Skip to main content
  • Mini review
  • Published:

Strategies for the identification of loci responsible for the pathogenesis of multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic, debilitating disease, which manifests itself by de-myelination of the central nervous system (CNS). MS is predominantly found in Caucasians of European decent and is more prominent in females than males. MS is one of the most prevalent causes of disability of young adults in the world. The exact cause of MS is not known, however genetic susceptibility to MS is linked to the major histocompability complex (MHC). Self reactive CD4+ T cells, specific for CNS antigens, such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and proteolipid protein (PLP), are detectable in MS patients along with pathogenic autoantibodies specific to these CNS antigens produced by B cells. These observations suggest that MS is an autoimmune disease. Epidemiology of MS along with the analysis of sibling pairs and twins suggest that the multiple genetic factors and their interaction with environment contribute to disease susceptibility. Recent developments and advancements in genetic analysis may aid in accurate determination of genetic risk factors for the development of MS. We review these developments, advances in technology and discuss recent results in this article.

Abbreviations

CNS:

central nervous system

EAE:

experimental allergic encephalomyelitis

HLA:

human leukocyte antigen

MBP:

myelin basic protein

MHC:

major histocompability complex

MOG:

myelin oligodendrocyte glycoprotein

MS:

multiple sclerosis

PLP:

proteolipid protein

QLT:

quantitative trait loci

SNP:

single nucleotide polymorphism

References

  1. Stern, J. N., Keskin, D. B., Zhang, H., Lv, H., Kato, Z. and Strominger, J. L. Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice. Proc. Natl. Acad. Sci. U.S.A. 105 (2008) 5172–5176.

    Article  PubMed  CAS  Google Scholar 

  2. Illes, Z., Stern, J. N., Keskin, D. B., Reddy, J., Brosnan, C. F., Waldner, H., Santambrogio, L., Kuchroo, V. K. and Strominger, J. L. Copolymer effects on microglia and T cells in the central nervous system of humanized mice. Eur. J. Immunol. 35 (2005) 3683–3693.

    Article  PubMed  CAS  Google Scholar 

  3. Stern, J. N., Illes, Z., Reddy, J., Keskin, D. B., Fridkis-Hareli, M., Kuchroo, V. K. and Strominger, J. L. Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 1620–1625.

    Article  PubMed  CAS  Google Scholar 

  4. Stern, J. N., Illes, Z., Reddy, J., Keskin, D. B., Sheu, E., Fridkis-Hareli, M., Nishimura, H., Brosnan, C. F., Santambrogio, L., Kuchroo, V. K. and Strominger, J. L. Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms. Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 11743–11748.

    Article  PubMed  CAS  Google Scholar 

  5. Illes, Z., Stern, J. N., Reddy, J., Waldner, H., Mycko, M. P., Brosnan, C. F., Ellmerich, S., Altmann, D. M., Santambrogio, L., Strominger, J. L. and Kuchroo, V. K. Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells. Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 11749–11754.

    Article  PubMed  CAS  Google Scholar 

  6. O’Connor, K. C., McLaughlin, K. A., De Jager, P. L., Chitnis, T., Bettelli, E., Xu, C., Robinson, W. H., Cherry, S. V., Bar-Or, A., Banwell, B., Fukaura, H., Fukazawa, T., Tenembaum, S., Wong, S. J., Tavakoli, N. P., Idrissova, Z., Viglietta, V., Rostasy, K., Pohl, D., Dale, R. C., Freedman, M., Steinman, L., Buckle, G. J., Kuchroo, V. K., Hafler, D. A. and Wucherpfennig, K. W. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat. Med. 13 (2007) 211–217.

    Article  PubMed  CAS  Google Scholar 

  7. Gasser, D. L., Newlin, C. M., Palm, J. and Gonatas, N. K. Genetic control of susceptibility to experimental allergic encephalomyelitis in rats. Science 181 (1973) 872–873.

    Article  PubMed  CAS  Google Scholar 

  8. McFarlin, D. E., Blank, S. E., Kibler, R. F., McKneally, S. and Shapira, R. Experimental allergic encephalomyelitis in the rat: response to encephalitogenic proteins and peptides. Science 179 (1973) 478–480.

    Article  PubMed  CAS  Google Scholar 

  9. Genain, C. P. and Hauser, S. L. Creation of a model for multiple sclerosis in Callithrix jacchus marmosets. J. Mol. Med. 75 (1997) 187–197.

    Article  PubMed  CAS  Google Scholar 

  10. Kurtzke, J. F., Gudmundsson, K. R. and Bergmann, S. Multiple sclerosis in Iceland: 1. Evidence of a postwar epidemic. Neurology 32 (1982) 143–150.

    PubMed  CAS  Google Scholar 

  11. Sadovnick, A. D., Baird, P. A. and Ward, R. H. Multiple sclerosis: updated risks for relatives. Am. J. Med. Genet. 29 (1988) 533–541.

    Article  PubMed  CAS  Google Scholar 

  12. Wucherpfennig, K. W. and Strominger, J. L. Molecular mimicry in T cellmediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 80 (1995) 695–705.

    Article  PubMed  CAS  Google Scholar 

  13. Serafini, B., Rosicarelli, B., Franciotta, D., Magliozzi, R., Reynolds, R., Cinque, P., Andreoni, L., Trivedi, P., Salvetti, M., Faggioni, A. and Aloisi, F. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204 (2007) 2899–2912.

    Article  PubMed  CAS  Google Scholar 

  14. Derfuss, T., Gurkov, R., Then Bergh, F., Goebels, N., Hartmann, M., Barz, C., Wilske, B., Autenrieth, I., Wick, M., Hohlfeld, R. and Meinl, E. Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response. Brain 124 (2001) 1325–1335.

    Article  PubMed  CAS  Google Scholar 

  15. Theiler, M. Spontaneous Encephalomyelitis of Mice—a New Virus Disease. Science 80 (1934) 122.

    Article  PubMed  Google Scholar 

  16. Jersild, C., Fog, T., Hansen, G. S., Thomsen, M., Svejgaard, A. and Dupont, B. Histocompatibility determinants in multiple sclerosis, with special reference to clinical course. Lancet 2 (1973) 1221–1225.

    Article  PubMed  CAS  Google Scholar 

  17. Risch, N. and Merikangas, K. The future of genetic studies of complex human diseases. Science 273 (1996) 1516–1517.

    Article  PubMed  CAS  Google Scholar 

  18. Sachidanandam, R., Weissman, D., Schmidt, S. C., Kakol, J. M., Stein, L. D., Marth, G., Sherry, S., Mullikin, J. C., Mortimore, B. J., Willey, D. L., Hunt, S. E., Cole, C. G., Coggill, P. C., Rice, C. M., Ning, Z., Rogers, J., Bentley, D. R., Kwok, P. Y., Mardis, E. R., Yeh, R. T., Schultz, B., Cook, L., Davenport, R., Dante, M., Fulton, L., Hillier, L., Waterston, R. H., McPherson, J. D., Gilman, B., Schaffner, S., Van Etten, W. J., Reich, D., Higgins, J., Daly, M. J., Blumenstiel, B., Baldwin, J., Stange-Thomann, N., Zody, M. C., Linton, L., Lander, E. S. and Altshuler, D. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409 (2001) 928–933.

    Article  PubMed  CAS  Google Scholar 

  19. Rioux, J. D., Daly, M. J., Silverberg, M. S., Lindblad, K., Steinhart, H., Cohen, Z., Delmonte, T., Kocher, K., Miller, K., Guschwan, S., Kulbokas, E. J., O’Leary, S., Winchester, E., Dewar, K., Green, T., Stone, V., Chow, C., Cohen, A., Langelier, D., Lapointe, G., Gaudet, D., Faith, J., Branco, N., Bull, S. B., McLeod, R. S., Griffiths, A. M., Bitton, A., Greenberg, G. R., Lander, E. S., Siminovitch, K. A. and Hudson, T. J. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat. Genet. 29 (2001) 223–228.

    Article  PubMed  CAS  Google Scholar 

  20. Daly, M. J., Rioux, J. D., Schaffner, S. F., Hudson, T. J. and Lander, E. S. High-resolution haplotype structure in the human genome. Nat. Genet. 29 (2001) 229–232.

    Article  PubMed  CAS  Google Scholar 

  21. Jeffreys, A. J., Kauppi, L. and Neumann, R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat. Genet. 29 (2001) 217–222.

    Article  PubMed  CAS  Google Scholar 

  22. Graumann, U., Reynolds, R., Steck, A. J. and Schaeren-Wiemers, N. Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol. 13 (2003) 554–573.

    PubMed  CAS  Google Scholar 

  23. Lindberg, R. L., De Groot, C. J., Certa, U., Ravid, R., Hoffmann, F., Kappos, L. and Leppert, D. Multiple sclerosis as a generalized CNS disease—comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS. J. Neuroimmunol. 152 (2004) 154–167.

    Article  PubMed  CAS  Google Scholar 

  24. Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A., Strober, S., Cannella, B., Allard, J., Klonowski, P., Austin, A., Lad, N., Kaminski, N., Galli, S. J., Oksenberg, J. R., Raine, C. S., Heller, R. and Steinman, L. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8 (2002) 500–508.

    Article  PubMed  CAS  Google Scholar 

  25. van Noort, J. M., van Sechel, A. C., Bajramovic, J. J., el Ouagmiri, M., Polman, C. H., Lassmann, H. and Ravid, R. The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis. Nature 375 (1995) 798–801.

    Article  PubMed  Google Scholar 

  26. Chabas, D., Baranzini, S. E., Mitchell, D., Bernard, C. C., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M., Pedotti, R., Heller, R., Oksenberg, J. R. and Steinman, L. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294 (2001) 1731–1735.

    Article  PubMed  CAS  Google Scholar 

  27. Jansen, R. C. and Nap, J. P. Genetical genomics: the added value from segregation. Trends Genet. 17 (2001) 388–391.

    Article  PubMed  CAS  Google Scholar 

  28. Schadt, E. E., Monks, S. A., Drake, T. A., Lusis, A. J., Che, N., Colinayo, V., Ruff, T. G., Milligan, S. B., Lamb, J. R., Cavet, G., Linsley, P. S., Mao, M., Stoughton, R. B. and Friend, S. H. Genetics of gene expression surveyed in maize, mouse and man. Nature 422 (2003) 297–302.

    Article  PubMed  CAS  Google Scholar 

  29. Bystrykh, L., Weersing, E., Dontje, B., Sutton, S., Pletcher, M. T., Wiltshire, T., Su, A. I., Vellenga, E., Wang, J., Manly, K. F., Lu, L., Chesler, E. J., Alberts, R., Jansen, R. C., Williams, R. W., Cooke, M. P. and de Haan, G. Uncovering regulatory pathways that affect hematopoietic stem cell function using ‘genetical genomics’. Nat. Genet. 37 (2005) 225–232.

    Article  PubMed  CAS  Google Scholar 

  30. Hubner, N., Wallace, C. A., Zimdahl, H., Petretto, E., Schulz, H., Maciver, F., Mueller, M., Hummel, O., Monti, J., Zidek, V., Musilova, A., Kren, V., Causton, H., Game, L., Born, G., Schmidt, S., Muller, A., Cook, S. A., Kurtz, T. W., Whittaker, J., Pravenec, M. and Aitman, T. J. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat. Genet. 37 (2005) 243–253.

    Article  PubMed  CAS  Google Scholar 

  31. Chesler, E. J., Lu, L., Shou, S., Qu, Y., Gu, J., Wang, J., Hsu, H. C., Mountz, J. D., Baldwin, N. E., Langston, M. A., Threadgill, D. W., Manly, K. F. and Williams, R. W. Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat. Genet. 37 (2005) 233–242.

    Article  PubMed  CAS  Google Scholar 

  32. Butterfield, R. J., Blankenhorn, E. P., Roper, R. J., Zachary, J. F., Doerge, R. W. and Teuscher, C. Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis. Am. J. Pathol. 157 (2000) 637–645.

    PubMed  CAS  Google Scholar 

  33. Dean, G., McLoughlin, H., Brady, R., Adelstein, A. M. and Tallett-Williams, J. Multiple sclerosis among immigrants in Greater London. Br. Med. J. 1 (1976) 861–864.

    Article  PubMed  CAS  Google Scholar 

  34. Smith, M. W., Patterson, N., Lautenberger, J. A., Truelove, A. L., McDonald, G. J., Waliszewska, A., Kessing, B. D., Malasky, M. J., Scafe, C., Le, E., De Jager, P. L., Mignault, A. A., Yi, Z., De The, G., Essex, M., Sankale, J. L., Moore, J. H., Poku, K., Phair, J. P., Goedert, J. J., Vlahov, D., Williams, S. M., Tishkoff, S. A., Winkler, C. A., De La Vega, F. M., Woodage, T., Sninsky, J. J., Hafler, D. A., Altshuler, D., Gilbert, D. A., O’Brien, S. J. and Reich, D. A high-density admixture map for disease gene discovery in african americans. Am. J. Hum. Genet. 74 (2004) 1001–1013.

    Article  PubMed  CAS  Google Scholar 

  35. Chakraborty, R. and Weiss, K. M. Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 9119–9123.

    Article  PubMed  CAS  Google Scholar 

  36. Patterson, N., Hattangadi, N., Lane, B., Lohmueller, K. E., Hafler, D. A., Oksenberg, J. R., Hauser, S. L., Smith, M. W., O’Brien, S. J., Altshuler, D., Daly, M. J. and Reich, D. Methods for high-density admixture mapping of disease genes. Am. J. Hum. Genet. 74 (2004) 979–1000.

    Article  PubMed  CAS  Google Scholar 

  37. Reich, D., Patterson, N., De Jager, P. L., McDonald, G. J., Waliszewska, A., Tandon, A., Lincoln, R. R., DeLoa, C., Fruhan, S. A., Cabre, P., Bera, O., Semana, G., Kelly, M. A., Francis, D. A., Ardlie, K., Khan, O., Cree, B. A., Hauser, S. L., Oksenberg, J. R. and Hafler, D. A. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat. Genet. 37 (2005) 1113–1118.

    Article  PubMed  CAS  Google Scholar 

  38. McCauley, J. L., Kenealy, S. J., Margulies, E. H., Schnetz-Boutaud, N., Gregory, S. G., Hauser, S. L., Oksenberg, J. R., Pericak-Vance, M. A., Haines, J. L. and Mortlock, D. P. SNPs in Multi-species Conserved Sequences (MCS) as useful markers in association studies: a practical approach. B.M.C. Genomics 8 (2007) 266.

    Article  CAS  Google Scholar 

  39. Gregory, S. G., Schmidt, S., Seth, P., Oksenberg, J. R., Hart, J., Prokop, A., Caillier, S. J., Ban, M., Goris, A., Barcellos, L. F., Lincoln, R., McCauley, J. L., Sawcer, S. J., Compston, D. A., Dubois, B., Hauser, S. L., Garcia-Blanco, M. A., Pericak-Vance, M. A. and Haines, J. L. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat. Genet. 39 (2007) 1083–1091.

    Article  PubMed  CAS  Google Scholar 

  40. Hafler, D. A., Compston, A., Sawcer, S., Lander, E. S., Daly, M. J., De Jager, P. L., de Bakker, P. I., Gabriel, S. B., Mirel, D. B., Ivinson, A. J., Pericak-Vance, M. A., Gregory, S. G., Rioux, J. D., McCauley, J. L., Haines, J. L., Barcellos, L. F., Cree, B., Oksenberg, J. R. and Hauser, S. L. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357 (2007) 851–862.

    Article  PubMed  CAS  Google Scholar 

  41. de Koning, D. J., Carlborg, O. and Haley, C. S. The genetic dissection of immune response using gene-expression studies and genome mapping. Vet. Immunol. Immunopathol. 105 (2005) 343–352.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joel N. H. Stern.

Additional information

These authors contributed equally to this paper

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stern, J.N.H., Keskin, D.B. Strategies for the identification of loci responsible for the pathogenesis of multiple sclerosis. Cell Mol Biol Lett 13, 656–666 (2008). https://doi.org/10.2478/s11658-008-0030-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-008-0030-9

Key words