Multiple sclerosis (MS) is a complex human autoimmune-type disease with a predominantly unknown etiology. Immunologic destruction of myelin basic protein (MBP) throughout the nervous system is the major pathology of multiple sclerosis. This review will attempt to update new information about basic mechanisms and therapeutic management of the disease. The significance of the structure of MBP is discussed with respect to the contribution of such structures to the disease process. A number of MBP peptides that serve as the immunodominant antigens in MS patients have been identified. These peptides have been studied in animal models for their antigenic characteristics and ability to induce disease. Evidence for genetic contributions is reviewed with multigenerational twin studies providing the best evidence for susceptible haplotypes. The role of microorganisms/viruses and environmental agents are discussed as potential etiological factors but are now thought to be of minor importance to the primary causal development of the disease. Of major consideration are immunological mechanisms that contribute to the development of autoimmunity. In particular, antigen expression, cytokine and leukocyte interactions, and regulatory T-cells are discussed. Particular attention is given to regulatory T-cells (Treg), which help balance/modulate other T-cells such as Th1 and Th2 cells, and how such Treg regulate autoimmunity is addressed. The importance of the role of Tregs is exemplified by the demonstration that administration of oral antigens can induce specific Tregs that counteract experimental autoimmune encephalomyelitis in animal models. The significance of animal studies to human multiple sclerosis is discussed. A potential role for natural antibodies and innate immune mechanisms to help provide resistance to disease development is also reviewed. Finally, a variety of therapeutic agents that have been and continue to be utilized for multiple sclerosis is reviewed. Trials with oral antigens, such as glatirmer acetate (copolymer 1) especially in combination with interferon-β, have shown promise. Antibody therapy and bone marrow transplantation are also briefly discussed.
WeinshenkerBC. Epidemiology of multiple sclerosis. Neurol Clin14(2): 291–308, 1996.
2.
ClaudioL, KressY, FactorJ, BrosnanCF. Mechanisms of edema formation in experimental autoimmune encephalomyelitis: the contribution of inflammatory cells. Am J Pathol137: 1033–1045, 1990.
3.
MillerDH, RudgeP, JohnsonG, KendallBE, MacmanusDG, MoseleyIF. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain111: 927–939, 1988.
4.
LiningtonC, BradleyM, LassmannH, BrunnerC, VassK. Augmentation of demyelination in rat allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin oligodendrocyte glycoprotein. Am J Pathol130: 443–454, 1988.
5.
WestlandKW, PollardJD, SanderS, BonnerJG, LiningtonC, McLeodJG. Activated non-neural specific T cells open the blood-brain barrier to circulating antibodies. Brain122: 1283–1291, 1999.
6.
KjimaK, BergerT, LassmannH, Hinze-SelchD, ZhangY, GehrmannJ. Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100B molecule. J Exp Med180: 817–829, 1994.
7.
CarnegiePR. Amino acid sequence of the encephalitogenic basic protein from human myelin. Biochem J123: 57–67, 1971.
8.
EylarEH, BrostoffS, HashimG, CaccamJ, BurnettP. Basic A1 protein of the myelin membrane. The complete amino acid sequence. J Biol Chem246(18): 5770–5784, 1971.
9.
KamholzJ, deFerraF, PuckettC, LazzariniR. Identification of three forms of human myelin basic protein by cDNA cloning. Proc Natl Acad Sci U S A83(13): 4962–4966, 1986.
10.
KarthigasanJ, InouyeH, KirschnerDA. Implications of the sequence similarities between tau and myelin basic protein. Med Hypotheses45(3): 245–250, 1995.
11.
KirschnerDA, InouyeH, GanserAL, MannV. Myelin membrane structure and composition correlated: a phylogenetic study. J Neurochem53(5): 1599–1609, 1989.
12.
Perez-GilJ, KeoughKM. Structural similarities between myelin and hydrophobic surfactant associated proteins: protein motifs for interacting with bilayers. J Theor Biol169: 221–229, 1994.
SteinmanL. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell85: 299–302, 1996.
15.
SedzikJ, KirschnerDA. Is myelin basic protein crystallizable?Neurochem Res17(2): 157–166, 1992.
16.
BoggsJM, RangarajG, KoshyKM, AckerleyC, WoodDD, MoscarelloMA. Highly deiminated isoform of myelin basic protein from multiple sclerosis brain causes fragmentation of lipid vesicles. J Neurosci Res57(4): 529–535, 1999.
17.
KrogsgaardM, WucherpfennigKW, CanellaB, HansenBE, SvejgaardA, PyrdolJ, DitzelH, RaineC, EngbergJ, FuggerL. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the histocompatibility leukocyte antigen (HLA)-DR2-MBP 85-99 complex. J Exp Med191(8): 1395–1412, 2000.
18.
WucherpfennigKW, SetteA, SouthwoodS, OseroffC, MatsuiM, StromingerJL, HaflerDA. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med179: 279–290, 1994.
19.
ScholzC, PattonKT, AndersonDE, FreemanGJ, HaflerDA. Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. J Immunol160: 1532–1538, 1998.
20.
NoseworthyJH. Progress in determining the causes and treatment of multiple sclerosis. Nature399(24):A40–A47, 1999.
21.
BulmanD, EbersG. The geography of multiple sclerosis reflects genetic susceptibility. J Trop Geogr Neurol2: 66–72, 1992.
22.
DymentDA, CaderMZ, WillerCJ, RischN, SadovnickAD, EbersGC. A multigenerational family with multiple sclerosis. Brain125(7): 1474–1482, 2002.
23.
SawcerS, GoodfellowP, CompstonA. The genetic analysis of multiple sclerosis. Trends Genet13: 234–239, 1997.
24.
EbersGC, BulmanDE, SadovnickAD, PatyDW, WarrenS, HaderW, MurrayTJ, SelandTP, DuquetteP, GreyT. A population-based study of multiple sclerosis in twins. N Engl J Med315: 1638–1642, 1986.
25.
MartinR. Genetics of multiple sclerosis—how could disease-associated HLA-types contribute to pathogenesis?J Neural Trans Suppl49: 177–194, 1997.
26.
CompstonA. The genetics of multiple sclerosis. J Neurovirol6(2):S5–S9, 2000.
LaaksonenM, PastinenT, SjoroosM, KuokkanenS, RuutiainenJ, SumelahtiML, ReijonenH, SalonenR, WikstromJ, PaneliusM, PartanenJ, PenttiJ, IlonenJ. HLA class II associated risk and protection against multiple sclerosis—a Finnish family study. J Neuroimmunol122: 140–145, 2002.
29.
SoldanS, BertiR, SalemN, SecchieroP, FlamandL, CalabresiP. Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nat Med3(12): 1394–1397, 1997.
30.
SalvettiM, RistoriG, ButtinelliC, FioriP, FalconeM, BrittonW, AdamsE, PaoneG, GrassoMG, PozzilliC. The immune response to mycobacterial 70-kDa heat shock proteins frequently involves autoreactive T cells and is quantitatively disregulated in multiple sclerosis. J Neuroimmunol65: 143–153, 1996.
31.
ShimojiY, NgV, MatsumuraK, FischettiVA, RambukkanaA. A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion. Proc Natl Acad Sci U S A96(17): 9857–9862, 1999.
32.
MerelliE, BedinR, SolaP, BarozziP, MancardiGL, FicarraG, FranchiniG. Human herpes virus 6 and human herpes virus 8 DNA sequences in brains of multiple sclerosis patients, normal adults and children. J Neurol244(7): 450–454, 1997.
33.
vanNoortJ, van SechelAC, BajramovicJJ, el OuagmiriM, PolmanCH, LassmannH, RavidR. The small heat-shock protein alpha-beta-crystallin as candidate autoantigen in multiple sclerosis. Nature375: 391–394, 1998.
34.
MurrayP, McGavernDB, Xiaoqi LinM, NjengaK, LeibowitzJ, PeaseLR, RodriguezM. Perforin-dependent neurologic injury in a viral model of multiple sclerosis. J Neurosci18: 7306–7314, 1998.
35.
CironeM, CuomoL, ZompettaC, RuggieriS, FratiL, FaggioniA, RagonaG. Human herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and myelin basic protein antigens. J Med Virol68: 268–272, 2002.
36.
MasonD. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today19: 395–404, 1998.
37.
CermelliC, JacobsonS. Viruses and multiple sclerosis. Viral Immunol13(3): 255–267, 2000.
38.
BachJF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med347(12): 911–920, 2002.
39.
RosatiG, AielloI, MannuL. Incidence of multiple sclerosis in the town of Sassari, Sardinia, 1965–1985: evidence for increasing occurrence of the disease. Neurology38: 384–388, 1988.
40.
PoserS, StickelB, KrtschU, BurckhardtD, NordmanB. Increasing incidence of multiple sclerosis in South Lower Saxony, Germany. Neuroepidemiology8: 207–213, 1989.
41.
LeibowitzU, AntonovskyA, MedalieJM, SmithHA, HalpemL, AlterM. Epidemiological study of multiple sclerosis in Israel. II. Multiple sclerosis and level of sanitation. J Neurol Neurosurg Psychiatry29: 60–68, 1966.
42.
WeissST. Eat dirt—the hygiene hypothesis and allergic diseases. N Engl J Med347(12): 930–931, 2002.
43.
Braun-FahrlanderC, RiedlerJ, HerzU, EderW, WaserM, GrizeL, MaischS, CarrD, GerlachF, BufeA, LauenerRP, SchierlR, RenzH, NowakD, von MutiusE. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med347(12): 869–877, 2002.
44.
Tejada-SimonMV, HongJ, RiveraVM, ZhangJ. Skewed autoantibody reactivity to the extracellular domain of myelin oligodendrocyte glycoprotein in multiple sclerosis. Immunol107(4): 403–410, 2002.
45.
Tejada-SimonMV, HongJ, RiveraVM, ZhangJZ. Reactivity pattern and cytokine profile of T cells primed by myelin peptides in multiple sclerosis and healthy individuals. Eur J Immunol31: 907–917, 2001.
46.
Olivares-VillagomezD, WenskyAK, WangY, LafailleJJ. Repertoire requirements of CD4 cells that prevent spontaneous autoimmune encephalomyelitis. J Immunol164: 5499–5507, 2000.
47.
Ben-NunA, EisensteinS, CohenIR. Experimental autoimmune encephalomyelitis (EAE) in genetically resistant rats: PVG rats resist active induction of EAE but are susceptible to and can generate EAE effector T cell lines. J Immunol129: 918–925, 1982.
48.
CohenIR. Regulation of autoimmune disease physiological and therapeutic. Immunol Rev94: 5–12, 1986.
49.
FowellD, MasonD. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes: characterization of the CD4 T cell subsets that inhibits this autoimmune potential. J Exp Med177: 627–639, 1993.
50.
HaflerDA, WeinerHL. Immunologic mechanisms and therapy in multiple sclerosis. Immunol Rev144: 75–86, 1995.
51.
OtaK, MatsuiM, MilfordEL, MackinGA, WeinerHL, HaflerDA. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature346: 183–185, 1990.
52.
HempelK, FreitagA, FreitagA, EndresB, MaiB, LiebaldtG. Unresponsiveness to experimental allergic encephalomyelitis in Lewis rats pretreated with complete Freund's adjuvant. Int Arch Allergy Appl Immunol76: 193–199, 1985.
53.
QinHY, SadelainMW, HitchonC, LauzonJ, SinghB. Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice. J Immunol150: 2072–2080, 1993.
54.
NakamuraK, KitaniA, StroberW. Cell contact-dependent immunosuppression by CD4(+), CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med194: 629–644, 2001.
55.
Al-SabbaghA, MillerA, SantosLM, WeinerHL. Antigen-driven tissue specific suppression following oral tolerance: orally administered myelin basic protein suppresses proteolipid protein-induced experimental autoimmune encephalomyelitis in the SJL mouse. Eur J Immunol24: 2104–2109, 1994.
56.
WeinerHL, FriedmanA, MillerA. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol12: 809–837, 1994.
57.
SoosJM, HobeikaAC, ButfiloskiEJ, SchiffenbauerJ, JohnsonH. Accelerated induction of experimental allergic encephalomyelitis in PL/J mice by a non-V beta 8-specific superantigen. Proc Natl Acad Sci U S A92: 6082–6086, 1995.
58.
SoosJM, SchiffenbauerJ, JohnsonHM. Treatment of PL/J mice with the superantigen, staphylococcal enterotoxin B, prevents development of experimental allergic encephalomyelitis. J Neuroimmunol43: 39–43, 1993.
59.
KimC, SiminovitchKA, OchiA. Reduction of lupus nephritis in MRL/lpr mice by a bacterial superantigen treatment. J Exp Med174: 1431–1437, 1991.
60.
MarieJC, KehrenJ, Trescol-BiemontMC. Mechanism of measles virus-induced suppression of inflammatory immune responses. Immunity14: 69–79, 2001.
61.
ZinkernagelRM. Maternal antibodies, childhood infections, and autoimmune diseases. N Engl J Med345: 1331–1335, 2001.
62.
MacDonaldTT, MonteleoneG. IL-12 and Thl immune responses in human Peyer's patches. Trends Immunol22(5): 244–247, 2001.
FredriksonS, SunJ, XiaoBG, LinkH. Cord blood contains cells secreting antibodies to nervous system components. Clin Exp Immunol84(2): 353–358, 1991.
65.
RodmanTC, ToSE, SullivanJJ, WinstonR. Innate natural antibodies. Primary roles indicated by specific epitopes. Hum Immunol55: 57–64, 1997.
66.
RodmanTC, SullivanJJ, BaiX, WinstonR. The human uniqueness of HIV. Innate immunity and the viral Tat protein. Hum Immunol60: 631–637, 1999.
67.
RodmanTC, LuttonJD, JiangS, Al-KouatlyHB, WinstonR. Circulating natural IgM antibodies and their corresponding human cord blood cell-derived Mabs specifically combat the Tat protein of HIV. Exp Hematol29: 1004–1009, 2001.
68.
WarringtonAE, AsakuraK, BieberAJ, CiricB, Van KeulenV, KaveriSV, KyleRA, PeaseLR, RodriguezM. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci U S A97(12): 6820–6825, 2000.
69.
McFarlandHI, LobitoAA, JohnsonMM, PalardyGR, YeeCSK, JordanEK, FrankJA, TresserN, GenainCP, MuellerJP, MatisLA, LenardoMJ. Effective antigen-specific immunotherapy in the marmoset model of multiple sclerosis. J Immunol166: 2116–2121, 2001.
70.
WeinerHL. Oral tolerance for the treatment of autoimmune diseases. Ann Rev Med48: 341–351, 1997.
71.
HoholMJ, KhourySJ, CookSL. Three-year open protocol continuation study of oral tolerization with myelin antigens in multiple sclerosis and design of Phase III pivotal trial. In: WeinerHL, MayerLF, Eds. Oral Tolerance: Mechanisms and Applications. New York: NY Acad Sci, pp 243–250, 1996.
72.
WeinerHL. Oral tolerance with copolymer 1 for the treatment of multiple sclerosis. Proc Natl Acad Sci U S A96: 3333–3335, 1999.
73.
TeitelbaumD, *ArnonR, SelaM. Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1. Proc Natl Acad Sci U S A96: 3842–3847, 1999.
74.
MillerA, LiderO, WeinerHL. Antigen-driven bystander suppression following oral administration of antigens. J Exp Med174: 791–798, 1991.
75.
AharoniR, TeitelbaumD, *ArnonR, SelaM. Copolymer 1 acts against the immunodominant epitope 82–100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc Natl Acad Sci U S A96: 634–639, 1999.
76.
MaronR, SlavinAJ, HoffmannE, KomagataY, WeinerHL. Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. Int Immunol14(2): 131–138, 2002.
77.
SoosJM, StuveO, YoussefS, BravoM, JohnsonHM, WeinerHL, ZamvilSS. Cutting edge: oral type IFN-τ promotes a Th2 bias and enhances suppression of autoimmune encephalomyelitis by oral glatiramer acetate. J Immunol169: 2231–2235, 2002.
78.
LublinFG, CutterR, ElfontO, KhanR, LisakH, McFarlandH, PanitchJ, NoseworthyS, ReingoldJ, WhitakerJ. A trial to assess the safety of combining therapy with interferon β-1α and glatiramer acetate in patients with relapsing MS. Neurology56(Suppl 3): 41–48, 2001.
79.
SoosJM, JohnsonHM. Interferon tau prospects for clinical use in autoimmune disease. Bio Drugs11: 125–126, 1999.
80.
SoosJM, SubramaniamPS, HobeikaAC, SchiffenbauerJ, JohnsonHM. The IFN pregnancy recognition hormone, IFN-τ, blocks both development and superantigen reactivation of experimental allergic encephalomyelitis without associated toxicity. J Immunol155: 2747–2756, 1995.
81.
SoosJM, MujtabaGM, SubramaniamPS, StreitWJ, JohnsonHM. Oral feeding of interferon τ can prevent acute and chronic relapsing forms of experimental allergic encephalomyelitis. J Neuroimmunol75: 43–51, 1997.
82.
OlekMJ, SmithDJ, CookSL, KhourySJ, WeinerHL. Phase I study of oral recombinant ovine interferon τ in relapsing-remitting multiple sclerosis. Neurology56(Suppl 3):A76–A77, 2001.
83.
SubramanianS, MatejukA, ZamoraA, VandenbarkAV, OffnerH. Oral feeding with ethinyl estradiol suppresses and treats experimental autoimmune encephalomyelitis in SJL mice and inhibits the recruitment of inflammatory cells into the central nervous system. J Immunol170: 1548–1555, 2003.
84.
KumpfelT, HeydariN, HolfeldR. Antegren (natalizumab). A promising new approach to therapy of multiple sclerosis. Nervenarzt73(6): 552–555, 2002.
85.
MillerDH, KhanOA, SheremutaWA, BlumhardtLD, RiceGPA, LibonatiMA, Willmer-HulmeAJ, DaltonCM, MiszkielKA, O'connorPW. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med348(1): 15–23, 2003.
86.
GhoshS, GoldinE, GordonFH, MalchowHA, Rusk-MadsenJ, RutgeertsP, VyhnalekP, ZadorovaZ, PalmerT, DonoghueS. Natalizumab for active Crohn's Disease. N Engl J Med348(1): 24–32, 2003.
87.
OpenshawH. Conference synopsis: hematopoietic stem cell therapy in autoimmune diseases. Bio Blood Marrow Transpl8: 407–411, 2002.
88.
FassasA. Autologous stem cell transplants in treatment of multiple sclerosis: where we stand and future prospects. Int J Hematol76(Suppl 1): 223–225, 2002.
WelteT, ZhangSM, WangT, ZhangZ, HessleinDT, YinZ, KanoA, IwamotoY, LiE, CraftJE, BothwellAM, FikrigE, KoniPA, FlavellRA, FuXY. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A100(4): 1879–1884, 2003.
91.
MadsenLS, AnderssonEC, JanssonL, KrogsgaardM, AndersenCB, EngbergJ, StromingerJL, SevjgaardA, HjorthJP, HolmdahlR, WucherpfennigKW, FuggerL. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nat Genet23: 343–347, 1999.
92.
SorensenPS. The role of intravenous immunoglobulin in the treatment of multiple sclerosis. J Neurol Sci206(2): 123–130, 2003.
93.
BrodSA. Ingested type I interferon: a potential treatment for autoimmunity. J Interferon Cytokine Res22(12): 1153–1166, 2002.
94.
FujinoM, FuneshimaN, KitazawaY, KimuraH, AmemiyaH, SuzukiS, LiXK. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther305(1): 70–77, 2003.
