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Multiple sclerosis associates with LILRA3 deletion in Spanish patients

Genes & Immunity volume 10, pages 579–585 (2009)Cite this article

Abstract

The genetic susceptibility to multiple sclerosis (MS) is only partially explained, and it shows geographic variations. We analyse here two series of Spanish patients and healthy controls and show that relapsing MS (R-MS) is associated with a gene deletion affecting the hypothetically soluble leukocyte immunoglobulin (Ig)-like receptor A3 (LILRA3, 19q13.4), in agreement with an earlier finding in German patients. Our study points to a gene-dose-dependent, protective role for LILRA3, the deletion of which synergizes with HLA-DRB1*1501 to increase the risk of R-MS. We also investigated whether the risk of suffering R-MS might be influenced by the genotypic diversity of killer-cell Ig-like receptors (KIRs), located only ∼400 kb telomeric to LILRA3, and implicated in autoimmunity and defence against viruses. The relationship of LILRA3 deletion with R-MS is not secondary to linkage disequilibrium with a KIR gene, but we cannot exclude some contributions of KIR to the genetic susceptibility to R-MS.

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References

  1. Compston A, Coles A . Multiple sclerosis. Lancet 2008; 372: 1502–1517.

    Article  CAS  Google Scholar 

  2. Schmidt H, Williamson D, Ashley-Koch A . HLA-DR15 haplotype and multiple sclerosis: a HuGE review. Am J Epidemiol 2007; 165: 1097–1109.

    Article  Google Scholar 

  3. Svejgaard A . The immunogenetics of multiple sclerosis. Immunogenetics 2008; 60: 275–286.

    Article  CAS  Google Scholar 

  4. Haines JL, Bradford Y, Garcia ME, Reed AD, Neumeister E, Pericak-Vance MA et al. Multiple susceptibility loci for multiple sclerosis. Hum Mol Genet 2002; 11: 2251–2256.

    Article  CAS  Google Scholar 

  5. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851–862.

    Article  CAS  Google Scholar 

  6. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 2007; 39: 1083–1091.

    Article  CAS  Google Scholar 

  7. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom E, Khademi M et al. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 2007; 39: 1108–1113.

    Article  CAS  Google Scholar 

  8. Koch S, Goedde R, Nigmatova V, Epplen JT, Muller N, de Seze J et al. Association of multiple sclerosis with ILT6 deficiency. Genes Immun 2005; 6: 445–447.

    Article  CAS  Google Scholar 

  9. Arm JP, Nwankwo C, Austen KF . Molecular identification of a novel family of human Ig superfamily members that possess immunoreceptor tyrosine-based inhibition motifs and homology to the mouse gp49B1 inhibitory receptor. J Immunol 1997; 159: 2342–2349.

    CAS  PubMed  Google Scholar 

  10. Borges L, Hsu ML, Fanger N, Kubin M, Cosman D . A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J Immunol 1997; 159: 5192–5196.

    CAS  PubMed  Google Scholar 

  11. Colonna M, Navarro F, Bellon T, Llano M, Garcia P, Samaridis J et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp Med 1997; 186: 1809–1818.

    Article  CAS  Google Scholar 

  12. Torkar M, Haude A, Milne S, Beck S, Trowsdale J, Wilson MJ . Arrangement of the ILT gene cluster: a common null allele of the ILT6 gene results from a 6.7-kbp deletion. Eur J Immunol 2000; 30: 3655–3662.

    Article  CAS  Google Scholar 

  13. López-Botet M, Bellón T . Natural killer cell activation and inhibition by receptors for MHC class I. Curr Opin Immunol 1999; 11: 301–307.

    Article  Google Scholar 

  14. Lanier LL . Face off – the interplay between activating and inhibitory immune receptors. Curr Opin Immunol 2001; 13: 326–331.

    Article  CAS  Google Scholar 

  15. Cosman D, Fanger N, Borges L, Kubin M, Chin W, Peterson L et al. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 1997; 7: 273–282.

    Article  CAS  Google Scholar 

  16. Chapman TL, Heikeman AP, Bjorkman PJ . The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 1999; 11: 603–613.

    Article  CAS  Google Scholar 

  17. Valés-Gómez M, Shiroishi M, Maenaka K, Reyburn HT . Genetic variability of the major histocompatibility complex class I homologue encoded by human cytomegalovirus leads to differential binding to the inhibitory receptor ILT2. J Virol 2005; 79: 2251–2260.

    Article  Google Scholar 

  18. Kabalak G, Koch S, Dobberstein B, The YH, Matthias T, Schnarr S et al. Immunoglobulin-like transcripts as risk genes for autoimmunity. Ann N Y Acad Sci 2007; 1110: 10–14.

    Article  CAS  Google Scholar 

  19. Wilson MJ, Torkar M, Haude A, Milne S, Jones T, Sheer D et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci USA 2000; 97: 4778–4783.

    Article  CAS  Google Scholar 

  20. Vilches C, Parham P . KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002; 20: 217–251.

    Article  CAS  Google Scholar 

  21. Norman PJ, Parham P . Complex interactions: the immunogenetics of human leukocyte antigen and killer cell immunoglobulin-like receptors. Semin Hematol 2005; 42: 65–75.

    Article  CAS  Google Scholar 

  22. Parham P . MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 2005; 5: 201–214.

    Article  CAS  Google Scholar 

  23. Khakoo SI, Carrington M . KIR and disease: a model system or system of models? Immunol Rev 2006; 214: 186–201.

    Article  CAS  Google Scholar 

  24. Estefanía E, Gómez-Lozano N, Portero F, de Pablo R, Solís R, Sepúlveda S et al. Influence of KIR-gene diversity on the course of HSV-1 infection: resistance to the disease is associated with the absence of KIR2DL2 and KIR2DS2. Tissue Antigens 2007; 70: 34–41.

    Article  Google Scholar 

  25. Moretta A, Locatelli F, Moretta L . Human NK cells: from HLA class I-specific killer Ig-like receptors to the therapy of acute leukemias. Immunol Rev 2008; 224: 58–69.

    Article  CAS  Google Scholar 

  26. Reyburn HT, Mandelboim O, Vales-Gomez M, Davis DM, Pazmany L, Strominger JL . The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 1997; 386: 514–517.

    Article  CAS  Google Scholar 

  27. Farrell HE, Davis-Poynter NJ, Andrews DM, Degli-Esposti MA . Function of CMV-encoded MHC class I homologues. Curr Top Microbiol Immunol 2002; 269: 131–151.

    CAS  PubMed  Google Scholar 

  28. Gumá M, Angulo A, Lopez-Botet M . NK cell receptors involved in the response to human cytomegalovirus infection. Curr Top Microbiol Immunol 2006; 298: 207–223.

    PubMed  Google Scholar 

  29. Ressing ME, Horst D, Griffin BD, Tellam J, Zuo J, Khanna R et al. Epstein–Barr virus evasion of CD8 and CD4 T cell immunity via concerted actions of multiple gene products. Semin Cancer Biol 2008; 25: 25.

    Google Scholar 

  30. Pappworth IY, Wang EC, Rowe M . The switch from latent to productive infection in Epstein–Barr virus-infected B cells is associated with sensitization to NK cell killing. J Virol 2007; 81: 474–482.

    Article  CAS  Google Scholar 

  31. Guerreiro-Cacais AO, Uzunel M, Levitskaya J, Levitsky V . Inhibition of heavy chain and beta2-microglobulin synthesis as a mechanism of major histocompatibility complex class I downregulation during Epstein–Barr virus replication. J Virol 2007; 81: 1390–1400.

    Article  CAS  Google Scholar 

  32. Christensen T . Human herpesviruses in MS. Int MS J 2007; 14: 41–47.

    CAS  PubMed  Google Scholar 

  33. Morandi B, Bramanti P, Bonaccorsi I, Montalto E, Oliveri D, Pezzino G et al. Role of natural killer cells in the pathogenesis and progression of multiple sclerosis. Pharmacol Res 2008; 57: 1–5.

    Article  CAS  Google Scholar 

  34. Sospedra M, Martin R . Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683–747.

    Article  CAS  Google Scholar 

  35. Lunemann JD, Kamradt T, Martin R, Munz C . Epstein–Barr virus: environmental trigger of multiple sclerosis? J Virol 2007; 81: 6777–6784.

    Article  CAS  Google Scholar 

  36. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P et al. Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J Exp Med 2007; 204: 2899–2912.

    Article  CAS  Google Scholar 

  37. Friese MA, Jakobsen KB, Friis L, Etzensperger R, Craner MJ, McMahon RM et al. Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. Nat Med 2008; 14: 1227–1235.

    Article  CAS  Google Scholar 

  38. Pericak-Vance MA, Rimmler JB, Martin ER, Haines JL, Garcia ME, Oksenberg JR et al. Linkage and association analysis of chromosome 19q13 in multiple sclerosis. Neurogenetics 2001; 3: 195–201.

    Article  CAS  Google Scholar 

  39. Yeo TW, De Jager PL, Gregory SG, Barcellos LF, Walton A, Goris A et al. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol 2007; 61: 228–236.

    Article  Google Scholar 

  40. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

    Article  CAS  Google Scholar 

  41. Hirayasu K, Ohashi J, Kashiwase K, Takanashi M, Satake M, Tokunaga K et al. Long-term persistence of both functional and non-functional alleles at the leukocyte immunoglobulin-like receptor A3 (LILRA3) locus suggests balancing selection. Hum Genet 2006; 119: 436–443.

    Article  CAS  Google Scholar 

  42. Green A . The epidemiologic approach to studies of association between HLA and disease. II. Estimation of absolute risks, etiologic and preventive fraction. Tissue Antigens 1982; 19: 259–268.

    Article  CAS  Google Scholar 

  43. Consortium IMSG . Refining genetic associations in multiple sclerosis. Lancet Neurol 2008; 7: 567–569.

    Article  Google Scholar 

  44. Kotsch K, Wehling J, Blasczyk R . Sequencing of HLA class II genes based on the conserved diversity of the non-coding regions: sequencing based typing of HLA-DRB genes. Tissue Antigens 1999; 53: 486–497.

    Article  CAS  Google Scholar 

  45. Svejgaard A, Ryder LP . HLA and disease associations: detecting the strongest association. Tissue Antigens 1994; 43: 18–27.

    Article  CAS  Google Scholar 

  46. Vilches C, Castaño J, Gómez-Lozano N, Estefanía E . Facilitation of KIR genotyping by a PCR-SSP method that amplifies short DNA fragments. Tissue Antigens 2007; 70: 415–422.

    Article  CAS  Google Scholar 

  47. Norman PJ, Cook MA, Carey BS, Carrington CV, Verity DH, Hameed K et al. SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex. Immunogenetics 2004; 56: 225–237.

    Article  Google Scholar 

  48. Sawcer S, Ban M, Maranian M, Yeo TW, Compston A, Kirby A et al. A high-density screen for linkage in multiple sclerosis. Am J Hum Genet 2005; 77: 454–467.

    Article  Google Scholar 

  49. Yeo TW, Roxburgh R, Maranian M, Singlehurst S, Gray J, Hensiek A et al. Refining the analysis of a whole genome linkage disequilibrium association map: the United Kingdom results. J Neuroimmunol 2003; 143: 53–59.

    Article  CAS  Google Scholar 

  50. Abecasis GR, Noguchi E, Heinzmann A, Traherne JA, Bhattacharyya S, Leaves NI et al. Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 2001; 68: 191–197.

    Article  CAS  Google Scholar 

  51. Dunning AM, Durocher F, Healey CS, Teare MD, McBride SE, Carlomagno F et al. The extent of linkage disequilibrium in four populations with distinct demographic histories. Am J Hum Genet 2000; 67: 1544–1554.

    Article  CAS  Google Scholar 

  52. Bonetti A, Koivisto K, Pirttila T, Elovaara I, Reunanen M, Laaksonen M et al. A follow-up study of chromosome 19q13 in multiple sclerosis susceptibility. J Neuroimmunol 2009; 208: 119–124.

    Article  CAS  Google Scholar 

  53. Yawata M, Yawata N, Abi-Rached L, Parham P . Variation within the human killer cell immunoglobulin-like receptor (KIR) gene family. Crit Rev Immunol 2002; 22: 463–482.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Fernando García for helpful suggestions and Javier Castaño for excellent technical assistance. This work was supported by grants BFU2005-04622 from the Spanish Ministerio de Educación y Ciencia (to CV) and Red HERACLES-RD06/0009 from Instituto de Salud Carlos III (to JR and MLB). AJS and ER are supported by Fondo de Investigaciones Sanitarias (Spanish Ministerio de Ciencia e Innovación; CA07/410 and CA06/85, respectively).

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Authors and Affiliations

  1. Inmunogenética - HLA, Hospital Universitario Puerta de Hierro, Majadahonda, Spain

    D Ordóñez, E Cisneros, M Moraru & C Vilches

  2. Neuroinmunología, Hospital Universitario Puerta de Hierro, Majadahonda, Spain

    A J Sánchez, E Ramil & A García-Merino

  3. Neurología, Hospital del Mar-Institut Municipal d′Investigació Mèdica (IMIM), Barcelona, Spain

    J E Martínez-Rodríguez, E Munteis & J Roquer

  4. Molecular Immunopathology Unit, IMIM-Hospital del Mar, Universitat Pompeu Fabra, Barcelona, Spain

    N Romo & M López-Botet

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  1. D Ordóñez
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Correspondence to C Vilches.

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Ordóñez, D., Sánchez, A., Martínez-Rodríguez, J. et al. Multiple sclerosis associates with LILRA3 deletion in Spanish patients. Genes Immun 10, 579–585 (2009). https://doi.org/10.1038/gene.2009.34

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