Onset of multiple sclerosis in childhood occurs in 3-5% of patients. There is limited, but growing knowledge about the underlying pathobiology of pediatric MS. It is crucial to better understand this area in order to address central questions in the field: 1) Can pediatric multiple sclerosis inform us about factors related to disease initiation and propagation? 2) What are the biomarkers of disease course in pediatric multiple sclerosis; 3) Does pediatric multiple sclerosis pathogenesis differ from adult-onset multiple sclerosis; 4) How can we optimize treatment in pediatric demyelinating diseases? 5) Can pediatric multiple sclerosis provide insights into the environmental risk factors for multiple sclerosis in general? Here we review the current knowledge of the pathogenesis of multiple sclerosis in children, and address the five questions raised above.
ChitnisTGlanzBJaffinSHealyB. Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler. 2009;15:627–631.
2.
BoikoAVorobeychikGPatyD. Early onset multiple sclerosis: a longitudinal study. Neurology. 2002;59:1006–1010.
3.
GhezziADeplanoVFaroniJ. Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler. 1997;3:43–46.
4.
SindernEHaasJStarkEWursterU. Early onset MS under the age of 16: clinical and paraclinical features. Acta Neurol Scand. 1992;86:280–284.
5.
BanwellBKennedyJSadovnickD. Incidence of acquired demyelination of the CNS in Canadian children. Neurology. 2009;72:232–239.
6.
PohlDHennemuthIvon KriesRHanefeldF. Paediatric multiple sclerosis and acute disseminated encephalomyelitis in Germany: results of a nationwide survey. Eur J Pediatr. 2007;166:405–412.
7.
Langer-GouldAZhangJLChungJ. Incidence of acquired CNS demyelinating syndromes in a multiethnic cohort of children. Neurology. 2011;77:1143–1148.
8.
BanwellBBar-OrAArnoldDL. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol. 2011;10:436–445.
9.
GormanMPHealyBCPolgar-TurcsanyiMChitnisT. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol. 2009;66:54–59.
10.
YehEAWeinstock-GuttmanBRamanathanM. Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis. Brain. 2009;132(pt 12):3392–3400.
11.
WaubantEChabasDOkudaDT. Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults. Arch Neurol. 2009;66:967–971.
12.
AmatoMPGorettiBGhezziA. Cognitive and psychosocial features of childhood and juvenile MS. Neurology. 2008;70:1891–1897.
13.
MacAllisterWSBelmanALMilazzoM. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology. 2005;64:1422–1425.
14.
RenouxCVukusicSMikaeloffY. Natural history of multiple sclerosis with childhood onset. N Engl J Med. 2007;356:2603–2613.
15.
SimoneILCarraraDTortorellaC. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology. 2002;59:1922–1928.
16.
TrojanoMPaolicelliDBellacosaA. Atypical forms of multiple sclerosis or different phases of a same disease?Neurol Sci. 2004;25(suppl 4): S323–S325.
17.
PrineasJWWrightRG. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest. 1978;38:409–421.
18.
PrineasJWRaineCS. Electron microscopy and immunoperoxidase studies of early multiple sclerosis lesions. Neurology. 1976;26(6 pt 2):29–32.
19.
TrappBDPetersonJRansohoffRM. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338278–285.
20.
LucchinettiCBruckWParisiJ. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47:707–717.
21.
IshizuTOsoegawaMMeiFJ. Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain. 2005;128(pt 5):988–1002.
22.
VishwasMSChitnisTPienaarR. Tract-based analysis of callosal, projection, and association pathways in pediatric patients with multiple sclerosis: a preliminary study. AJNR Am J Neuroradiol. 2010;31:121–128.
23.
KutzelniggALucchinettiCFStadelmannC. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128(pt 11):2705–2712.
24.
KutzelniggAFaber-RodJCBauerJ. Widespread demyelination in the cerebellar cortex in multiple sclerosis. Brain Pathol. 2007;17:38–44.
25.
AbsintaMRoccaMAMoiolaL. Cortical lesions in children with multiple sclerosis. Neurology. 2011;76:910–913.
26.
HowellOWReevesCANicholasR. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011;134(pt 9):2755–2771.
27.
MagliozziRHowellOVoraA. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130(pt 4):1089–1104.
28.
SerafiniBRosicarelliBMagliozziR. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14:164–174.
29.
ItohTShimizuMKitamiK. Primary extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type in the CNS. Neuropathology. 2001;21:174–180.
30.
Rangel-MorenoJHartsonLNavarroC. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest. 2006;116:3183–3194.
31.
SerafiniBRosicarelliBFranciottaD. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007;204:2899–2912.
32.
LassmannHNiedobitekGAloisiFMiddeldorpJM. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue—report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain. 2011;134(pt 9):2772–2786.
33.
AloisiFSerafiniBMagliozziR. Detection of Epstein-Barr virus and B-cell follicles in the multiple sclerosis brain: what you find depends on how and where you look. Brain. 2010;133(pt 12): e157.
34.
WillisSNStadelmannCRodigSJ. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain. 2009;132(pt 12):3318–3328.
35.
AndersonRCConnollyESJrKomotarRJ. Clinicopathological review: tumefactive demyelination in a 12-year-old girl. Neurosurgery. 2005;56:1051–1057; discussion 1051-1057.
36.
DastgirJDiMarioFJJr. Acute tumefactive demyelinating lesions in a pediatric patient with known diagnosis of multiple sclerosis: review of the literature and treatment proposal. J Child Neurol. 2009;24:431–437.
37.
McAdamLCBlaserSIBanwellBL. Pediatric tumefactive demyelination: case series and review of the literature. Pediatr Neurol. 2002;26:18–25.
38.
RivaDChiappariniLPolloB. A case of pediatric tumefactive demyelinating lesion misdiagnosed and treated as glioblastoma. J Child Neurol. 2008;23:944–947.
39.
VanlandinghamMHaniganWVedanarayananVFratkinJ. An uncommon illness with a rare presentation: neurosurgical management of ADEM with tumefactive demyelination in children. Childs Nerv Syst. 2010;26:655–661.
BanwellBKruppLKennedyJ. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol. 2007;6:773–781.
42.
YoungNPWeinshenkerBGParisiJE. Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis. Brain. 133(Pt 2):333–348.
43.
IngleseMSalviFIannucciG. Magnetization transfer and diffusion tensor MR imaging of acute disseminated encephalomyelitis. AJNR Am J Neuroradiol. 2002;23:267–272.
44.
VishwasMSHealyBCPienaarR. Diffusion tensor analysis of pediatric multiple sclerosis and clinically isolated syndromes. Am J Neuroradiol. In press.
45.
PolmanCHReingoldSCEdanG. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.”Ann Neurol. 2005;58:840–846.
46.
FreedmanMSThompsonEJDeisenhammerF. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol. 2005;62:865–870.
47.
TintoreMRoviraABrievaL. Isolated demyelinating syndromes: comparison of CSF oligoclonal bands and different MR imaging criteria to predict conversion to CDMS. Mult Scler. 2001;7:359–363.
48.
GhezziAPozzilliCLiguoriM. Prospective study of multiple sclerosis with early onset. Mult Scler. 2002;8:115–118.
49.
RuggieriMPolizziAPavoneLGrimaldiLM. Multiple sclerosis in children under 6 years of age. Neurology. 1999;53:478–484.
50.
PohlDRostasyKReiberHHanefeldF. CSF characteristics in early-onset multiple sclerosis. Neurology. 2004;63:1966–1967.
51.
HanefeldFBauerHJChristenHJ. Multiple sclerosis in childhood: report of 15 cases. Brain Dev. 1991;13:410–416.
52.
RiikonenR. The role of infection and vaccination in the genesis of optic neuritis and multiple sclerosis in children. Acta Neurol Scand. 1989;80:425–431.
53.
AtzoriMBattistellaPAPeriniP. Clinical and diagnostic aspects of multiple sclerosis and acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study. Mult Scler. 2009;15:363–370.
54.
DaleRCde SousaCChongWK. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain. 2000;123(pt 12):2407–2422.
55.
HynsonJLKornbergAJColemanLT. Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology. 2001;56:1308–1312.
56.
TenembaumSChamolesNFejermanN. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology. 2002;59:1224–1231.
57.
MikaeloffYSuissaSValleeL. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J Pediatr. 2004;144:246–252.
58.
ChabasDNessJBelmanA. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology. 2010;74:399–405.
59.
ChitnisT. The role of CD4 T cells in the pathogenesis of multiple sclerosis. Int Rev Neurobiol. 2007;79:43–72.
60.
Markovic-PleseSCorteseIWandingerKP. CD4+CD28– costimulation-independent T cells in multiple sclerosis. J Clin Invest. 2001;108:1185–1194.
61.
ZhangJMarkovic-PleseSLacetB. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med. 1994;179:973–984.
62.
Bar-OrA. The immunology of multiple sclerosis. Semin Neurol. 2008;28:29–45.
63.
ChitnisTKhourySJ. Cytokine shifts and tolerance in experimental autoimmune encephalomyelitis. Immunol Res. 2003;28:223–239.
64.
MosmannTRCherwinskiHBondMW. Two types of murine helper T cell clone, I: Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–2357.
65.
BalashovKESmithDRKhourySJ. Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. Proc Natl Acad Sci U S A. 1997;94:599–603.
66.
ComabellaMBalashovKIssazadehS. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest. 1998;102:671–678.
67.
BeckJRondotPCatinotL. Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations?Acta Neurol Scand. 1988;78:318–323.
68.
KornTBettelliEOukkaMKuchrooVK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517.
69.
StromnesIMCerrettiLMLiggittD. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat Med. 2008;14:337–342.
70.
LockCHermansGPedottiR. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8:500–508.
71.
MatuseviciusDKivisakkPHeB. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999;5:101–104.
72.
GraberJJAllieSRMullenKM. Interleukin-17 in transverse myelitis and multiple sclerosis. J Neuroimmunol. 2008;196:124–132.
73.
FrisulloGNocitiVIorioR. IL17 and IFNgamma production by peripheral blood mononuclear cells from clinically isolated syndrome to secondary progressive multiple sclerosis. Cytokine. 2008;44:22–25.
74.
Brucklacher-WaldertVStuernerKKolsterM. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain. 2009;132(pt 12):3329–3341.
75.
IferganIKebirHBernardM. The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells. Brain. 2008;131(pt 3):785–799.
76.
KebirHKreymborgKIferganI. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13:1173–1175.
77.
VigliettaVBaecher-AllanCWeinerHLHaflerDA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971–979.
78.
CrucianBDunnePFriedmanH. Alterations in levels of CD28–/CD8+ suppressor cell precursor and CD45RO+/CD4+ memory T lymphocytes in the peripheral blood of multiple sclerosis patients. Clin Diagn Lab Immunol. 1995;2:249–252.
79.
KaraszewskiJWRederATAnlarB. Increased lymphocyte beta-adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28– suppressor cell. Ann Neurol. 1991;30:42–47.
80.
CorrealeJGilmoreWMcMillanM. Patterns of cytokine secretion by autoreactive proteolipid protein-specific T cell clones during the course of multiple sclerosis. J Immunol. 1995;154:2959–2968.
81.
PelfreyCMRudickRACotleurAC. Quantification of self-recognition in multiple sclerosis by single-cell analysis of cytokine production. J Immunol. 2000;165:1641–1651.
82.
FukauraHKentSCPietrusewiczMJ. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest. 1996;98:70–77.
83.
ChitnisTImitolaJKhourySJ. Therapeutic strategies to prevent neurodegeneration and promote regeneration in multiple sclerosis. Curr Drug Targets Immune Endocr Metabol Disord. 2005;5:11–26.
84.
WeinerHL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease?Ann Neurol. 2009;65:239–248.
85.
TaubDDLongoDL. Insights into thymic aging and regeneration. Immunol Rev. 2005;205:72–93.
86.
CossarizzaAOrtolaniCPaganelliR. CD45 isoforms expression on CD4+ and CD8+ T cells throughout life, from newborns to centenarians: implications for T cell memory. Mech Ageing Dev. 1996;86:173–195.
87.
CastleSCUyemuraKCrawfordW. Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12. Exp Gerontol. 1999;34:243–252.
88.
WekslerME. Changes in the B-cell repertoire with age. Vaccine. 2000;18:1624–1628.
89.
VallejoAN. Age-dependent alterations of the T cell repertoire and functional diversity of T cells of the aged. Immunol Res. 2006;36:221–228.
90.
GoronzyJJLeeWWWeyandCM. Aging and T-cell diversity. Exp Gerontol. 2007;42:400–406.
91.
GorczynskiRMKennedyMMacRaeS.Altered lymphocyte recognition repertoire during ageing, III: Changes in MHC restriction patterns in parental T lymphocytes and diminution in T suppressor function. Immunology. 1984;52:611–620.
92.
FariaAMde MoraesSMde FreitasLH. Variation rhythms of lymphocyte subsets during healthy aging. Neuroimmunomodulation. 2008;15:365–379.
93.
SimoneRZiccaASaverinoD. The frequency of regulatory CD3+CD8+CD28– CD25+ T lymphocytes in human peripheral blood increases with age. J Leukoc Biol. 2008;84:1454–1461.
94.
ChitnisTKhourySJ.Role of costimulatory pathways in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. J Allergy Clin Immunol. 2003;112:837–849; quiz 850.
95.
CostantinoCMBaecher-AllanCHaflerDA. Multiple sclerosis and regulatory T cells. J Clin Immunol. 2008;28:697–706.
96.
BanwellBBar-OrACheungR. Abnormal T-cell reactivities in childhood inflammatory demyelinating disease and type 1 diabetes. Ann Neurol. 2008;63:98–111.
97.
CorrealeJTenembaumSN. Myelin basic protein and myelin oligodendrocyte glycoprotein T-cell repertoire in childhood and juvenile multiple sclerosis. Mult Scler. 2006;12:412–420.
FrohmanEMRackeMKRaineCS. Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med. 2006;354:942–955.
100.
OwensGPBennettJLLassmannH. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann Neurol. 2009;65:639–649.
101.
O'ConnorKCChitnisTGriffinDE. Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions. J Neuroimmunol. 2003;136:140–148.
102.
O'ConnorKCMcLaughlinKADe JagerPL. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med. 2007;13:211–217.
103.
CrossAHTrotterJLLyonsJ. B cells and antibodies in CNS demyelinating disease. J Neuroimmunol. 2001;112:1–14.
104.
AntelJBar-OrA. Roles of immunoglobulins and B cells in multiple sclerosis: from pathogenesis to treatment. J Neuroimmunol. 2006;180:3–8.
105.
McLaughlinKAChitnisTNewcombeJ. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J Immunol. 2009;183:4067–4076.
106.
BrilotFDaleRCSelterRC. Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann Neurol. 2009;66:833–842.
107.
Di PauliFMaderSRostasyK. Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases. Clin Immunol.2011;138:247–254.
108.
ProbstelAKDornmairKBittnerR. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology. 2011;77:580–588.
109.
BettelliEBaetenDJagerA. Myelin oligodendrocyte glycoprotein-specific T and B cells cooperate to induce a Devic-like disease in mice. J Clin Invest. 2006;116:2393–2402.
110.
KrishnamoorthyGLassmannHWekerleHHolzA. Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J Clin Invest. 2006;116:2385–2392.
111.
MoscarelloMAMastronardiFGWoodDD. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem Res. 2007;32:251–256.
HauserSLWaubantEArnoldDL. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676–688.
114.
CrossAHStarkJLLauberJ. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2006;180:63–70.
115.
DuddyMNiinoMAdatiaF. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol. 2007;178:6092–6099.
116.
YouinouPJaminCPersJO. B lymphocytes are required for development and treatment of autoimmune diseases. Ann N YAcad Sci. 2005;1050:19–33.
117.
RovarisMGalloAFaliniA. Axonal injury and overall tissue loss are not related in primary progressive multiple sclerosis. Arch Neurol. 2005;62:898–902.
118.
RostasyKWithutEPohlD. Tau, phospho-tau, and S-100B in the cerebrospinal fluid of children with multiple sclerosis. J Child Neurol. 2005;20:822–825.
119.
DhaunchakASBeckerCSchulmanH. Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis. Ann Neurol. 2012;71:601–613.
120.
StewartGJMcLeodJGBastenABashirHV. HLA family studies and multiple sclerosis: a common gene, dominantly expressed. Hum Immunol. 1981;3:13–29.
121.
HainesJLTerwedowHABurgessK. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. the Multiple Sclerosis Genetics Group. Hum Mol Genet. 1998;7:1229–1234.
122.
SawcerSGoodfellowPN. Inheritance of susceptibility to multiple sclerosis. Curr Opin Immunol. 1998;10:697–703.
123.
HaflerDACompstonASawcerS. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007;357:851–862.
124.
GormanMPHealyBCPolgar-TurcsanyiMChitnisT. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol. 2009;66:54–59.
125.
KennedyJO'ConnorPSadovnickAD. Age at onset of multiple sclerosis may be influenced by place of residence during childhood rather than ancestry. Neuroepidemiology. 2006;26:162–167.
126.
DisantoGMagalhaesSHandelAE. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology. 2011;76:781–786.
Bar-OrASmithD. Epidemiology of multiple sclerosis. In: BatchelorTand CudcowiczM, eds, Principles of Neuroepidemiology. Boston, MA: Butterworth–Heinemann; 2001.
131.
GaleCRMartynCN. Migrant studies in multiple sclerosis. Prog Neurobiol. 1995;47:425–448.
132.
AlotaibiSKennedyJTellierR. Epstein-Barr virus in pediatric multiple sclerosis. J Am Med Assoc. 2004;291:1875–1879.
133.
AscherioAMungerK. Epidemiology of multiple sclerosis: from risk factors to prevention. Semin Neurol. 2008;28:17–28.
134.
LunemannJDHuppkePRobertsS. Broadened and elevated humoral immune response to EBNA1 in pediatric multiple sclerosis. Neurology. 2008;71:1033–1035.
135.
PohlDKroneBRostasyK. High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. Neurology. 2006;67:2063–2065.
136.
WaubantEMowryEMKruppL. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology. 2011;76:1989–1995.
137.
van der MeiIAPonsonbyALDwyerT. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ. 2003;327:316.
138.
MungerKLLevinLIHollisBW. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. J Am Med Assoc. 2006;296:2832–2838.
139.
CantornaMTHayesCE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci U S A. 1996;93:7861–7864.
140.
GarcionESindjiLNatafS. Treatment of experimental autoimmune encephalomyelitis in rat by 1,25-dihydroxyvitamin D3 leads to early effects within the central nervous system. Acta Neuropathol. 2003;105:438–448.
141.
MattnerFSmiroldoSGalbiatiF. Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D3. Eur J Immunol. 2000;30:498–508.
142.
MeehanTFDeLucaHF. The vitamin D receptor is necessary for 1alpha,25-dihydroxyvitamin D3 to suppress experimental autoimmune encephalomyelitis in mice. Arch Biochem Biophys. 2002;408:200–204.
143.
MeehanTFDeLucaHF. CD8+ T cells are not necessary for 1 alpha,25-dihydroxyvitamin D3 to suppress experimental autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S Am. 2002;99:5557–5560.
144.
NasholdFEHoagKAGovermanJHayesCE. Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D3 prevention of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2001;119:16–29.
145.
NasholdFEMillerDJ, Hayes CE. 1,25-Dihydroxyvitamin D3 treatment decreases macrophage accumulation in the CNS of mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2000;103:171–179.
146.
NatafSGarcionE, Darcy F, et al. 1,25 Dihydroxyvitamin D3 exerts regional effects in the central nervous system during experimental allergic encephalomyelitis. J Neuropathol Exp Neurol. 1996;55:904–914.
147.
SpachKMHayesCE. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J Immunol. 2005;175:4119–4126.
148.
PennaGAmuchasteguiS, Giarratana N, et al. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol. 2007;178:145–153.
149.
AdoriniLPennaGGiarratanaN. Dendritic cells as key targets for immunomodulation by vitamin D receptor ligands. J Steroid Biochem Mol Biol. 2004;89-90:437–441.
150.
PennaG, Adorini L. 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 2000;164:2405–2411.
151.
GriffinMDLutzWPhanVA. Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci U S A. 2001;98:6800–6805.
152.
AlroyITowersTLFreedmanLP. Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol. 1995;15:5789–5799.
153.
MullerK, Bendtzen K. 1,25-Dihydroxyvitamin D3 as a natural regulator of human immune functions. J Invest Dermatol Symp Proc. 1996;1:68–71.
154.
MuthianGRaikwarHPRajasinghJBrightJJ.1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res. 2006;83:1299–1309.
155.
Cohen-LahavMDouvdevaniAChaimovitzCShanyS. The anti-inflammatory activity of 1,25-dihydroxyvitamin D3 in macrophages. J Steroid Biochem Mol Biol. 2007;103:558–562.
156.
KoliK, Keski-Oja J. 1alpha,25-dihydroxyvitamin D3 and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells. Cell Growth Differ. 2000;11:221–229.
157.
RahmanAHersheySAhmedS. Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice. J Steroid Biochem Mol Biol. 2007;103:416–419.
158.
PedersenLBNasholdFESpachKM, Hayes CE. 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. J Neurosci Res. 2007;85:2480–2490.
159.
BranisteanuDDWaerMSobisH. Prevention of murine experimental allergic encephalomyelitis: cooperative effects of cyclosporine and 1 alpha, 25-(OH)2D3. J Neuroimmunol. 1995;61:151–160.
160.
GoldbergPFlemingMCPicardEH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses. 1986;21:193–200.
161.
WingerchukDMLesauxJRiceGP. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76:1294–1296.
162.
NiinoMFukazawaTYabeI. Vitamin D receptor gene polymorphism in multiple sclerosis and the association with HLA class II alleles. J Neurologic Sci. 2000;177:65–71.
163.
TajouriLOvcaricMCurtainR. Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population. J Neurogenet. 2005;19:25–38.
164.
PartridgeJMWeatherbySJWoolmoreJA. Susceptibility and outcome in MS: associations with polymorphisms in pigmentation-related genes. Neurology. 2004;62:2323–2325.
165.
DickinsonJLPereraDIvan der MeiAF. Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 vitamin D receptor variant in this interaction. Mult Scler. 2009;15:563–570.
166.
RamagopalanSVMaugeriNJHandunnetthiL. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 2009;5: e1000369.
167.
MowryEMKruppLBMilazzoM. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol.2010;67:618–624.
168.
MikaeloffYCaridadeGTardieuMSuissaS. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007;130(pt 10):2589–2595.
169.
MungerKLChitnisTAscherioA. Body size and risk of MS in two cohorts of US women. Neurology. 2009;73:1543–1550.
170.
ChitnisTTenembaumSBanwellB. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18:116–127.
