1Ewing, C & Bernard, CC (1998) Insights into the aetiology and pathogenesis of multiple sclerosis. Immunol Cell Biol. 76, 47–54.
2Noseworthy, JH (1999) Progress in determining the causes and treatment of multiple sclerosis. Nature 399, Suppl. 24, A40–A46.
3Martino, G & Hartung, H-P (1999) Immunopathogenesis of multiple sclerosis: the role of T cells. Curr Opin Neurol 12, 309–321.
4Hafler, DA (2004) Multiple Sclerosis. J. Clin Invest. 113, 788–794.
5Fredrikson, S, Soderstrom, M, Hillert, J, et al. (1994) Multiple sclerosis: occurrence of myelin basic protein peptide-reactive T cells in healthy family members. Acta Neurol Scand 89, 184–189.
6Kerlero de Rosbo, N, Milo, R, Lees, MB, et al. (1993) Reactivity to myelin antigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. J Clin Invest 92, 2602–8.
7Kerlero de Rosbo, N, Hoffman, M, Mendel, I, et al. (1997) Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions. Eur J Immunol 27, 3059–69.
8Chou, YK, Bourdette, DN, Offner, H, et al. (1992) Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. J Neuroimmunol 38, 105–114.
9Ota, K, Matsui, M, Milford, EL, et al. (1990) T cell recognition of an immunodominant myelin basic epitope in multiple sclerosis. Nature 346, 183–187.
10Burns, J, Bartholomew, B & Lobo, S (1999) Isolation of myelin basic protein-specific T cells predominantly from the memory T-cell compartment in multiple sclerosis. Ann Neurol 45, 33–39.
11Zhang, J, Markovic-Plese, S, Lacet, B, et al. (1994) 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 179, 973–984.
12Tejada-Simon, MV, Hong, J, Rivera, VM, et al. (2001) Reactivity pattern and cytokine profile of T cells primed by myelin peptides in multiple sclerosis and healthy individuals. Eur J Immunol 31, 907–917.
13Bielekova, B, Goodwin, B, Richert, N, Cortese, I, Kondo, T, Afshar, G, Gran, B, Eaton, J, et al. (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Medicine 6, 1167–1175.
14Navikas, V & Link, H (1996) Review: cytokines and the pathogenesis of multiple sclerosis. J Neurosci Res 45, 322–333.
15McCarron, RM, Wang, L, Racke, MK, et al. (1993) Cytokine-regulated adhesion between encephalitogenic T lymphocytes and cerebrovascular endothelial cells. J Neuroimmunol 43, 23–30.
16Selmaj, K, Raine, CS, Farooq, M, et al. (1991) Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J Immunol 147, 1522–1529.
17Vartanian, T, Li, Y, Zhao, M, et al. (1995) Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis. Mol Med 1, 732–743.
18Kuroda, Y & Shimamoto, Y (1991) Human tumor necrosis factor-alpha augments experimental allergic encephalomyelitis in rats. J Neuroimmunol 34, 159–164.
19Issazadeh, S, Lorentzen, JC, Mustafa, MI, et al. (1996) Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-beta. J Neuroimmunol 69, 103–115.
20Ruddle, NH, Bergman, CM, McGrath, KM, et al. (1990) An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 172, 1193–1200.
21Cannella, B & Raine, CS (1995) The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 37, 424–435.
22Merrill, JE, Strom, SR, Ellison, GW, et al. (1989) In vitro study of mediators of inflammation in multiple sclerosis. J Clin Immunol 9, 84–96.
23Maimone, D, Reder, AT & Gregory, S (1993) T cell lymphokine-induced secretion of cytokines by monocytes from patients with multiple sclerosis. Cell Immunol 146, 96–106.
24Hirsch, RL, Panitch, HS & Johnson, KP (1985) Lymphocytes from multiple sclerosis patients produce elevated levels of gamma interferon in vitro. J Clin Immunol 5, 386–389.
25Hollifield, RD, Harbige, LS, Pham-Dinh, D & Sharief, M (2003) Evidence for cytokine dysregulation in multiple sclerosis: peripheral blood mononuclear cell production of pro-inflammatory and anti-inflammatory cytokines during relapse and remission. Autoimmunity 36, 133–141.
26Imamura, K, Suzumura, A, Hayashi, F, et al. (1993) Cytokine production by peripheral blood monocytes/macrophages in multiple sclerosis patients. Acta Neurol Scand 87, 281–285.
27Philippe, J, Debruyne, J, Leroux-Roels, G, et al. (1996) In vitro TNF-alpha, IL-2 and IFN-gamma production as markers of relapses in multiple sclerosis. Clin Neurol Neurosurg 98, 286–290.
28Bertolotto, A, Malucchi, S, Capobianco, M, et al. (1999) Quantitative PCR reveals increased levels of tumor necrosis factor-alpha mRNA in peripheral blood mononuclear cells of multiple sclerosis patients during relapses. J Interferon Cytokine Res 19, 575–581.
29Beck, J, Rondot, P, Catinot, L, et al. (1988) Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 78, 318–323.
30Sharief, MK & Hentges, R (1991) Association between tumour necrosis factor-alpha and disease progression in patients with multiple sclerosis. N. Engl. J. Med. 325, 467–472.
31Sharief, MK & Thompson, EJ (1992) In vivo relationship of tumor necrosis factor-alpha to blood-brain barrier damage in patients with active multiple sclerosis. J Neuroimmunol 38, 27–33.
32Rieckmann, P, Albrecht, M, Kitze, B, et al. (1994) Cytokine mRNA levels in mononuclear blood cells from patients with multiple sclerosis. Neurology 44, 1523–1526.
33Lu, CZ, Jensen, MA & Arnason, BG (1993) Interferon gamma- and interleukin-4-secreting cells in multiple sclerosis. J Neuroimmunol 46, 123–128.
34Bertolotto, A, Capobianco, M, Malucchi, S, et al. (1999) Transforming growth factor beta1 (TGFbeta1) mRNA level correlates with magnetic resonance imaging disease activity in multiple sclerosis patients. Neurosci Lett 263, 21–4.
35Mokhtarian, F, Shi, Y, Shirazian, D, et al. (1994) Defective production of anti-inflammatory cytokine, TGF-beta by T cell lines of patients with active multiple sclerosis. J Immunol 152, 6003–6010.
36De Stefano, N, Narayanan, S, Francis, GS, Arnaoutelis, R, Tartaglia, MC, Antel, JP, Matthews, PM & Arnold, DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol. 58, 65–70.
37Bjartmar, C, Wujek, JR & Trapp, BD (2003) Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J. Neuro. Sci. 206, 165–171.
38Lassmann, H, Bruck, W & Lucchinettii, C (2001) Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends in Molecular Medicine. 7, 115–121.
39Matute, C & Perez-Cerda, F (2005) Multiple sclerosis: novel perspectives on newly forming lesions. Trends in Neurosciences 28, 173–175.
40Swank, RL (1950) Multiple sclerosis: a correlation of its incidence with dietary fat. Am. J. Med. Sci. 220, 421–430.
41Alter, M, Yamoor, M & Harshe, M (1974) Multiple sclerosis and nutrition. Arch. Neurol. 31, 267–272.
42Wolfgram, F (1975) Similar geographical distribution of multiple sclerosis and cancer of the colon. Acta. Neurol. Scandinav. 52, 294–302.
43Agranoff, BW & Goldberg, D (1974) Diet and the geographical distribution of multiple sclerosis. Lancet, 1061–1066.
44Ghadirian, P, Jain, M, Ducic, S, et al. (1998) Nutritional factors in the aetiology of multiple sclerosis: a case-control study in Montreal, Canada. Int J Epidemiol. 27, 845–852.
45Murrell, TGC, Harbige, LS & Robinson, IC (1991) A review of the aetiology of multiple sclerosis: an ecological approach. Ann Hum Biol. 18, 95–112.
46Malosse, D, Perron, H, Sasco, A & Seigneurin, JM (1992) Correlation between milk and dairy product consumption and multiple sclerosis prevalence: a worldwide study. Neuroepidemiology 11, 304–312.
47Esparza, ML, Sasaki, S & Kesteloot, H (1995) Nutrition, latitude, and multiple sclerosis mortality: an ecologic study. Am. J. Epidemiol. 142, 733–737.
48Zhang, SM, Willet, WC, Hernan, MA, Olek, MJ & Ascherio, A (2000) Dietary fat in relation to risk of multiple sclerosis among two large cohorts of women. Am J Epidemiol 152, 1056–1064.
49Baker, RWR, Thompson, RHS & Zilkha, KJ (1964) Serum fatty acids in multiple sclerosis. J Neuro Neurosurg Psychiatry 27, 408–414.
50Sanders, H, Thompson, RH, Wright, HP & Zilkha, KJ (1968) Further studies on platelet adhesiveness and serum cholesteryl linoleate levels in multiple sclerosis. J. Neurol. Neurosurg. Psychiat. 31, 321–325.
51Gul, S, Smith, AD, Thompson, RHS, et al. (1970) Fatty acid composition of phospholipids from platelets and erythrocytes in multiple sclerosis. J Neurol Neurosurg Psychiat 33, 506–510.
52Thompson, RHS (1973) Fatty acid metabolism in multiple sclerosis. Biochemical Society Symposium 35, 103–111.
53Thompson, RHS (1975) Unsaturated fatty acids in multiple sclerosis. In Multiple Sclerosis Resaerch, pp. 184–193 [Davison, AN, Humphrey, JH, Liversedge, AL, McDonald, WI and Porterfield, JS, editors]. USA, Elsevier: North Holland.
54Tsang, WM, Belin, J, Monro, JA, Smith, AD, Thompson, RHS & Zilkha, KJ (1976) Relationship between plasma and lymphocyte linoleate in multiple sclerosis. J Neurol Neurosurg Psychiatry 39, 767–771.
55Homa, ST, Belin, J, Smith, AD, et al. (1980) Levels of linoleate and arachidonate in red blood cells of healthy individuals and patients with multiple sclerosis. J Neurol Neurosurg Psychiat 43, 106–110.
56Neu, IS (1983) Essential fatty acids in the serum and cerebrospinal fluid of multiple sclerosis patients. Acta. Neurol. Scand. 67, 151–163.
57Cherayil, GD (1984) Sialic acid and fatty acid concentrations in lymphocytes, red blood cells, and plasma from patients with multiple sclerosis. J Neuro Sci. 63, 1–10.
58Fisher, M, Johnson, MH, Natale, AM, et al. (1987) Linoleic acid levels in white blood cells, platelets and serum of multiple sclerosis patients. Acta Neurol Scand 76, 241–245.
59Navarro, X & Segura, R (1989) Red blood cell fatty acids in multiple sclerosis. Acta Neurol Scand 79, 32–37.
60Holman, RT, Johnson, SB & Kokmen, E (1989) Deficiencies of polyunsaturated fatty acids and replacement by nonessential fatty acids in plasma lipids in multiple sclerosis. Proc. Natl. Acad. Sci. USA. 86, 4720–4724.
61Shukla, VKS & Clausen, J (1978) Linoleate and fatty acid patterns of serum lipids in multiple sclerosis. Acta. Neurol. Scandinav 57, 270–274.
62Yoshida, M, Takase, S, Itahara, K & Nakanishi, T (1983) Linoleate and fatty acid compositions in the serum lipids of Japanese patients with multiple sclerosis. Acta Neurol Scand 68, 362–364.
63Heipertz, R, Klauke, W, Pilz, H & Ritter, G (1977) Serum fatty acids in multiple sclerosis. J. Neurology 214, 153–157.
64Nightingale, S, Woo, E, Smith, AD, et al. (1990) Red blood cell and adipose tissue fatty acids in mild inactive multiple sclerosis. Acta Neurol Scand 82, 43–50.
65Love, WC, Cashell, A, Reynolds, M & Callaghan, N (1974) Linoleate and fatty acid patterns of serum lipids in multiple sclerosis and other diseases. Br Med J 3, 18–21.
66Jones, R & Harbige, LS (1987) Erythrocytes in multiple sclerosis: effect of increased intake of essential fatty acids on phosphoglycerides and electrophoretic mobility. In Multiple Sclerosis, Immunological, Diagnostic and Therapeutic Aspects, pp. 201–209 [Clifford Rose, F and Jones, R, editors]. London: John Libbey & Co Ltd.
67Harbige, LS, Crawford, MA, Jones, R, Preece, AW & Forti, A (1986) Dietary intervention studies on the phosphoglyceride fatty acids and electrophoretic mobility of erythrocytes in multiple sclerosis. Prog. Lipid Res 25, 243–248.
68Homa, ST, Conroy, DM, Belin, J, Smith, AD, Monro, JA & Zilkha, KJ (1981) Fatty acid patterns of red blood cell phospholipids in patients with multiple sclerosis. Lancet, 474.
69Nordvik, I, Myhr, K-M, Nyland, H & Bjerve, KS (2000) Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta. Neurol Scand 102, 143–149.
70Field, EJ & Joyce, G (1983) Multiple sclerosis: effect of gamma-linolenate administration upon membranes and the need for extended clinical trials of unsaturated fatty acids. Eur. Neurol. 22, 78–83.
71Field, EJ, Joyce, G & Smith, BM (1977) Erythrocyte-UFA (Eufa) mobility test for pathogenesis and handling of the disease. J Neurol 214, 113–127.
72Harbige, LS (2003) Fatty acids, the immune response, and autoimmunity: a question of n-6 essentiality and the balance between n-6 and n-3. Lipids 38, 323–341.
73Meade, CJ, Mertin, J, Sheena, J & Hunt, R (1978) Reduction by linoleic acid of the severity of experimental allergic encephalomyelitis in the guinea-pig. J Neuro Sci 35, 291–308.
74Mertin, J & Stackpoole, A (1978) Suppression by essential fatty acids of experimental allergic encephalomyelitis is abolished by indomethacin. Prostaglandins and Medicine 1, 283–291.
75Harbige, LS, Yeatman, N, Amor, S & Crawford, MA (1995) Prevention of experimental autoimmune encephalomyelitis in Lewis rats by a novel source of γ-linolenic acid. Br J Nutr 74, 701–715.
76Harbige, LS, Layward, L, Morris-Downes, MM, et al. (2000) The protective effects of omega-6 fatty acids in experimental autoimmune encephalomyelitis (EAE) in relation to transforming growth factor-beta 1 (TGF-beta1) up-regulation and increased prostaglandin E2 (PGE2) production. Clin Exp Immunol 122, 445–452.
77Adda, DH, Beraud, E & Depieds, R (1977) Evidence for suppressor cells in Lewis rats' experimental allergic encephalomyelitis. Eur J Immunol 7, 620–623.
78Karpus, WJ & Swanborg, RH (1991) CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-β. J Immunol 146, 1163–1168.
79Rack, MK, Sriram, S, Calrlini, J, Cannella, B, Raine, CS & McFarlin, DE (1993) Long-term treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-β2. J Neuroimmunol 46, 175–183.
80Santambrogio, L, Hochwald, GM, Saxena, B, Leu, CH, Martz, JE, Carlino, JA, Ruddle, NH, Palladino, MA, Gold, LI & Thorbecke, GJ (1993) Studies on the mechanisms by which Transforming Growth Factor-β protects against allergic encephalomyelitis. J Immunol 151, 1116–1127.
81Ovadia, H & Paterson, PY (1982) Effect of indomethacin treatment upon actively-induced and transferred experimental allergic encephalomyelitis (EAE) in Lewis rats. Clin Exp Immunol 49, 386–392.
82Liblau, RS, Singer, SM & McDevitt, (1995) Th1 and Th2 CD4+T cells in the pathogenesis of organ-specific autoimmune diseases. Immunology Today 16, 34–38.
83Khoury, SJ, Hancock, WW & Weiner, HL (1992) Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor β, interleukin 4, and prostaglandin E expression in the brain. J Exp Med 176, 1355–1364.
84Bates, D, Fawcett, PRW, Shaw, DA & Weightman, D (1978) Polyunsaturated fatty acids in the treatment of acute remitting multiple sclerosis. Br Med J. 2, 1390–1391.
85Millar, JHD, Zilkha, KJ, Langman, MJS, Payling-Wright, H, et al. (1973) Double-blind trial of linoleate supplementation of the diet in multiple sclerosis. Br Med J 1, 765–768.
86Paty, DW, Cousin, HK, Read, S & Adlakha, K (1978) Linoleic acid in multiple sclerosis: failure to show any therapeutic benefit. Acta Neuro Scand 58, 53–58.
87Dworkin, RH, Bates, D, Millar, JHD, et al. (1984) Linoleic acid and multiple sclerosis: a reanalysis of three double blind trials. Neurology 34, 1441–1445.
88Bates, D, Cartlidge, NEF, French, JM, et al. (1989) A double-blind controlled trial of long chain n-3 polyunsaturated fatty acids in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry 52, 18–22.
89Swank, RL (1970) Multiple sclerosis: twenty years on a low fat diet. Arch. Neurol. 23, 460–474.
90Fitzgerald, G, Harbige, LS, Forti, A & Crawford, MA (1987) The effect of nutritional counselling on diet and plasma EFA status in multiple sclerosis patients over 3 years. Numan Nutrition: Applied Nutrition, 41A, 297–310.
91Swank, RL & Grimsgaard, A (1988) Multiple sclerosis: the lipid relationship. Am. J. Clin. Nutr 48, 1387–1393.
92Swank, RL & Dugan, BB (1990) Effect of low saturated fat diet in early and late cases of multiple sclerosis. Lancet, 336, 37–39.
93Harbige, LS, Jones, R, Jenkins, R, Fitzgerald, G, Forti, A & Budowski, P (1990) Nutritional management in multiple sclerosis with reference to experimental models. Ups J Med Sci 48, 189–207.
94Harbige, LS, Hollifield, RD, Pinto, E, Xiang, M, Leach, M & Sharief, MK (2007) Polyunsaturated fatty acids (n-6) in the treatment and pathogenesis of multiple sclerosis: ii results of a randomised, double blind, placebo controlled trial for. Lancet.
95Neuringer, M, Anderson, GJ & Conner, WE (1988) The essentiality of n-3 fatty acids for the development and function of the retina and brain. Ann. Rev. Nutr. 8, 517–541.
96Birch, EE, Garfield, S, Castaneda, Y, Hughbanks-Wheaton, D, Uauy, R & Hoffman, D (2007) Visual acuity and cognitive outcomes at 4 years of age in a double-blind, randomized trial of long-chain polyunsaturated fatty acid-supplemented infant formula. Early. Hum. Dev. 83, 279–284.
97Martinez, M, Vazquez, E, Garcia-Silva, MT, et al. (2000) Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders. Am. J. Clin. Nutr 71, Suppl, 376S–85S.
98Crawford, MA, Costeloe, K, Ghebremeskel, K, et al. (1997) Are deficits of arachidonic and docosahexaenoic acids responsible for the neural and vascular complications of preterm babies. Am. J. Clin. Nutr. 66, Suppl, 1032S–41S.
99Xiang, M, Alfven, G, Blennow, M, Trygg, M & Zetterstrom, R (2000) Long chain polyunsaturated fatty acids in human milk and brain growth during early infancy. Acta Paediatr 89, 142–147.
100De la Pressa Owens, S & Innis, SM (2000) Diverse, region specific effects of addition of arachidonic and docosahexaenoic acids to formula with low or adequate linoleic and alpha-linolenic acids on piglet brain monoaminergic neurotransmitters. Pediatr Res 48, 125–130.
101Conklin, SM, Gianaros, PJ, Brown, SM, et al. (2007) Long-chain omega-3 fatty acid intake is associated positively with corticolimbic grey matter volume in healthy adults. Neurosci Lett 421, 209–212.
102Holman, RT (1960) The ratio of trienoic: tetraenoic acids in tissue lipids as a measure of essential fatty acid requirements. J. Nutr 70, 405–410.
103Xiang, M, Rahman, MA, Ai, H, Li, X & Harbige, LS (2006) Diet and gene expression: delta-5 and delta-6 desaturases in healthy Chinese and European subjects. Ann Nutr Metab 50, 492–498.
104Sinclair, AJ & Crawford, MA (1972) The accumulation of arachidonate and docosahexaenote in the developing rat brain. J. Neurochem 19, 1753–1758.
105Merrill, JE & Zimmerman, RP (1991) Natural and induced cytotoxicity of oligodendrocytes by microglia is inhibitable by TGF beta. Glia 4, 327–331.
106Copeland, C, Curzner, ML, Groome, N & Diemel, LT (2000) Temporal analysis of growth factor mRNA expression in myelinating rat brain aggregate cultures: increments in CNTF, FGF-2, IGF-I, and PDGF-AA mRNA are induced by antibody-mediated demyelination. Glia 30, 342–351.
107Serafina, S, Sanchez, M, Campeggi, L, Suchanek, G, Breitschop, H & Lassmann, H (1996) Accelerated myelinogenesis by dietary lipids in rat brain. Journal Neurochemistry 67, 1744–1750.
108Van Meeteren, ME, Baron, W, Beermann, C, Dijkstra, CD & van Tol, EA (2006) Polyunsaturated fatty acid supplementation stimulates differentiation of oligodendroglia cells. Dev Neurosci 28, 196–208.