, 60:275 | Cite as

The immunogenetics of multiple sclerosis

  • Arne Svejgaard


The discoveries in the 1970s of strong associations between various diseases and certain human leukocyte antigen (HLA) factors were a revolution within genetic epidemiology in the last century by demonstrating for the first time how genetic markers can help unravel the genetics of disorders with complex genetic backgrounds. HLA controls immune response genes and HLA associations indicate the involvement of autoimmunity. Multiple sclerosis (MS) was one of the first conditions proven to be HLA associated involving primarily HLA class II factors. We review how HLA studies give fundamental information on the genetics of the susceptibility to MS, on the importance of linkage disequilibrium in association studies, and on the pathogenesis of MS. The HLA-DRB1*1501 molecule may explain about 50% of MS cases and its role in the pathogenesis is supported by studies of transgenic mice. Studies of polymorphic non-HLA genetic markers are discussed based on linkage studies and candidate gene approaches including complete genome scans. No other markers have so far rivaled the importance of HLA in the genetic susceptibility to MS. Recently, large international collaborations provided strong evidence for the involvement of polymorphism of two cytokine receptor genes in the pathogenesis of MS: the interleukin 7 receptor α chain gene (IL7RA) on chromosome 5p13 and the interleukin 2 receptor α chain gene (IL2RA (=CD25)) on chromosome 10p15. It is estimated that the C allele of a single nucleotide polymorphism, rs6897932, within the alternative spliced exon 6 of IL7RA is involved in about 30% of MS cases.


Multiple sclerosis Genetics HLA Major histocompatibility complex Interleukin receptor genes Linkage Association 



This study was aided by grants from the Danish Medical Research Council and the Lundbeck Foundation.


  1. Bagos PG, Karnaouri AC, Nikolopoulos GK, Hamodrakas SJ (2007) No evidence for association of CTLA-4 gene polymorphisms with the risk of developing multiple sclerosis: a meta-analysis. Mult Scler 13:156–168PubMedCrossRefGoogle Scholar
  2. Baisch JM, Weeks T, Giles R, Hoover M, Stastny P, Capra JD (1990) Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N Engl J Med 322:1836–1841PubMedGoogle Scholar
  3. Barcellos LF, Klitz W, Field LL, Tobias R, Bowcock AM, Wilson R, Nelson MP, Nagatomi J, Thomson G (1997) Association mapping of disease loci, by use of a pooled DNA genomic screen. Am J Hum Genet 61:734–747PubMedCrossRefGoogle Scholar
  4. Barcellos LF, Oksenberg JR, Begovich AB, Martin ER, Schmidt S, Vittinghoff E, Goodin DS, Pelletier D, Lincoln RR, Bucher P, Swerdlin A, Pericak-Vance MA, Haines JL, Hauser SL (2003) HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 72:710–716PubMedCrossRefGoogle Scholar
  5. Barcellos LF, Sawcer S, Ramsay PP, Baranzini SE, Thomson G, Briggs F, Cree BC, Begovich AB, Villoslada P, Montalban X, Uccelli A, Savettieri G, Lincoln RR, DeLoa C, Haines JL, Pericak-Vance MA, Compston A, Hauser SL, Oksenberg JR (2006) Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet 15:2813–2824PubMedCrossRefGoogle Scholar
  6. Begovich AB, Caillier SJ, Alexander HC, Penko JM, Hauser SL, Barcellos LF, Oksenberg JR (2005) The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis. Am J Hum Genet 76:184–187PubMedCrossRefGoogle Scholar
  7. Bertrams J, Kuwert E, Liedtke U (1972) HL-A antigens and multiple sclerosis. Tissue Antigens 2:405–408PubMedGoogle Scholar
  8. Bodmer JG, Marsh SG, Albert ED, Bodmer WF, Dupont B, Erlich HA, Mach B, Mayr WR, Parham P, Sasazuki T (1994) Nomenclature for factors of the HLA system, 1994. Tissue Antigens 44:1–18PubMedGoogle Scholar
  9. Brand OJ, Lowe CE, Heward JM, Franklyn JA, Cooper JD, Todd JA, Gough SC (2007) Association of the interleukin-2 receptor alpha (IL-2Ralpha)/CD25 gene region with Graves’ disease using a multilocus test and tag SNPs. Clin Endocrinol (Oxf) 66:508–512Google Scholar
  10. Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, Hillert J (2007) HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS ONE 2:e664PubMedCrossRefGoogle Scholar
  11. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St CD, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskivina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop TD, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Matthew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop MG, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hilder SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Newport M, Sirugo G, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Davison D, Ferreira T, Pereira-Gale J, Hallgrimsdo'ttir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Brown MA, Compston A, Farrall M, Hall AS, Hattersley AT, Hill AV, Parkes M, Pembrey M, Stratton MR, Mitchell SL, Newby PR, Brand OJ, Carr-Smith J, Pearce SH, McGinnis R, Keniry A, Deloukas P, Reveille JD, Zhou X, Sims AM, Dowling A, Taylor J, Doan T, Davis JC, Savage L, Ward MM, Learch TL, Weisman MH, Brown M (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–1337PubMedCrossRefGoogle Scholar
  12. Caballero A, ves-Leon S, Papais-Alvarenga R, Fernandez O, Navarro G, Alonso A (1999) DQB1*0602 confers genetic susceptibility to multiple sclerosis in Afro-Brazilians. Tissue Antigens 54:524–526PubMedCrossRefGoogle Scholar
  13. Clerici N, Hernandez M, Fernandez M, Rosique J, varez-Cermeno J (1989) Multiple sclerosis is associated with HLA-DR2 antigen in Spain. Tissue Antigens 34:309–311PubMedGoogle Scholar
  14. Coraddu F, Reyes-Yanez MP, Parra A, Gray J, Smith SI, Taylor CJ, Compston DA (1998) HLA associations with multiple sclerosis in the Canary Islands. J Neuroimmunol 87:130–135PubMedCrossRefGoogle Scholar
  15. De Jager PL, Sawcer S, Waliszewska A, Farwell L, Wild G, Cohen A, Langelier D, Bitton A, Compston A, Hafler DA, Rioux JD (2006) Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn’s disease and multiple sclerosis. Eur J Hum Genet 14:317–321PubMedCrossRefGoogle Scholar
  16. Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C, Armstrong H, Cousin K, Bell RB, Hader W, Paty DW, Hashimoto S, Oger J, Duquette P, Warren S, Gray T, O’Connor P, Nath A, Auty A, Metz L, Francis G, Paulseth JE, Murray TJ, Pryse-Phillips W, Nelson R, Freedman M, Brunet D, Bouchard JP, Hinds D, Risch N (1996) A full genome search in multiple sclerosis. Nat Genet 13:472–476PubMedCrossRefGoogle Scholar
  17. Ellmerich S, Mycko M, Takacs K, Waldner H, Wahid FN, Boyton RJ, King RH, Smith PA, Amor S, Herlihy AH, Hewitt RE, Jutton M, Price DA, Hafler DA, Kuchroo VK, Altmann DM (2005) High incidence of spontaneous disease in an HLA-DR15 and TCR transgenic multiple sclerosis model. J Immunol 174:1938–1946PubMedGoogle Scholar
  18. Falchuk ZM, Rogentine GN, Strober W (1972) Predominance of histocompatibility antigen HL-A8 in patients with gluten-sensitive enteropathy. J Clin Invest 51:1602–1605PubMedCrossRefGoogle Scholar
  19. Fogdell A, Hillert J, Sachs C, Olerup O (1995) The multiple sclerosis- and narcolepsy-associated HLA class II haplotype includes the DRB5*0101 allele. Tissue Antigens 46:333–336PubMedGoogle Scholar
  20. Green A (1982) The epidemiologic approach to studies of association between HLA and disease. II. Estimation of absolute risks, etiologic and preventive fraction. Tissue Antigens 19:259–268PubMedGoogle Scholar
  21. Gregersen JW, Kranc KR, Ke X, Svendsen P, Madsen LS, Thomsen AR, Cardon LR, Bell JI, Fugger L (2006) Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443:574–577PubMedGoogle Scholar
  22. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL (2007) Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39:1083–1091PubMedCrossRefGoogle Scholar
  23. Haas J, Fritzsching B, Trubswetter P, Korporal M, Milkova L, Fritz B, Vobis D, Krammer PH, Suri-Payer E, Wildemann B (2007) Prevalence of newly generated naive regulatory T cells (Treg) is critical for Treg suppressive function and determines Treg dysfunction in multiple sclerosis. J Immunol 179:1322–1330PubMedGoogle Scholar
  24. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851–862PubMedCrossRefGoogle Scholar
  25. Haines JL, Ter-Minassian M, Bazyk A, Gusella JF, Kim DJ, Terwedow H, Pericak-Vance MA, Rimmler JB, Haynes CS, Roses AD, Lee A, Shaner B, Menold M, Seboun E, Fitoussi RP, Gartioux C, Reyes C, Ribierre F, Gyapay G, Weissenbach J, Hauser SL, Goodkin DE, Lincoln R, Usuku K, Oksenberg JR (1996) A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex. The Multiple Sclerosis Genetics Group. Nat Genet 13:469–471PubMedCrossRefGoogle Scholar
  26. Haines JL, Terwedow HA, Burgess K, Pericak-Vance MA, Rimmler JB, Martin ER, Oksenberg JR, Lincoln R, Zhang DY, Banatao DR, Gatto N, Goodkin DE, Hauser SL (1998) Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. Hum Mol Genet 7:1229–1234PubMedCrossRefGoogle Scholar
  27. Haldane JB (1956) The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 20:309–311PubMedCrossRefGoogle Scholar
  28. Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS, Fernald GH, Gerlitz B, Robinson WH, Baranzini SE, Grinnell BW, Raine CS, Sobel RA, Han DK, Steinman L (2008) Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets 1. Nature 451:1076–1081PubMedCrossRefGoogle Scholar
  29. Hansen BE, Rasmussen AH, Jakobsen BK, Ryder LP, Svejgaard A (2007) Extraordinary cross-reactivity of an autoimmune T-cell receptor recognizing specific peptides both on autologous and on allogeneic HLA class II molecules. Tissue Antigens 70:42–52PubMedCrossRefGoogle Scholar
  30. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH (2008) B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N Engl J Med 358:676–688PubMedCrossRefGoogle Scholar
  31. Hohlfeld R, Wekerle H (2001) Immunological update on multiple sclerosis. Curr Opin Neurol 14:299–304PubMedCrossRefGoogle Scholar
  32. Hummelshoj T, Bodtger U, Datta P, Malling HJ, Oturai A, Poulsen LK, Ryder LP, Sorensen PS, Svejgaard E, Svejgaard A (2003) Association between an interleukin-13 promoter polymorphism and atopy. Eur J Immunogenet 30:355–359PubMedCrossRefGoogle Scholar
  33. Hummelshoj T, Ryder LP, Madsen HO, Odum N, Svejgaard A (2006) A functional polymorphism in the Eta-1 promoter is associated with allele specific binding to the transcription factor Sp1 and elevated gene expression. Mol Immunol 43:980–986PubMedCrossRefGoogle Scholar
  34. Jersild C, Svejgaard A, Fog T (1972) HL-A antigens and multiple sclerosis. Lancet 1:1240–1241PubMedCrossRefGoogle Scholar
  35. Jersild C, Fog T, Hansen GS, Thomsen M, Svejgaard A, Dupont B (1973a) Histocompatibility determinants in multiple sclerosis, with special reference to clinical course. Lancet 2:1221–1225PubMedCrossRefGoogle Scholar
  36. Jersild C, Svejgaard A, Fog T, Ammitzboll T (1973b) HL-A antigens and diseases. I. Multiple sclerosis. Tissue Antigens 3:243–250PubMedGoogle Scholar
  37. Krogsgaard M, Wucherpfennig KW, Cannella B, Hansen BE, Svejgaard A, Pyrdol J, Ditzel H, Raine C, Engberg J, Fugger L (2000) Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85–99 complex. J Exp Med 191:1395–1412PubMedCrossRefGoogle Scholar
  38. Kuokkanen S, Sundvall M, Terwilliger JD, Tienari PJ, Wikstrom J, Holmdahl R, Pettersson U, Peltonen L (1996) A putative vulnerability locus to multiple sclerosis maps to 5p14–p12 in a region syntenic to the murine locus Eae2. Nat Genet 13:477–480PubMedCrossRefGoogle Scholar
  39. Kwon OJ, Karni A, Israel S, Brautbar C, Amar A, Meiner Z, Abramsky O, Karussis D (1999) HLA class II susceptibility to multiple sclerosis among Ashkenazi and non-Ashkenazi Jews. Arch Neurol 56:555–560PubMedCrossRefGoogle Scholar
  40. Lang HL, Jacobsen H, Ikemizu S, Andersson C, Harlos K, Madsen L, Hjorth P, Sondergaard L, Svejgaard A, Wucherpfennig K, Stuart DI, Bell JI, Jones EY, Fugger L (2002) A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 3:940–943PubMedCrossRefGoogle Scholar
  41. Lobnig BM, Chantelau E, Vidgren G, Van Landeghem AA, Kinnunen L, Tuomilehto-Wolf E (2002) HLA-patterns in patients with multiple sclerosis and type I diabetes mellitus: evidence for possible mutual exclusion of both diseases. Diabetes Metab 28:217–221PubMedGoogle Scholar
  42. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom E, Khademi M, Oturai A, Ryder LP, Saarela J, Harbo HF, Celius EG, Salter H, Olsson T, Hillert J (2007) Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 39:1108–1113PubMedCrossRefGoogle Scholar
  43. Ma JJ, Nishimura M, Mine H, Saji H, Ohta M, Saida K, Ozawa K, Kawakami H, Saida T, Uchiyama T (1998) HLA-DRB1 and tumor necrosis factor gene polymorphisms in Japanese patients with multiple sclerosis. J Neuroimmunol 92:109–112PubMedCrossRefGoogle Scholar
  44. Madsen LS, Andersson EC, Jansson L, krogsgaard M, Andersen CB, Engberg J, Strominger JL, Svejgaard A, Hjorth JP, Holmdahl R, Wucherpfennig KW, Fugger L (1999) A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nat Genet 23:343–347PubMedCrossRefGoogle Scholar
  45. Marrosu MG, Murru MR, Costa G, Murru R, Muntoni F, Cucca F (1998) DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population. Hum Mol Genet 7:1235–1237PubMedCrossRefGoogle Scholar
  46. Marrosu MG, Cocco E, Lai M, Spinicci G, Pischedda MP, Contu P (2002) Patients with multiple sclerosis and risk of type 1 diabetes mellitus in Sardinia, Italy: a cohort study. Lancet 359:1461–1465PubMedCrossRefGoogle Scholar
  47. McDonnell GV, Mawhinney H, Graham CA, Hawkins SA, Middleton D (1999) A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its influence on prognosis. J Neurol Sci 165(1):77–83PubMedCrossRefGoogle Scholar
  48. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913–919PubMedCrossRefGoogle Scholar
  49. Mignot E, Lin X, Arrigoni J, Macaubas C, Olive F, Hallmayer J, Underhill P, Guilleminault C, Dement WC, Grumet FC (1994) DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans. Sleep 17:S60–S67PubMedGoogle Scholar
  50. Mignot E, Tafti M, Dement WC, Grumet FC (1995) Narcolepsy and immunity. Adv Neuroimmunol 5:23–37PubMedCrossRefGoogle Scholar
  51. Naito S, Namerow N, Mickey MR, Terasaki PI (1972) Multiple sclerosis: association with HL-A3. Tissue Antigens 2:1–4PubMedGoogle Scholar
  52. Oksenberg JR, Barcellos LF, Cree BA, Baranzini SE, Bugawan TL, Khan O, Lincoln RR, Swerdlin A, Mignot E, Lin L, Goodin D, Erlich HA, Schmidt S, Thomson G, Reich DE, Pericak-Vance MA, Haines JL, Hauser SL (2004) Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 74:160–167PubMedCrossRefGoogle Scholar
  53. Olerup O, Hillert J (1991) HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antigens 38:1–15PubMedGoogle Scholar
  54. Ono T, Zambenedetti MR, Yamasaki K, Kawano Y, Kamikawaji N, Ito H, Sakurai M, Nishimura Y, Kira J, Kanazawa I, Sasazuki T (1998) Molecular analysis of HLA class I (HLA-A and -B) and HLA class II (HLA-DRB1) genes in Japanese patients with multiple sclerosis (Western type and Asian type). Tissue Antigens 52:539–542PubMedGoogle Scholar
  55. Oturai A, Larsen F, Ryder LP, Madsen HO, Hillert J, Fredrikson S, Sandberg-Wollheim M, Laaksonen M, Koch-Henriksen N, Sawcer S, Fugger L, Sorensen PS, Svejgaard A (1999) Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis. Ann Neurol 46:612–616PubMedCrossRefGoogle Scholar
  56. Oturai AB, Ryder LP, Fredrikson S, Myhr KM, Celius EG, Harbo HF, Andersen O, Akesson E, Hillert J, Madsen HO, Nyland H, Spurkland A, Datta P, Svejgaard A, Sorensen PS (2004) Concordance for disease course and age of onset in Scandinavian multiple sclerosis coaffected sib pairs. Mult Scler 10:5–8PubMedCrossRefGoogle Scholar
  57. Ramagopalan SV, Morris AP, Dyment DA, Herrera BM, Deluca GC, Lincoln MR, Orton SM, Chao MJ, Sadovnick AD, Ebers GC (2007) The inheritance of resistance alleles in multiple sclerosis. PLoS. Genet. 3:1607–1613PubMedCrossRefGoogle Scholar
  58. Randolph DA, Fathman CG (2006) Cd4+Cd25+ regulatory T cells and their therapeutic potential. Annu Rev Med 57:381–402PubMedCrossRefGoogle Scholar
  59. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES (2001) Linkage disequilibrium in the human genome. Nature 411:199–204PubMedCrossRefGoogle Scholar
  60. Risch NJ (2000) Searching for genetic determinants in the new millennium. Nature 405:847–856PubMedCrossRefGoogle Scholar
  61. Russell TJ, Schultes LM, Kuban DJ (1972) Histocompatibility (HL-A) antigens associated with psoriasis. N Engl J Med 287:738–740PubMedGoogle Scholar
  62. Sanjeevi CB, Landin-Olsson M, Kockum I, Dahlquist G, Lernmark A (1995) Effects of the second HLA-DQ haplotype on the association with childhood insulin-dependent diabetes mellitus. Tissue Antigens 45:148–152PubMedGoogle Scholar
  63. Sawcer S, Compston A (2003) The genetic analysis of multiple sclerosis in Europeans: concepts and design. J Neuroimmunol 143:13–16PubMedCrossRefGoogle Scholar
  64. Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J, Robertson N, Clayton D, Goodfellow PN, Compston A (1996) A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 13:464–468PubMedCrossRefGoogle Scholar
  65. Sellebjerg F, Jensen J, Madsen HO, Svejgaard A (2000) HLA DRB1*1501 and intrathecal inflammation in multiple sclerosis. Tissue Antigens 55:312–318PubMedCrossRefGoogle Scholar
  66. Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMedGoogle Scholar
  67. Siegel JM (1999) Narcolepsy: a key role for hypocretins (orexins). Cell 98:409–412PubMedCrossRefGoogle Scholar
  68. Smestad C, Brynedal B, Jonasdottir G, Lorentzen AR, Masterman T, Akesson E, Spurkland A, Lie BA, Palmgren J, Celius EG, Hillert J, Harbo HF (2007) The impact of HLA-A and -DRB1 on age at onset, disease course and severity in Scandinavian multiple sclerosis patients. Eur J Neurol 14:835–840PubMedCrossRefGoogle Scholar
  69. Sospedra M, Martin R (2005a) Antigen-specific therapies in multiple sclerosis. Int Rev Immunol 24:393–413PubMedCrossRefGoogle Scholar
  70. Sospedra M, Martin R (2005b) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747PubMedCrossRefGoogle Scholar
  71. Spurkland A, Celius EG, Knutsen I, Beiske A, Thorsby E, Vartdal F (1997) The HLA-DQ(alpha 1*0102, beta 1*0602) heterodimer may confer susceptibility to multiple sclerosis in the absence of the HLA-DR(alpha 1*01, beta 1*1501) heterodimer. Tissue Antigens 50:15–22PubMedGoogle Scholar
  72. Suppiah V, Alloza I, Heggarty S, Goris A, Dubois B, Carton H, Vandenbroeck K (2005) The CTLA4 +49 A/G*G-CT60*G haplotype is associated with susceptibility to multiple sclerosis in Flanders. J Neuroimmunol 164:148–153PubMedCrossRefGoogle Scholar
  73. Svejgaard A (1996) MHC and disease associations, chapter 37. In: Weir’s handbook of experimental immunology in four volumes, 5th edn. Blackwell Scientific, New York, pp 37.1–37.13Google Scholar
  74. Svejgaard A (2006) HLA and disease. Lessons learnt from multiple sclerosis. In: Hansen JA (ed) Immunobiology of the human MHC. Proceedings of the 13th International Histocompatibility Workshop and Congress 2002. International Histocompatibility Working Group Press, Seattle, pp 160–169Google Scholar
  75. Svejgaard A, Ryder LP (1994) HLA and disease associations: detecting the strongest association. Tissue Antigens 43:18–27PubMedCrossRefGoogle Scholar
  76. Svejgaard A, Platz P, Ryder LP (1980) Insulin-dependent diabetes mellitus. In: Terasaki PI (ed) Histocompatibility testing 1980. UCLA Tissue Typing Laboratory, Los Angeles, pp 638–656Google Scholar
  77. Taheri S, Zeitzer JM, Mignot E (2002) The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu Rev Neurosci 25:283–313PubMedCrossRefGoogle Scholar
  78. The Games Collaborative GroupBan M, Booth D, Heard R, Stewart G, Goris A, Vandenbroeck K, Dubois B, Laaksonen M, Ilonen J, Alizadeh M, Edan G, Babron MC, Brassat D, Clanet M, Cournu-Rebeix I, Fontaine B, Semana G, Goedde R, Epplen J, Weber A, Infante-Duarte C, Zipp F, Rajda C, Bencsik K, Vecsei L, Heggarty S, Graham C, Hawkins S, Liguori M, Momigliano-Richiardi P, Caputo D, Grimaldi LM, Leone M, Massacesi L, Milanese C, Salvetti M, Savettieri G, Trojano M, Bielecki B, Mycko MP, Selmaj K, Santos M, Maciel P, Pereira C, Silva A, Silva BM, Coraddu F, Marrosu MG, Akesson E, Hillert J, Datta P, Oturai A, Harbo HF, Spurkland A, Goertsches R, Villoslada P, Eraksoy M, Hensiek A, Compston A, Setakis E, Gray J, Yeo TW, Sawcer S (2006) Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans. J Neuroimmunol 179:108–116PubMedCrossRefGoogle Scholar
  79. The MHC sequencing consortium (1999) Complete sequence of a human major histocompatibility complex. Nature 401:921–923CrossRefGoogle Scholar
  80. Vang T, Miletic AV, Bottini N, Mustelin T (2007) Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity 40:453–461PubMedCrossRefGoogle Scholar
  81. Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B, Jones R, Ring SM, McArdle W, Pembrey ME, Strachan DP, Dunger DB, Twells RC, Clayton DG, Todd JA (2005) Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 76:773–779PubMedCrossRefGoogle Scholar
  82. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199:971–979PubMedCrossRefGoogle Scholar
  83. Wucherpfennig KW, Strominger JL (1995) Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80:695–705PubMedCrossRefGoogle Scholar
  84. Yeo TW, De Jager PL, Gregory SG, Barcellos LF, Walton A, Goris A, Fenoglio C, Ban M, Taylor CJ, Goodman RS, Walsh E, Wolfish CS, Horton R, Traherne J, Beck S, Trowsdale J, Caillier SJ, Ivinson AJ, Green T, Pobywajlo S, Lander ES, Pericak-Vance MA, Haines JL, Daly MJ, Oksenberg JR, Hauser SL, Compston A, Hafler DA, Rioux JD, Sawcer S (2007) A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol 61:228–236PubMedCrossRefGoogle Scholar
  85. Zhang Z, Duvefelt K, Svensson F, Masterman T, Jonasdottir G, Salter H, Emahazion T, Hellgren D, Falk G, Olsson T, Hillert J, Anvret M (2005) Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun 6:145–152PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Clinical Immunology, Section 7631University Hospital of CopenhagenCopenhagen 0Denmark

Personalised recommendations