SJ, Rodriguez M (2008) Benign multiple sclerosis: a distinct clinical entity with therapeutic implications. Curr Top Microbiol Immunol 318:1–17PubMedCrossRef Pittock SJ, Rodriguez M (2008) Benign multiple sclerosis: a distinct clinical entity with therapeutic implications. Curr Top Microbiol Immunol 318:1–17PubMedCrossRef
go back to reference Pleasure D, Abramsky O, Silberberg D, Quinn B, Parris J, Saida T (1977) Lipid synthesis by an oligodendroglial fraction in suspension culture. Brain Res 134:377–382PubMedCrossRef Pleasure D, Abramsky O, Silberberg D, Quinn B, Parris J, Saida T (1977) Lipid synthesis by an oligodendroglial fraction in suspension culture. Brain Res 134:377–382PubMedCrossRef
go back to reference Poloni G, Minagar A, Haacke EM, Zivadinov R (2011) Recent developments in imaging of multiple sclerosis. Neurologist 17:185–204PubMedCrossRef Poloni G, Minagar A, Haacke EM, Zivadinov R (2011) Recent developments in imaging of multiple sclerosis. Neurologist 17:185–204PubMedCrossRef
go back to reference Ramagopalan SV, Cukjati M, Cernilec M, DeLuca GC, Dyment DA, Degenhardt A, Sadovnick AD, Serbec VC, Ebers GC, Duquette P (2008a) Mutations in the hemochromatosis gene and the clinical outcome of multiple sclerosis. J Neuroimmunol 203:104–107PubMedCrossRef Ramagopalan SV, Cukjati M, Cernilec M, DeLuca GC, Dyment DA, Degenhardt A, Sadovnick AD, Serbec VC, Ebers GC, Duquette P (2008a) Mutations in the hemochromatosis gene and the clinical outcome of multiple sclerosis. J Neuroimmunol 203:104–107PubMedCrossRef
go back to reference Ramagopalan SV, Deluca GC, Morrison KM, Herrera BM, Dyment DA, Lincoln MR, Orton SM, Chao MJ, Degenhardt A, Pugliatti M, Sadovnick AD, Sotgiu S, Ebers GC (2008b) Analysis of 45 candidate genes for disease modifying activity in multiple sclerosis. J Neurol 255:1215–1219PubMedCrossRef Ramagopalan SV, Deluca GC, Morrison KM, Herrera BM, Dyment DA, Lincoln MR, Orton SM, Chao MJ, Degenhardt A, Pugliatti M, Sadovnick AD, Sotgiu S, Ebers GC (2008b) Analysis of 45 candidate genes for disease modifying activity in multiple sclerosis. J Neurol 255:1215–1219PubMedCrossRef
go back to reference Ramagopalan SV, Ebers GC (2009) Multiple sclerosis: major histocompatibility complexity and antigen presentation. Genome Med 1:105PubMedCrossRef Ramagopalan SV, Ebers GC (2009) Multiple sclerosis: major histocompatibility complexity and antigen presentation. Genome Med 1:105PubMedCrossRef
go back to reference Ramagopalan SV, Knight JC, Ebers GC (2009) Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol 22:219–225PubMedCrossRef Ramagopalan SV, Knight JC, Ebers GC (2009) Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol 22:219–225PubMedCrossRef
go back to reference Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC (2011) Ann Neurol 70:881–886PubMedCrossRef Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC (2011) Ann Neurol 70:881–886PubMedCrossRef
go back to reference Reekers JA, Lee MJ, Belli AM, Barkhof F (2011) Cardiovascular and interventional radiological society of europe commentary on the treatment of chronic cerebrospinal venous insufficiency. Cardiovasc Intervent Radiol 34:1–2PubMedCrossRef Reekers JA, Lee MJ, Belli AM, Barkhof F (2011) Cardiovascular and interventional radiological society of europe commentary on the treatment of chronic cerebrospinal venous insufficiency. Cardiovasc Intervent Radiol 34:1–2PubMedCrossRef
go back to reference Ristić S, Lovrecić L, Brajenović-Milić B, Starcević-Cizmarević N, Jazbec SS, Sepcić J, Kapović M, Peterlin B (2005) Mutations in the hemochromatosis gene (HFE) and multiple sclerosis. Neurosci Lett 383:301–304PubMedCrossRef Ristić S, Lovrecić L, Brajenović-Milić B, Starcević-Cizmarević N, Jazbec SS, Sepcić J, Kapović M, Peterlin B (2005) Mutations in the hemochromatosis gene (HFE) and multiple sclerosis. Neurosci Lett 383:301–304PubMedCrossRef
go back to reference Rodrigue KM, Haacke EM, Raz N (2011) Differential effects of age and history of hypertension on regional brain volumes and iron. Neuroimage 54(2):750–759PubMedCrossRef Rodrigue KM, Haacke EM, Raz N (2011) Differential effects of age and history of hypertension on regional brain volumes and iron. Neuroimage 54(2):750–759PubMedCrossRef
go back to reference Rodriguez M (2009) Have we finally identified an autoimmune demyelinating disease? Ann Neurol 66:572–573PubMedCrossRef Rodriguez M (2009) Have we finally identified an autoimmune demyelinating disease? Ann Neurol 66:572–573PubMedCrossRef
go back to reference Rooney RN, Kotze MJ, de Villiers JN, Hillermann R, Cohen JA (1999) Multiple sclerosis, porphyria-like symptoms, and a history of iron deficiency anaemia in a family of Scottish descent. Am J Med Genet 86:194–196PubMedCrossRef Rooney RN, Kotze MJ, de Villiers JN, Hillermann R, Cohen JA (1999) Multiple sclerosis, porphyria-like symptoms, and a history of iron deficiency anaemia in a family of Scottish descent. Am J Med Genet 86:194–196PubMedCrossRef
go back to reference Rubio JP, Bahlo M, Tubridy N, Stankovich J, Burfoot R, Butzkueven H, Chapman C, Johnson L, Marriott M, Mraz G, Tait B, Wilkinson C, Taylor B, Speed TP, Foote SJ, Kilpatrick TJ (2004) Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis. Hum Genet 114:573–580PubMedCrossRef Rubio JP, Bahlo M, Tubridy N, Stankovich J, Burfoot R, Butzkueven H, Chapman C, Johnson L, Marriott M, Mraz G, Tait B, Wilkinson C, Taylor B, Speed TP, Foote SJ, Kilpatrick TJ (2004) Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis. Hum Genet 114:573–580PubMedCrossRef
go back to reference Schwartz R, Datta S (1989) Autoimmunity and autoimmune diseases. In: Paul W (ed) Fundamental immunology, 2nd edn. Raven, New York, pp 819–866 Schwartz R, Datta S (1989) Autoimmunity and autoimmune diseases. In: Paul W (ed) Fundamental immunology, 2nd edn. Raven, New York, pp 819–866
go back to reference Selzer RR, Rosenblatt DS, Laxova R, Hogan K (2003) Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 349:45–50PubMedCrossRef Selzer RR, Rosenblatt DS, Laxova R, Hogan K (2003) Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 349:45–50PubMedCrossRef
go back to reference Sfagos C, Makis AC, Chaidos A, Hatzimichael EC, Dalamaga A, Kosma K, Bourantas KL (2005) Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients. Mult Scler 11:272–275PubMedCrossRef Sfagos C, Makis AC, Chaidos A, Hatzimichael EC, Dalamaga A, Kosma K, Bourantas KL (2005) Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients. Mult Scler 11:272–275PubMedCrossRef
go back to reference Singh AV, Zamboni P (2009) Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab 29:1867–1878PubMedCrossRef Singh AV, Zamboni P (2009) Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab 29:1867–1878PubMedCrossRef
go back to reference Sriram S, Steiner I (2005) Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol 58:939–945PubMedCrossRef Sriram S, Steiner I (2005) Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol 58:939–945PubMedCrossRef
go back to reference Steiner I, Wirguin I (2000) Multiple sclerosis - in need of a critical reappraisal. Med Hypotheses 54:99–106PubMedCrossRef Steiner I, Wirguin I (2000) Multiple sclerosis - in need of a critical reappraisal. Med Hypotheses 54:99–106PubMedCrossRef
go back to reference Strasser-Fuchs S, Enzinger C, Ropele S, Wallner M, Fazekas F (2008) Clinically benign multiple sclerosis despite large T2 lesion load: can we explain this paradox? Mult Scler 14:205–211PubMedCrossRef Strasser-Fuchs S, Enzinger C, Ropele S, Wallner M, Fazekas F (2008) Clinically benign multiple sclerosis despite large T2 lesion load: can we explain this paradox? Mult Scler 14:205–211PubMedCrossRef
go back to reference Sundström P, Nyström L, Hallmans G (2008) Smoke exposure increases the risk for multiple sclerosis. Eur J Neurol 15:579–583PubMedCrossRef Sundström P, Nyström L, Hallmans G (2008) Smoke exposure increases the risk for multiple sclerosis. Eur J Neurol 15:579–583PubMedCrossRef
go back to reference Sundqvist E, Bäärnhielm M, Alfredsson L, Hillert J, Olsson T, Kockum I (2010) Confirmation of association between multiple sclerosis and CYP27B1. Eur J Hum Genet 18:1349–1352PubMedCrossRef Sundqvist E, Bäärnhielm M, Alfredsson L, Hillert J, Olsson T, Kockum I (2010) Confirmation of association between multiple sclerosis and CYP27B1. Eur J Hum Genet 18:1349–1352PubMedCrossRef
go back to reference Suominen P, Punnonen K, Rajamäki A, Irjala K (1998) Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits. Blood 92:2934–2939PubMed Suominen P, Punnonen K, Rajamäki A, Irjala K (1998) Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits. Blood 92:2934–2939PubMed
go back to reference Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338:1550–1554PubMedCrossRef Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338:1550–1554PubMedCrossRef
go back to reference The International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium 2 (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219CrossRef The International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium 2 (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219CrossRef
go back to reference Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR (2009) Oligodendrocytes and myelination: the role of iron. Glia 57:467–478PubMedCrossRef Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR (2009) Oligodendrocytes and myelination: the role of iron. Glia 57:467–478PubMedCrossRef
go back to reference Todorich B, Zhang X, Connor JR (2011) H-ferritin is the major source of iron for oligodendrocytes. Glia 59:927–935PubMedCrossRef Todorich B, Zhang X, Connor JR (2011) H-ferritin is the major source of iron for oligodendrocytes. Glia 59:927–935PubMedCrossRef
go back to reference Trapp BD (2004) Pathogenesis of multiple sclerosis: the eyes only see what the mind is prepared to comprehend. Ann Neurol 55:455–457PubMedCrossRef Trapp BD (2004) Pathogenesis of multiple sclerosis: the eyes only see what the mind is prepared to comprehend. Ann Neurol 55:455–457PubMedCrossRef
go back to reference Ungley CC, Campbell H (1951) Effect of vitamin B12c in pernicious anemia and subacute combined degeneration of the cord. Br Med J 1(4699):152–157PubMedCrossRef Ungley CC, Campbell H (1951) Effect of vitamin B12c in pernicious anemia and subacute combined degeneration of the cord. Br Med J 1(4699):152–157PubMedCrossRef
go back to reference van Rensburg SJ, Haug PD, Kotze M (2009/2010) Multiple sclerosis. In: Snyman JR, Strydom L (eds) MIMS disease review. MIMS (Avusa Media Limited), Saxonwold, South Africa, pp 369–374 van Rensburg SJ, Haug PD, Kotze M (2009/2010) Multiple sclerosis. In: Snyman JR, Strydom L (eds) MIMS disease review. MIMS (Avusa Media Limited), Saxonwold, South Africa, pp 369–374
go back to reference van Rensburg SJ, Kotze MJ, Hon D, Haug P, Kuyler J, Hendricks M, Botha J, Potocnik FC, Matsha T, Erasmus RT (2006) Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metab Brain Dis 21:121–137PubMedCrossRef van Rensburg SJ, Kotze MJ, Hon D, Haug P, Kuyler J, Hendricks M, Botha J, Potocnik FC, Matsha T, Erasmus RT (2006) Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metab Brain Dis 21:121–137PubMedCrossRef
go back to reference van Rensburg SJ, van Toorn R (2010) The controversy of CCSVI and iron in multiple sclerosis: is ferritin the key? Neurology 75:1581–1582PubMedCrossRef van Rensburg SJ, van Toorn R (2010) The controversy of CCSVI and iron in multiple sclerosis: is ferritin the key? Neurology 75:1581–1582PubMedCrossRef
go back to reference van Rensburg SJ, van Zyl J, Hon D, Daniels W, Hendricks J, Potocnik F, Erasmus R (2004) Biochemical model for inflammation of the brain: the effect of iron and transferrin on monocytes and lipid peroxidation. Metab Brain Dis 19:97–112PubMedCrossRef van Rensburg SJ, van Zyl J, Hon D, Daniels W, Hendricks J, Potocnik F, Erasmus R (2004) Biochemical model for inflammation of the brain: the effect of iron and transferrin on monocytes and lipid peroxidation. Metab Brain Dis 19:97–112PubMedCrossRef
go back to reference van Toorn R, Schoeman JF, Solomons R, Rensburg MA, van Rensburg SJ (2010) Iron status in children with recurrent episodes of tumefactive cerebral demyelination. J Child Neurol 25:1401–1407PubMedCrossRef van Toorn R, Schoeman JF, Solomons R, Rensburg MA, van Rensburg SJ (2010) Iron status in children with recurrent episodes of tumefactive cerebral demyelination. J Child Neurol 25:1401–1407PubMedCrossRef
go back to reference Voet D, Voet JG (2004) Biochemistry. Wiley International Edition, John Wiley, Hoboken Voet D, Voet JG (2004) Biochemistry. Wiley International Edition, John Wiley, Hoboken
go back to reference Walther EU, Hohlfeld R (1999) Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology 53:1622–1627PubMedCrossRef Walther EU, Hohlfeld R (1999) Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology 53:1622–1627PubMedCrossRef
go back to reference Warren SA, Svenson LW, Warren KG (2008) Contribution of incidence to increasing prevalence of multiple sclerosis in Alberta, Canada. Mult Scler 14:872–879PubMedCrossRef Warren SA, Svenson LW, Warren KG (2008) Contribution of incidence to increasing prevalence of multiple sclerosis in Alberta, Canada. Mult Scler 14:872–879PubMedCrossRef
go back to reference Weinstock-Guttman B, Zivadinov R, Qu J, Cookfair D, Duan X, Bang E, Bergsland N, Hussein S, Cherneva M, Willis L, Heininen-Brown M, Ramanathan M (2011) Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 82:189–195PubMedCrossRef Weinstock-Guttman B, Zivadinov R, Qu J, Cookfair D, Duan X, Bang E, Bergsland N, Hussein S, Cherneva M, Willis L, Heininen-Brown M, Ramanathan M (2011) Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 82:189–195PubMedCrossRef
go back to reference Wekerle H, Hohlfeld R (2010) Molecular oracles for multiple sclerosis therapy. Nat Med 16:376–377PubMedCrossRef Wekerle H, Hohlfeld R (2010) Molecular oracles for multiple sclerosis therapy. Nat Med 16:376–377PubMedCrossRef
go back to reference Worthington V, Killestein J, Eikelenboom MJ, Teunissen CE, Barkhof F, Polman CH, Uitdehaag BM, Petzold A (2010) Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurology 75:1617–1622PubMedCrossRef Worthington V, Killestein J, Eikelenboom MJ, Teunissen CE, Barkhof F, Polman CH, Uitdehaag BM, Petzold A (2010) Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurology 75:1617–1622PubMedCrossRef
go back to reference Yang Y, Sun R, Yang H, Zheng F, Gong F (2010) 308 G > A of TNF-α gene promoter decreases the risk of multiple sclerosis: a meta-analysis. Mult Scler 17:658–665PubMedCrossRef Yang Y, Sun R, Yang H, Zheng F, Gong F (2010) 308 G > A of TNF-α gene promoter decreases the risk of multiple sclerosis: a meta-analysis. Mult Scler 17:658–665PubMedCrossRef
go back to reference Zamboni P (2006) The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med 99:589–593PubMedCrossRef Zamboni P (2006) The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med 99:589–593PubMedCrossRef
go back to reference Zhang X, Surguladze N, Slagle-Webb B, Cozzi A, Connor JR (2006) Cellular iron status influences the functional relationship between microglia and oligodendrocytes. Glia 54:795–804PubMedCrossRef Zhang X, Surguladze N, Slagle-Webb B, Cozzi A, Connor JR (2006) Cellular iron status influences the functional relationship between microglia and oligodendrocytes. Glia 54:795–804PubMedCrossRef
Metadata
Title
The conundrum of iron in multiple sclerosis – time for an individualised approach
Authors
Susan J. van Rensburg
Maritha J. Kotze
Ronald van Toorn
Publication date
01-09-2012
Publisher
Springer US
Published in
Metabolic Brain Disease / Issue 3/2012
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI
https://doi.org/10.1007/s11011-012-9290-1

Other articles of this Issue 3/2012

Metabolic Brain Disease 3/2012 Go to the issue

Editorial

Editorial