Major components of myelin in the mammalian CNS and PNS 19 of the protein. Cell-type specific alternative splicing between neurons and myelinating cells accounts for two of the splice isoforms; neuronal isoforms include a mucin domain, while myelinating cells include an additional FNIII domain (Southwood et al., 2004; Tait et al., 2000). At least two promoters have been identified and may confer relative cell-type specific expression in neurons and oligodendrocytes (unpublished). Nfasc is a type I glycoprotein with a single trans- membrane domain. It is an IgSF member belonging to the L1 subgroup and typically contains six Ig domains and three FNIII domains in its extracellular region. Although Nfasc has been studied because of its neurite outgrowth promoting activity and par- ticipation in axon–axon interactions (Volkmer et al., 1996), it has most recently been characterized with regard to its roles in myelination and node of Ranvier formation. In the CNS, both the neuronal and myelin iso- forms of Nfasc are targeted to paranodal regions of myelin sheaths where they participate in formation of axoglial junctions along with contactin and Caspr (Sherman et al., 2005; Tait et al., 2000). Neuronal splicing of the Nfasc gene encodes a 186 kD form of the protein (NF186) while oligodendrocytes and Schwann cells synthesize NF155. NF186 is also targeted to nodes of Ranvier, where it may par- ticipate in macromolecular complexes to stabilize the association of astrocyte processes with the nodal axonal membrane. In the PNS, NF155 synthesized by Schwann cells is targeted to myelin paranodes and axons target NF186 only to nodes of Ranvier. Deletion of the Nfasc gene in mice results in the absence of axoglial junctions at myelin paranodes, the failure of Schwann cell microvilli adhesion to the nodal axon, reduced saltatory conduction in a subpopulation of myelinated fibers, and early death (Sherman et al., 2005). Myelin lipids Traditionally, scholarly contributions from brain lipid research to our understanding of the molecular components of the nervous system have been promin- ent, although a switch to proteinaceous components triggered by recombinant DNA technologies in recent decades has shifted the focus of neurochemistry. A renaissance of lipid biochemistry in the nervous system is in progress and has yielded very important insights into function, particularly at the level of the myelin sheath (Taylor et al., 2004). To underscore their importance, lipids comprise 37% of total rat brain dry weight, but in purified myelin it exceeds 70% and is more than 50% complex lipids and cholesterol. Indeed, myelin is one of the most protein-poor membranes known (Norton and Cammer, 1984). Recent studies show that, like pro- teins, myelin lipids do not simply form the amorphous structures that were envisioned in the fluid mosaic model (Singer and Nicolson, 1972), but rather are assembled into highly organized domains that regu- late structural protein clustering, receptor signaling activity, protein–protein and cell–cell interactions. The most intensively studied of these domains are lipid rafts, which are detergent resistant and enriched in glycolipids and cholesterol (Taylor et al., 2002). Several knockout mice have been generated to ablate different classes of myelin glycolipids and these have focussed on inactivating key enzymes in the biosynthetic pathways. Thus, ablation of the genes encoding ceramide sulfotransferase (CST), to eliminate sulfated glycolipids, or ceramide galactosyltrans- ferase (CGT) to eliminate galactosyl and sulfated gly- colipids, cause axoglial junction phenotypes largely limited to the CNS (Coetzee et al., 1996; Honke et al., 2002). These junctions form during myelinogenesis but eventually dissipate and cause myelin paranodal loops to dissociate from the axon with variable loss of compartmentalization and mixing of nodal and juxtaparanodal ion channels. Elimination of complex gangliosides by ablating GM2/GD2 synthase also causes myelination defects, although the phenotype is mild and appears to be more like a late-onset pro- gressive disorder related more to motorneuron dys- function and Wallerian degeneration than to myelin sheath abnormalities (Chiavegatto et al., 2000). Myelin glycolipids are also of importance to disease involving the immune system, particularly Guillain– Barré syndrome and other inflammatory neuropathies which lead to PNS myelin or neuromuscular dys- function (Hughes and Cornblath, 2005; Overell and Willison, 2005). Thus, molecular mimicry stemming from infectious illnesses (often Hemophilus influenzae and Campylobacter jejuni infections) leads to the pro- duction of antibodies that cross-react with PNS gan- gliosides (GD1, GD3, or GQ1b) and myelin proteins that may disrupt myelin paranodes (Kwa et al., 2003). Transcriptional regulation of myelin genes Transcriptional regulation of myelin genes has been an area of study for relatively few laboratories in the myelin field and, in general, the data are relatively NICP_C02 04/05/2007 12:27PM Page 19 20 ALEXANDER GOW difficult to obtain. Working with primary oligoden- drocyte cultures is difficult because large numbers of cells are not easily obtained, particularly from mice, and transfection efficiencies are low. A few cell lines have been generated for myelinating cells; however, these studies yield data of variable quality and should be interpreted with a healthy dose of skepticism as illustrated below. Accordingly, I only deal with two transcription factors for which in vivo data are avail- able from knockout mouse studies. Importantly, these data provide genetic evidence of genes that are downstream of the transcription factor activity; they do not demonstrate that the transcription factor binds to the promoters/enhancers of those down- stream genes. Nkx6-2 (Gtx) The transcription factor, Nkx6-2, is a homeodomain protein expressed in neurons during development and in oligodendrocytes postnatally (Awatramani et al., 1997; Cai et al., 1999; Komuro et al., 1993). From oligodendrocyte cell culture experiments, Nkx6-2 was found to act as a repressor of the PLP1 and MBP genes (Awatramani et al., 2000) and several consensus Nkx6-2 binding sites are present in the proximal promoter regions of these genes. Using an in silico approach, Farhadi and colleagues identified evolu- tionarily conserved binding sites in the MBP pro- moter/enhancer (Farhadi et al., 2003). However, expression of these genes is unperturbed in Nkx6-2- null mice (Cai et al., 2001; Southwood et al., 2004), indicating that the transfection data are largely in vitro artifact. Consistent with the cell culture experi- ments, Nkx6-2 appears to act as a repressor in oligo- dendrocytes in vivo, but this transcription factor actually regulates at least two genes associated with axoglial junction formation, NF155 and contactin (Southwood et al., 2004). Olig1 and Olig2 The transcription factors, Olig1 and Olig2, are basic helix-loop-helix proteins coordinately expressed in neural progenitor cells and oligodendrocytes during development and in oligodendrocytes postnatally. Both proteins appear to regulate expression of the same genes in oligodendrocytes and each can parti- ally compensate for the other. However, Olig1 func- tion is far more important in brain than spinal cord and the converse is true for Olig2 (Lu et al., 2002, Xin et al., 2005). In Olig1-null mice, oligodendrocyte progenitors born in the brain are able to migrate, proliferate, and differentiate to the point of recognizing and making contact with axons; however, myelinogenesis is arrested at this point which is just prior to expression of major myelin genes such as MAG, PLP1, and MBP (Xin et al., 2005). Arnett and colleagues (Arnett et al., 2004) suggest that Olig1 is only required for remye- lination in the brain; however, this partial pheno- type likely stems from a technical problem with the knockout construct that masks the developmental phenotype by enabling Olig2 to compensate for the absence of Olig1 during myelinogenesis. Thus, Olig1 is genetically upstream of a number of myelin-specific genes in vivo, although it seems unlikely that these genes are direct targets of Olig1. In contrast, Olig1- null oligodendrocytes in primary cell culture can override this arrest in myelinogenesis and can syn- thesize myelin membrane and at least some myelin proteins (Xin et al., 2005). In Olig2-null mice, spinal cord oligodendrocyte precursor cells are apparently never born so it is unclear if this transcription factor regulates myelin gene expression (Lu et al., 2002). The notion of myelin as an immune-privileged compartment Originally, the concept of immune privilege arose from transplantation studies because of the relative lack of immune system activation toward grafted tissue in specific locations in the body such as the brain and the eye (reviewed by Bechmann, 2005). In light of the discovery that adaptive immunity, to dis- tinguish “self” from “non-self”, is established perinat- ally in at least some mammals, the immune-privileged compartment concept was expanded to account for the absence of immune activation toward proteins that are not expressed until well after birth. From early morphological studies on Sertoli cells in the testis and subsequently in oligodendrocyte myelin sheaths, a common perception about the function of tight junctions assembled in these cells was that they defined immune-privileged compart- ments (reviewed in Abraham, 1991; Mugnaini and Schnapp, 1974). Thus, spermatocyte- and myelin- specific proteins that are not expressed in the peri- natal period during the establishment of immune self-tolerance require lifelong sequestration from the immune system to avoid recognition as foreign antigens. This notion is consistent with the pathogenesis of autoimmune orchiditis in the testis and multiple NICP_C02 04/05/2007 12:27PM Page 20 Major components of myelin in the mammalian CNS and PNS 21 sclerosis in the CNS, which were postulated to stem from the dysfunction of tight junctions and the release of “protected antigens” into the interstitium where they could be recognized by the immune system. However, the phenotype of claudin 11-null mice, which includes male sterility and reduced saltatory conduction velocity in the CNS, does not include signs of autoimmune disease in the testis or CNS, either in terms of infiltrating immune cells or the production of autoimmune antibodies (Gow et al., 1999). Accordingly, this mutant casts doubt on the longstanding notion that myelin proteins are shielded from the immune system by myelin tight junctions to protect against the induction of multiple sclerosis. Acknowledgments This work was supported by grants from NINDS, NIH (NS43783) and the National Multiple Sclerosis Society (RG2891). References Abraham, M., 1991. The male germ cell protective bar- rier along phylogenesis. Int Rev Cytol, 130, 111–90. Arnett, H.A., Fancy, S.P., Alberta, J.A. et al. 2004. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science, 306, 2111–15. Arroyo, E.J. and Scherer, S.S. 2000. On the molecular architecture of myelinated fibers. Histochem Cell Biol, 113, 1–18. Awatramani, R., Beesley, J., Yang, H. et al. 2000. Gtx, an oligodendrocyte-specific homeodomain protein, has repressor activity. J Neurosci Res, 61, 376–87. Awatramani, R., Scherer, S., Grinspan, J. et al. 1997. Evidence that the homeodomain protein Gtx is involved in the regulation of oligodendrocyte myeli- nation. J Neurosci, 17, 6657–68. Ballenthin, P.A. and Gardinier, M.V. 1996. Myelin/ oligodendrocyte glycoprotein is alternatively spliced in humans but not mice. J Neurosci Res, 46, 271–81. Banerjee, S.A. and Patterson, P.H. 1995. Schwann cell CD9 expression is regulated by axons. Mol Cell Neurosci, 6, 462–73. Bartsch, S., Montag, D., Schachner, M. and Bartsch, U. 1997. Increased number of unmyelinated axons in optic nerves of adult mice deficient in the myelin- associated glycoprotein (MAG). Brain Res, 762, 231–4. Bechmann, I. 2005. Failed central nervous system regeneration: A downside of immune privilege? Neuromolecular Med, 7, 217–28. Berglund, E.O., Murai, K.K., Fredette, B. et al. 1999. Ataxia and abnormal cerebellar microorganization in mice with ablated contactin gene expression. Neuron, 24, 739–50. Bernard, C.C., Johns, T.G., Slavin, A. et al. 1997. Myelin oligodendrocyte glycoprotein: A novel candidate autoantigen in multiple sclerosis. J Mol Med, 75, 77–88. Bhat, M.A., Rios, J.C., Lu, Y. et al. 2001. Axon–glia interactions and the domain organization of myelin- ated axons requires neurexin iv/caspr/paranodin. Neuron, 30, 369–83. Bosse, F., Zoidl, G., Wilms, S., Gillen, C.P., Kuhn, H.G. and Muller, H.W. 1994. Differential expression of two mRNA species indicates a dual function of peripheral myelin protein PMP22 in cell growth and myelination. J Neurosci Res, 37, 529–37. Boucheix, C., Benoit, P., Frachet, P. et al. 1991. Molecular cloning of the CD9 antigen. A new family of cell surface proteins. J Biol Chem, 266, 117–22. Boyle, M.E., Berglund, E.O., Murai, K.K., Weber, L., Peles, E. and Ranscht, B. 2001. Contactin orches- trates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron, 30, 385–97. Braun, P.E. 1984. Molecular organization of myelin. In P. Morell (ed.), Myelin, Plenum Press, New York, pp. 97–116. Burger, D., Steck, A.J., Bernard, C.C. and Kerlero de Rosbo, N. 1993. Human myelin/oligodendrocyte glycoprotein: A new member of the L2/HNK-1 family. J Neurochem , 61, 1822–7. Cai, J., Qi, Y., Wu, R. et al. 2001. Mice lacking the Nkx6.2 (Gtx) homeodomain transcription factor develop and reproduce normally. Mol Cell Biol, 21, 4399–403. Cai, J., St Amand, T., Yin, H. et al. 1999. Expression and regulation of the chicken Nkx-6.2 homeobox gene suggest its possible involvement in the ventral neural patterning and cell fate specification. Dev Dyn, 216, 459–68. Cai, Z., Sutton-Smith, P., Swift, J. et al. 2002. Tomacula in MAG-deficient mice. J Peripher Nerv Syst, 7, 181–9. Campagnoni, A.T., Pribyl, T.M., Campagnoni, C.W. et al. 1993. Structure and developmental regulation of Golli-mbp, a 105-kilobase gene that encompasses the myelin basic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain. J Biol Chem, 268, 4930–8. Chance, P.F., Alderson, M.K., Leppig, K.A. et al. 1993. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell, 72, 143–51. Chiavegatto, S., Sun, J., Nelson, R.J. and Schnaar, R.L. 2000. A functional role for complex gangliosides: Motor deficits in GM2/GD2 synthase knockout mice. Exp Neurol, 166, 227–34. Coetzee, T., Fujita, N., Dupree, J. et al. 1996. Myelination in the absence of galactocerebroside and sulfatide: Normal structure with abnormal function and regional instability. Cell, 86, 209–19. NICP_C02 04/05/2007 12:27PM Page 21 22 ALEXANDER GOW de Ferra, F., Engh, H., Hudson, L. et al. 1985. Altern- ative splicing accounts for the four forms of myelin basic protein. Cell, 43, 721–7. Delarasse, C., Daubas, P., Mars, L.T. et al. 2003. Myelin/ oligodendrocyte glycoprotein-deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice. J Clin Invest, 112, 544–53. Duncan, I.D., Hammang, J.P., Goda, S. and Quarles, R.H. 1989. Myelination in the jimpy mouse in the absence of proteolipid protein. Glia, 2, 148–54. D’Urso, D. and Muller, H.W. 1997. Ins and outs of peripheral myelin protein-22: Mapping transmem- brane topology and intracellular sorting. J Neurosci Res, 49, 551–62. Edgar, J.M., McLaughlin, M., Barrie, J.A., McCulloch, M.C., Garbern, J. and Griffiths, I.R. 2004a. Age-related axonal and myelin changes in the rumpshaker mutation of the Plp gene. Acta Neuropathol (Berl), 107, 331–5. Edgar, J.M., McLaughlin, M., Yool, D. et al. 2004b. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J Cell Biol, 166, 121–31. Einheber, S., Zanazzi, G., Ching, W. et al. 1997. The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like para- nodal junctions that assemble during myelination. J Cell Biol, 139, 1495–506. Farhadi, H.F., Lepage, P., Forghani, R. et al. 2003. A combinatorial network of evolutionarily conserved myelin basic protein regulatory sequences confers distinct glial-specific phenotypes. J Neurosci, 23, 10214–23. Feng, J.M., Fernandes, A.O., Campagnoni, C.W., Hu, Y.H. and Campagnoni, A.T. 2004. The golli-myelin basic protein negatively regulates signal transduction in T lymphocytes. J Neuroimmunol, 152, 57–66. Fournier, A.E., GrandPre, T. and Strittmatter, S.M. 2001. Identification of a receptor mediating Nogo-66 in hibition of axonal regeneration. Nature, 409, 341–6. Gennarini, G., Cibelli, G., Rougon, G., Mattei, M.G. and Goridis, C. 1989. The mouse neuronal cell surface protein F3: A phosphatidylinositol-anchored member of the immunoglobulin superfamily related to chicken contactin. J Cell Biol, 109, 775–88. Giese, K.P., Martini, R., Lemke, G., Soriano, P. and Schachner, M. 1992. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell, 71, 565–76. Gow, A. 2004. Protein misfolding as a disease deter- minant. In R.A. Lazzarini (ed.), Myelin Biology and Disorders Vol. 1, Elsevier, Amsterdam, pp. 877–85. Gow, A., Davies, C., Southwood, C.M. et al. 2004. Deafness in Claudin 11-null mice reveals the critical contribution of basal cell tight junctions to stria vascularis function. J Neurosci, 24, 7051–62. Gow, A., Gragerov, A., Gard, A., Colman, D.R. and Lazzarini, R.A. 1997. Conservation of topology, but not conformation, of the proteolipid proteins of the myelin sheath. J Neurosci, 17, 181–9. Gow, A. and Smith, R. 1989. The thermodynamically stable state of myelin basic protein in aqueous solu- tion is a flexible coil. Biochem J, 257 , 535–40. Gow, A., Southwood, C.M., Li, J.S. et al. 1999. CNS myelin and Sertoli cell tight junction strands are absent in Osp/Claudin 11-null mice. Cell, 99, 649–59. GrandPre, T., Nakamura, F., Vartanian, T. and Strittmatter, S.M. 2000. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature, 403, 439–44. Holz, A., Schaeren-Wiemers, N., Schaefer, C., Pott, U., Colello, R.J. and Schwab, M.E. 1996. Molecular and developmental characterization of novel cDNAs of the myelin-associated/oligodendrocytic basic pro- tein. J Neurosci, 16, 467–77. Honke, K., Hirahara, Y., Dupree, J. et al. 2002. Paranodal junction formation and spermatogenesis require sul- foglycolipids. Proc Natl Acad Sci USA, 99, 4227–32. Huang, J.K., Phillips, G.R., Roth, A.D. et al. 2005. Glial membranes at the node of Ranvier prevent neurite outgrowth. Science, 310, 1813–17. Hudson, L.D. and Nadon, N.L. 1992. Amino acid sub- stitutions in proteolipid protein that cause dysmyeli- nation. In R.E. Martenson (ed.), Myelin: Biology and Chemistry, CRC Press, Boca Raton, pp. 677–702. Hughes, R.A. and Cornblath, D.R. 2005. Guillain- Barre syndrome. Lancet, 366, 1653–66. Hunt, D., Coffin, R.S. and Anderson, P.N. 2002. The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. J Neurocytol, 31, 93–120. Ishibashi, T., Ding, L., Ikenaka, K. et al. 2004. Tetraspanin protein CD9 is a novel paranodal com- ponent regulating paranodal junctional formation. J Neurosci, 24, 96–102. Jacobs, E.C. 2005. Genetic alterations in the mouse myelin basic proteins result in a range of dysmyeli- nating disorders. J Neurol Sci, 228, 195–7. Jacobs, E.C., Pribyl, T.M., Kampf, K. et al. 2005. Region- specific myelin pathology in mice lacking the golli products of the myelin basic protein gene. J Neurosci, 25, 7004–13. Kim, T., Fiedler, K., Madison, D.L., Krueger, W.H. and Pfeiffer, S.E. 1995. Cloning and characteriza- tion of MVP17: A developmentally regulated myelin protein in oligodendrocytes. J Neurosci Res, 42, 413–22. Kitajiri, S., Miyamoto, T., Mineharu, A. et al. 2004. Compartmentalization established by claudin-11- based tight junctions in stria vascularis is required for hearing through generation of endocochlear potential. J Cell Sci, 117, 5087–96. Klugmann, M., Schwab, M.H., Puhlhofer, A. et al. 1997. Assembly of CNS myelin in the absence of proteolipid protein. Neuron, 18, 59–70. Komuro, I., Schalling, M., Jahn, L. et al. 1993. Gtx: A novel murine homeobox-containing gene, expressed specifically in glial cells of the brain and germ cells NICP_C02 04/05/2007 12:27PM Page 22 Major components of myelin in the mammalian CNS and PNS 23 of testis, has a transcriptional repressor activity in vitro for a serum-inducible promoter. Embo J, 12, 1387–401. Kottis, V., Thibault, P., Mikol, D. et al. 2002. Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth. J Neurochem, 82, 1566–9. Kroepfl, J.F., Viise, L.R., Charron, A.J., Linington, C. and Gardinier, M.V. 1996. Investigation of myelin/ oligodendrocyte glycoprotein membrane topology. J Neurochem, 67, 2219–22. Kwa, M.S., van Schaik, I.N., De Jonge, R.R. et al. 2003. Autoimmunoreactivity to Schwann cells in patients with inflammatory neuropathies. Brain, 126, 361–75. Landry, C.F., Ellison, J.A., Pribyl, T.M., Campagnoni, C., Kampf, K. and Campagnoni, A.T. 1996. Myelin basic protein gene expression in neurons: Developmental and regional changes in protein targeting within neuronal nuclei, cell bodies, and processes. J Neurosci, 16, 2452–62. Le Naour, F., Rubinstein, E., Jasmin, C., Prenant, M. and Boucheix, C. 2000. Severely reduced female fertility in CD9-deficient mice. Science, 287, 319–21. Li, C., Trapp, B., Ludwin, S., Peterson, A. and Roder, J. 1998. Myelin associated glycoprotein modulates glia- axon contact in vivo. J Neurosci Res, 51, 210–17. Li, C., Tropak, M.B., Gerlai, R. et al. 1994. Myelination in the absence of myelin-associated glycoprotein. Nature, 369, 747–50. Li, S., Kim, J.E., Budel, S., Hampton, T.G. and Strittmatter, S.M. 2005. Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury. Mol Cell Neurosci, 29, 26–39. Linsley, P.S., Peach, R., Gladstone, P. and Bajorath, J. 1994. Extending the B7 (CD80) gene family. Protein Sci, 3, 1341–3. Lu, Q.R., Sun, T., Zhu, Z. et al. 2002. Common develop- mental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell, 109, 75–86. MacKenzie, M.L., Ghabriel, M.N. and Allt, G. 1984. Nodes of Ranvier and Schmidt–Lanterman incisures: An in vivo lanthanum tracer study. J Neurocytol, 13, 1043–55. Manfioletti, G., Ruaro, M.E., Del Sal, G., Philipson, L. and Schneider, C. 1990. A growth arrest-specific (gas) gene codes for a membrane protein. Mol Cell Biol, 10, 2924–30. Martin-Belmonte, F., Martinez-Menarguez, J.A., Aranda, J.F., Ballesta, J., de Marco, M.C. and Alonso, M.A. 2003. MAL regulates clathrin-mediated endocytosis at the apical surface of Madin-Darby canine kidney cells. J Cell Biol, 163, 155–64. Martini, R., Mohajeri, M.H., Kasper, S., Giese, K.P. and Schachner, M. 1995a. Mice doubly deficient in the genes for P0 and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. J Neurosci, 15, 4488–95. Martini, R., Zielasek, J., Toyka, K., Giese, K. and Schachner, M. 1995b. Protein zero (P0)-deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies. Nature Genet, 11, 281–6. Matsunami, N., Smith, B., Ballard, L. et al. 1992. Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. Nat Genet, 1, 176–9. McCallion, A.S., Stewart, G.J., Montague, P., Griffiths, I.R. and Davies, R.W. 1999. Splicing pattern, transcript start distribution, and DNA sequence of the mouse gene (Mobp) encoding myelin-associated oligodendrocytic basic protein. Mol Cell Neurosci, 13, 229–36. McKerracher, L. and Winton, M.J. 2002. Nogo on the go. Neuron, 36, 345–8. Mikol, D.D., Rongnoparut, P., Allwardt, B.A., Marton, L.S. and Stefansson, K. 1993. The oligodendrocyte- myelin glycoprotein of mouse: Primary structure and gene structure. Genomics, 17, 604–10. Miyado, K., Yamada, G., Yamada, S. et al. 2000. Requirement of CD9 on the egg plasma membrane for fertilization. Science, 287, 321–4. Miyamoto, T., Morita, K., Takemoto, D. et al. 2005. Tight junctions in Schwann cells of peripheral myeli- nated axons: A lesson from claudin-19-deficient mice. J Cell Biol, 169, 527–38. Montag, D., Giese, K.P., Bartsch, U. et al. 1994. Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron, 13, 229–46. Morita, K., Sasaki, H., Fujimoto, K., Furuse, M. and Tsukita, S. 1999. Claudin-11/OSP-based tight junc- tions of myelin sheaths in brain and Sertoli cells in testis. J Cell Biol, 145, 579–88. Mugnaini, E. and Schnapp, B. 1974. Possible role of zonula occludens of the myelin sheath in demyeli- nating conditions. Nature, 251, 725–7. Nakamura, Y., Iwamoto, R. and Mekada, E. 1996. Expression and distribution of CD9 in myelin of the central and peripheral nervous systems. Am J Pathol, 149, 575–83. Newman, S., Kitamura, K. and Campagnoni, A.T. 1987. Identification of a cDNA coding for a fifth form of myelin basic protein in mouse. Proc Natl Acad Sci USA, 84, 886–90. Nie, D.Y., Zhou, Z.H., Ang, B.T. et al. 2003. Nogo-A at CNS paranodes is a ligand of Caspr: Possible regulation of K(+) channel localization. Embo J, 22, 5666–78. Norton, W.T. and Cammer, W. 1984. Isolation and characterization of myelin. In P. Morell (ed.), Myelin, Plenum Press, New York, pp. 147–95. Oertle, T., Klinger, M., Stuermer, C.A. and Schwab, M.E. 2003. A reticular rhapsody: phylogenic evolution and nomenclature of the RTN/Nogo gene family. Faseb J, 17, 1238–47. NICP_C02 04/05/2007 12:27PM Page 23 24 ALEXANDER GOW Omlin, F., Webster, H.d.F., Pulkovits, C.G. and Cohen, S.R. 1982. Immunocytochemical localization of BP in major dense line regions of central and peripheral myelin. J Cell Biol, 95, 242–8. Overell, J.R. and Willison, H.J. 2005. Recent develop- ments in Miller Fisher syndrome and related dis- orders. Curr Opin Neurol, 18, 562–6. Park, J.B., Yiu, G., Kaneko, S. et al. 2005. A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron, 45, 345–51. Patel, P.I. and Lupski, J.R. 1994. Charcot-Marie-Tooth disease: A new paradigm for the mechanism of inher- ited disease. Trends Genet, 10, 128–33. Patel, P.I., Roa, B.B., Welcher, A.A. et al. 1992. The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nat Genet, 1, 159–65. Peles, E., Nativ, M., Lustig, M. et al. 1997. Identifica- tion of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein–protein interactions. Embo J, 16, 978–88. Perez, P., Puertollano, R. and Alonso, M.A. 1997. Structural and biochemical similarities reveal a family of proteins related to the MAL proteolipid, a compon- ent of detergent-insoluble membrane microdomains. Biochem Biophys Res Commun, 232, 618–21. Pham-Dinh, D., Della Gaspera, B., Kerlero de Rosbo, N. and Dautigny, A. 1995a. Structure of the human myelin/oligodendrocyte glycoprotein gene and multiple alternative spliced isoforms. Genomics, 29, 345–52. Pham-Dinh, D., Jones, E.P., Pitiot, G. et al. 1995b. Physical mapping of the human and mouse MOG gene at the distal end of the MHC class Ib region. Immunogenetics, 42, 386–91. Poliak, S., Gollan, L., Martinez, R. et al. 1999. Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and asso- ciates with K+ channels. Neuron, 24, 1037– 47. Pribyl, T.M., Campagnoni, C.W., Kampf, K. et al. 1993. The human myelin basic protein gene is included within a 179-kilobase transcription unit: Expression in the immune and central nervous systems. Proc Natl Acad Sci USA, 90, 10695–9. Puertollano, R. and Alonso, M.A. 1999. MAL, an inte- gral element of the apical sorting machinery, is an itinerant protein that cycles between the trans-Golgi network and the plasma membrane. Mol Biol Cell, 10, 3435–47. Rancano, C., Rubio, T. and Alonso, M. 1994. Altern- ative splicing of human T-cell-specific MAL mRNA and its correlation with the exon/intron organiza- tion of the gene. Genomics, 21, 447–50. Roa, B.B., Garcia, C.A., Suter, U. et al. 1993. Charcot- Marie-Tooth disease type 1A. Association with a spontaneous point mutation in the PMP22 gene. N Engl J Med, 329, 96–101. Schachner, M. and Bartsch, U. 2000. Multiple func- tions of the myelin-associated glycoprotein MAG (siglec-4a) in formation and maintenance of myelin. Glia, 29, 154–65. Schaeren-Wiemers, N., Bonnet, A., Erb, M. et al. 2004. The raft-associated protein MAL is required for maintenance of proper axon–glia interactions in the central nervous system. J Cell Biol, 166, 731–42. Schaeren-Wiemers, N., Valenzuela, D.M., Frank, M. and Schwab, M.E. 1995. Characterization of a rat gene, rMAL, encoding a protein with four hydrophobic domains in central and peripheral myelin. J Neurosci , 15, 5753–64. Shapiro, L., Doyle, J.P., Hensley, P., Colman, D.R. and Hendrickson, W.A. 1996. Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin. Neuron, 17, 435–49. Sherman, D.L., Tait, S., Melrose, S. et al. 2005. Neuro- fascins are required to establish axonal domains for saltatory conduction. Neuron, 48, 737–42. Singer, S.J. and Nicolson, G.L. 1972. The fluid mosaic model of the structure of cell membranes. Science, 175, 720–31. Smith, R. 1992. The basic protein of CNS myelin: Its structure and ligand binding. J Neurochem, 59, 1589–608. Southwood, C., He, C., Garbern, J., Kamholz, J., Arroyo, E. and Gow, A. 2004. CNS myelin paranodes require Nkx6-2 homeoprotein transcriptional activity for normal structure. J Neurosci, 24, 11215–25. Spiegel, I., Salomon, D., Erne, B., Schaeren-Wiemers, N. and Peles, E. 2002. Caspr3 and caspr4, two novel members of the caspr family are expressed in the nervous system and interact with PDZ domains. Mol Cell Neurosci, 20, 283–97. Stecca, B., Southwood, C.M., Gragerov, A., Kelley, K.A., Friedrich, V.L.J. and Gow, A. 2000. The evolution of lipophilin genes from invertebrates to tetrapods: DM-20 cannot replace PLP in CNS myelin. J Neurosci, 20, 4002–10. Steinman, L. 1993. Connections between the immune system and the nervous system [comment]. Proc Natl Acad Sci USA, 90, 7912–14. Stoeckli, E.T., Kuhn, T.B., Duc, C.O., Ruegg, M.A. and Sonderegger, P. 1991. The axonally secreted protein axonin-1 is a potent substratum for neurite growth. J Cell Biol, 112, 449–55. Sun, J., Link, H., Olsson, T. et al. 1991. T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis. J Immunol, 146, 1490–5. Suter, U., Snipes, G.J., Schoener-Scott, R. et al. 1994. Regulation of tissue-specific expression of altern- ative peripheral myelin protein-22 (PMP22) gene transcripts by two promoters. J Biol Chem, 269, 25795–808. Suter, U., Welcher, A.A., Ozcelik, T. et al. 1992. Trembler mouse carries a point mutation in a myelin gene. Nature, 356, 241–4. Tait, S., Gunn-Moore, F., Collinson, J.M. et al. 2000. An oligodendrocyte cell adhesion molecule at the NICP_C02 04/05/2007 12:27PM Page 24 Major components of myelin in the mammalian CNS and PNS 25 site of assembly of the paranodal axo-glial junction. J Cell Biol, 150, 657–66. Takahashi, N., Roach, A., Teplow, D.B., Prusiner, S.B. and Hood, L. 1985. Cloning and characterization of the myelin basic protein gene from mouse: one gene can encode both 14 kd and 18.5 kd MBPs by alternate use of exons. Cell, 42, 139–48. Taylor, C.M., Coetzee, T. and Pfeiffer, S.E. 2002. Detergent-insoluble glycosphingolipid/cholesterol microdomains of the myelin membrane. J Neurochem, 81, 993–1004. Taylor, C.M., Marta, C.B., Bansal, R. and Pfeiffer, S.E. 2004. The transport, assembly and function of myelin lipids. In R.A. Lazzarini (ed.), Myelin Biology and Disorders Vol. 1, Elsevier, Amsterdam, pp. 57–88. Teng, F.Y. and Tang, B.L. 2005. Why do Nogo/ Nogo-66 receptor gene knockouts result in inferior regeneration compared to treatment with neutraliz- ing agents? J Neurochem, 94, 865–74. Traka, M., Goutebroze, L., Denisenko, N. et al. 2003. Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J Cell Biol, 162, 1161–72. Volkmer, H., Leuschner, R., Zacharias, U. and Rathjen, F.G. 1996. Neurofascin induces neurites by hetero- philic interactions with axonal NrCAM while NrCAM requires F11 on the axonal surface to extend neurites. J Cell Biol, 135, 1059–69. Vourc’h, P. and Andres, C. 2004. Oligodendrocyte myelin glycoprotein (OMgp): Evolution, structure and function. Brain Res Brain Res Rev, 45, 115–24. Vourc’h, P., Moreau, T., Arbion, F., Marouillat-Vedrine, S., Muh, J.P. and Andres, C. 2003. Oligodendrocyte myelin glycoprotein growth inhibition function requires its conserved leucine-rich repeat domain, not its glycosylphosphatidyl-inositol anchor. J Neuro- chem, 85, 889–97. Waehneldt, T.V. 1990. Phylogeny of myelin proteins. Ann N Y Acad Sci, 605, 15–28. Wang, K.C., Koprivica, V., Kim, J.A. et al. 2002. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature, 417, 941–4. Waterhouse, R., Ha, C. and Dveksler, G.S. 2002. Murine CD9 is the receptor for pregnancy-specific glycoprotein 17. J Exp Med, 195, 277–82. Willard, H.F. and Riordan, J.R. 1985. Assignment of the gene for myelin proteolipid protein to the X chromosome: Implications for X-linked myelin dis- orders. Science, 230, 940–2. Xin, M., Yue, T., Ma, Z., Wu, F.F., Gow, A. and Lu, Q.R. 2005. Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1- null mice. J Neurosci, 25, 1354–65. Yamamoto, Y., Mizuno, R., Nishimura, T. et al. 1994. Cloning and expression of myelin-associated oligo- dendrocytic basic protein. A novel basic protein constituting the central nervous system myelin. J Biol Chem, 269, 31725–30. Yamamoto, Y., Yoshikawa, H., Nagano, S. et al. 1999. Myelin-associated oligodendrocytic basic protein is essential for normal arrangement of the radial component in central nervous system myelin. Eur J Neurosci, 11, 847–55. Yamashita, T., Fujitani, M., Yamagishi, S., Hata, K. and Mimura, F. 2005. Multiple signals regulate axon regeneration through the nogo receptor complex. Mol Neurobiol, 32, 105–11. Yin, X., Crawford, T.O., Griffin, J.W. et al. 1998. Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J Neurosci, 18, 1953–62. Yoo, D., Fang, L., Mason, A., Kim, B.Y. and Welling, P.A. 2005. A phosphorylation-dependent export structure in ROMK (Kir 1.1) channel overrides an endoplasmic reticulum localization signal. J Biol Chem, 280, 35281–9. NICP_C02 04/05/2007 12:27PM Page 25 The condition recognized today as multiple sclerosis (MS) was first described in the early nineteenth century (Cruveilhier, 1829–42; Carswell, 1838; Frerichs, 1849). Systematic clinical and patholo- gical characterizations of the disease, and the name “la sclerose en plaques” were provided by Charcot (1868). Comprehensive reviews of contemporary clinical and pathological observations were pub- lished by Charcot’s pupils, Bourneville and Guerard (1869) and Bourneville (1892). The subsequent development of microscopic techniques resulted in thorough analyses of inflammation, demyelination, and neuronal injury in the central nervous system (CNS), whereas advances in neurophysiology led to a better understanding of the protean clinical presentations of the disease. The etiology of MS, however, appeared elusive and most investigators explored toxic or microbial causes (Dejong, 1970). Autoimmunity as a prevailing hypothesis arose in the early twentieth century, when postvaccinal leukoencephalitis was observed in a proportion of patients who received vaccines against viral diseases, particularly rabies. The complication was initially attributed to the attenuated virus grown in rabbit brains. However, when Rhesus macaques injected with normal rabbit brain homogenate also developed a condition similar to postvaccinal leukoencephalitis, the autoantigen-triggered and T-cell mediated nature of the process gained support (Rivers and Schwentker, 1935). The animal model became known as experi- mental allergic (or autoimmune) encephalomyelitis (EAE), and it was reproduced in various species for studying immune-mediated pathways of demyelina- tion. After a long-lasting influence of this paradigm, activated myelin-specific T cells are not uniformly accepted any more as a primary cause of lesion development in typical MS. Several alternative hypo- theses of etiology are under investigation, but no deci- sive conclusion has been reached (Lassmann, 2005). The inspiring development of biotechnology and the resultant extraordinary amount of information in molecular immunology and genetics, clinical neurology, pathology, and imaging, are expected to reveal new correlations of data and a better under- standing of MS pathogenesis. Classical natural his- tory data serve today as reference information for evaluating disease heterogeneity and the response to therapy (Krementchutzky et al., 1999, 2006). The first disease-modifying drug was approved by the Food and Drug Administration (FDA) in 1993 (The IFNB Multiple Sclerosis Study Group, 1993). Since then, the methodology of designing, monitoring, and interpreting clinical trials has itself evolved into a new science while numerous new pharmaceutical agents were developed and tested. Novel strategies also continuously emerge in the area of molecular therapies (Imitola et al., 2006; Polman et al., 2006; Rudick et al., 2006a). The following sections summarize the most up-to-date observations concerning epidemiology and genetics, immune pathogenesis, histology, clin- ical and paraclinical features, and current therapies of MS and related immune-mediated disorders in the CNS. 3.1 Epidemiology and genetics (Bernadette Kalman) Epidemiology Epidemiological data of MS have accumulated since the early twentieth century. Davenport (1922) and Limburg (1950) demonstrated that a geographic distribution of MS exists. A north to south gradient was noted on the northern hemisphere including Europe, North America, and Japan (Kurtzke, 1975a,b, 1993; Kuroiwa et al., 1983), while a south to north gradient was observed in Australia and New Zealand on the southern hemisphere (McLeod et al., 1994; Miller et al., 1990; Skegg et al., 1987). Prevalence surveys from the 1960s to date distinguished high prevalence (30 or more / 100,000, e.g. north, western, 3 Multiple sclerosis Bernadette Kalman NICP_C03 04/05/2007 12:26PM Page 29 30 BERNADETTE KALMAN ET AL. Table 3.1 Epidemiological studies support both environmental and genetic etiology of MS. Evidence for environmental factors MS in immigrants occurs with a rate similar to that in the indigenous population when the immigration is before teenage years Epidemics of MS (e.g. on the Faroe Islands) Increasing prevalence and decreasing age of onset of MS in populations with stable genetics Evidence for genetic factors • Ethnic groups (genetic isolates) with varying susceptibility to MS • Increased familial recurrence • Higher concordance in monozygotic than in dizygotic twins • Higher risk for MS in full-sibs than in half-sibs; the presence of a maternal parental effect • Highly increased risk of MS in siblings of index cases from consanguineous parents • A similar risk of MS for nonbiological relatives and individuals in the general population and central Europe), medium (5–29/100,000, e.g. south Europe) and low prevalence regions (less than 5/100,000, e.g. most Asian countries) (Kurtzke, 2005). These distributions may be related to both environmental (climate, viruses, UV irradiation, and diet) and genetic factors (Table 3.1). Migration studies, history of epidemics, and serial epidemiological updates support the existence of environmental effects. European immigrants in South Africa develop MS with a similar frequency as the indigenous population, while an opposite trend is observed for offspring of individuals immigrating from India, South Africa, and the West Indies to the United Kingdom (Dean, 1967; Elian et al., 1990). A migration before mid-teenage years seems to confer to the migrant the recipient country’s risk for MS, possibly related to the effects of childhood infections on immune maturation (Alter et al., 1966). MS occurred on the Faroe Islands in four epi- demics between 1943 and 1990. These epidemics were attributed to a primary infectious agent imported into the islands by the occupying British forces during World War II, and to its transmission to subsequent generations (Kurtzke 1975a,b, 1993, 2005). Serial epidemiological updates suggest that the relative risk for MS is increasing in certain groups over time (Kurztke, 2005). This observation is well illus- trated in Sardinia, where the mean annual incidence rate significantly increased from 1.1/100,000 in 1965–9 to 5.8/100,000 in 1995–9 (Pugliatti et al., 2005). Estimates of MS in cohorts from World War II and the Korean conflict show a relative risk of 0.44 for African American men and 0.22 for other men as compared to white men, while estimates in similar ethnic cohorts from the Vietnam war and up to 1994 reveal a relative risk of 0.67 and 0.3, respectively (Kurtzke, 2005). The risk of MS for white women as compared to white men was 1.79 in the earlier cohorts, which also significantly increased in the more recent cohorts. Women of all races now have a risk ratio near to 3:1 as compared to white men (Kurtzke, 2005). Anticipation of age at onset may be another indic- ator for the involvement of environmental factors. Anticipation was demonstrated in two-generational MS families and longitudinal surveys of sporadic cases in Sardinia, where the mean age of onset decreased from the most remote to the most recent decade of birth from 41 to 21 years (Cocco et al., 2004). Inter- estingly, in another subset of the Sardinian popula- tion an increasing age of onset was noted (Pugliatti et al., 2005). In contrast to data supporting the involvement of environmental effects, ethnic, family, and twin studies suggest the involvement of genetic factors in MS (Table 3.1). While the highest prevalence rates (100/ 100,000 and beyond) correlate with the worldwide distribution of individuals of Scandinavian descent (Poser, 1994), several ethnic isolates with resistance to MS live in geographic locations where the disease is generally common. Examples include gypsies in Hungary (Gyodi et al., 1981), Indians and Orientals in North America (Ebers, 1983; Kurtzki et al., 1979), Lapps in Scandinavia (Gronning and Mellgren, 1985), Maoris in New Zealand (Skegg et al., 1987) and Aborigines in Australia (McLeod et al., 1994). The varying prevalence rates of MS in the genetically dis- tinct but geographically close populations of Malta, Sicily, and Sardinia also implicate genetic factors NICP_C03 04/05/2007 12:26PM Page 30 Multiple sclerosis 31 (Elian et al., 1987; Rosati 1986). In addition, some ethnic groups (e.g. Orientals and African Blacks) are characterized by very low occurrence of MS (Dean, 1967; Poser, 1994). Familial recurrence of MS was recognized long ago (Eichorst, 1896). The observed inheritance pat- terns are incompatible with Mendelian autosomal dominant, recessive, and X-linked or mitochondrial transmission patterns. MS is a complex trait disorder with the involvement of several genes, each exerting small effect, and probably in an interaction with the environment. There is an excess in the mother-to-child as compared to the father-to-child transmissions in families with vertical concordance (Sadovnick et al., 1991). The age-adjusted empirical recurrence risk for first-degree relatives is 3 to 5%, which is 30 to 50 times the 0.1% rate in the general population (Sadovnick et al., 1991, 1998). Individuals with a greater “genetic loading” have an earlier age of onset, and “genetic loading” is increased in individuals with affected parents (Sadovnick et al., 1998). In a population-based analysis of MS index cases and their siblings whose parents were related, Sadovnick et al. (2001) found a recurrence risk of 9% for sibs, which is significantly higher than the risk for sibs of MS index cases from nonconsanguineous parents. Data from several large twin studies consistently demonstrated a higher concordance rate of MS among monozygotic (21.05% to 40%) as compared to dizygotic twins (0 to 4.7%), strongly suggesting a genetic effect (Bobowick et al., 1978; Hansen et al., 2005; Heltberg and Holm, 1982; Kinnunen et al., 1988; Mumford et al., 1994; Sadovnick et al., 1993). The concordance rate among dizygotic twins (4.7%) is similar to that observed among siblings (5.1%) (Sadovnick et al., 1993). Further confirmation of genetic effects is gained from studies on adoptees revealing that the frequency of MS among first-degree nonbiological relatives living with an index case is not greater than expected from the general population (Ebers et al., 1995). The largest half-sib study (Ebers et al., 2004) defines an age adjusted recurrence risk of 3.11% and 1.89% for full-siblings and half-siblings, respectively. The moderately significant excess of maternal vs. pater- nal half-sibling risk (2.35% vs. 1.31%, respectively) suggests a maternal effect on susceptibility to MS. Early case–control candidate gene association studies Associations of MS with polymorphic alleles of candidate genes involved in immune regulation and myelin production have been extensively investigated based on the autoimmune hypothesis of demyelina- tion (Table 3.2). The first association noted with the haplotype of class I human leukocyte antigen (HLA) A3 and B7 alleles was extended to the Class II DR2 allele in both population and family studies ( Jersild et al., 1973; Stewart et al., 1979). Since then, the association of MS with the HLA A3, B7, DR2, Dw2 haplotype has been the most consistent finding in Caucasians (Francis et al., 1991; Gyodi et al., 1981; Olerup and Hillert, 1991), while HLA DR4 was detected in Sardinians and Jordanian Arabs, and DR6 was described in Japanese and Mexicans (Gorodezky et al., 1986; Kurdi et al., 1977; Marrosu et al., 1988; Naito et al., 1978). Further studies revealed that the DR15, DQ6 alleles define the MS- associated DR2, DW2 haplotype, which is described today in DNA-based terminology as DRB1*1501, DQA1*0102, DQB1*0602 haplotype (Hillert et al., Table 3.2 Studies in MS. Region of interest Approach Major finding Case–control association Polymorphic alleles of candidate genes Hypothesis-based MHC DRB1 alleles define a major proportion of genetic susceptibility and resistance to MS Linkage Full genome or regional scans Hypothesis-free Multiple susceptibility loci with small effect including 1q44, 2q35, 5p15–5q13, 6p21, 17q11, 17q22, 18p11, 19q13 LD mapping Full genome or regional scans Hypothesis-free or hypothesis-directed Distribution of LD genome wide; identification of chromosomal segments carrying MS susceptibility genes and variants in progress NICP_C03 04/05/2007 12:26PM Page 31 [...]...NICP_C03 04/05 /20 07 12: 26PM Page 32 32 BERNADETTE KALMAN ET AL Class II DP DN DO DQ 0 Class III DR 1000 21 -OH Hsp C4 BFC2 Class I TNF HLA-B HLA-C αβ 20 00 HLA-H HLA-G HLA-A HLA-F HLA-X HLA-E 3000 MOG 4000 kb Telomere Centromere Fig 3.1 The figure depicts the MHC class II, class III, and class I regions encompassing 4 MB in chromosome 6p21.3 MS-associated haplotypes have been consistently detected in the DRB1–DQB1... stage The ensuing firm adhesion is mediated by 2 integrins and includes vascular cell adhesion molecule (VCAM )-1 , very late antigen (VLA )-4 , intracellular adhesion molecule (ICAM )-1 , and lymphocyte function-associated antigen (LFA )-1 (Miller et al., 20 03; Yednock et al., 19 92) Antibodies against LFA-1 and ICAM-1 were shown suppressing EAE in some studies, and a rise in ICAM-1 levels was seen in the same... dissemination of lesions in time (McDonald et al., 20 01) If the first scan is performed three months or more after the clinical onset, a gadoliniumenhancing lesion (not at the site involved in the original clinical event) is needed; if no enhancing lesion is present, a follow-up scan with new T 2- or gadolinium-enhancing lesion in another three months or later is needed to fulfill the criterion for dissemination... CNS Myelin-reactive T cells from patients with MS produce cytokines more consistent with a proinflammatory Th1-mediated response, whereas myelin-reactive T cells from healthy persons are more likely to produce Th2 cytokines which exert immunoregulatory response Cytokines associated with a Th2 response include interleukin (IL-4) and IL-5 IL- 12 is a cytokine that is strongly associated with proinflammatory... al., 20 00) Patients exhibited a surge of T cells reactive with the corresponding myelin basic protein peptide at the time of clinical activity This finding supports the view that a self-reactive in ammatory process directed against myelin constituents plays a central role in MS The cytokine profile produced by myelin-specific T cells determines the ability of these cells to initiate in ammation in the... changes are different in RR- and PP-MS, but are markedly similar in SP- and PP-MS (Confavreux et al., 20 00; Ebers 20 04; Kremenchutzky et al., 20 06) Analyses of long-term outcomes (time to EDSS 3, 6, 8, and 10) suggest that patients with relapsing-progressive (RP) course can be reassigned either to SP- or PP-MS, and patients with PR-course SP-MS Disability Disability RR-MS PP-MS PR-MS Disability Time... Th2 phenotype (Wandinger et al., 20 01) IL- 12 and IL -2 3 are heterodimers and share the same p40 subunit They affect regulation of T-cell responses in a way that may be relevant to the disease process of MS (Trinchieri et al., 20 03) Development of EAE depends on a sequencial expression of distinct cytokine patterns Mice deficient in both IL- 12 and IL -2 3 are resistant to EAE, whereas animals deficient in. .. criteria of dissemination in time 2 Incorporation of spinal cord lesions into the imaging requirements: A spinal lesion characteristic of MS (little or no swelling in the cord, hyperintense on T2, at least 3 mm in size, less than two vertebral segment in length and occupies part of the cord’s cross-section) is helpful to eliminate alternative diagnosis or to confirm MS when no dissemination in space is detected... CD8+ T cells reactive with constituent proteins of the myelin can induce in ammatory demyelination in the CNS (Ando et al., 1989; Huseby et al., 20 01; Pettinelli and McFarlin, 1981) Myelin basic protein is one of these proteins T cells reactive with myelin basic protein can be demonstrated in individuals with MS and in normal controls The myelin-specific T cells from patients with MS generally exhibit... by Polman et al (20 05) confirmed these criteria and provided clarification for the incorporation of spinal cord lesions into the criteria (see text) 2 One gadolinium-enhancing lesion or nine T2-weighted hyperintense lesions if there is no enhancing lesion One infratentorial lesion One juxtacortical lesion Three periventricular lesions Box 3 .2 MRI determination of lesion dissemination in time (a) MRI criteria . HLA-B HLA-C HLA-X HLA-E HLA-H HLA-A HLA-F HLA-G MOG αβ 21 -OH C4 BFC2 20 00 3000 4000 Telomere kb Fig. 3.1 The figure depicts the MHC class II, class III, and class I regions encompassing 4 MB in. whereas animals deficient in IL- 12 alone develop severe dis- ease. Interleukin -2 3 induces IL-17 production by T cells. IL-17 is expressed in brain lesions and appears to be a regulator of CNS in ammation. T. brain and germ cells NICP_C 02 04/05 /20 07 12: 27PM Page 22 Major components of myelin in the mammalian CNS and PNS 23 of testis, has a transcriptional repressor activity in vitro for a serum-inducible