Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

Abstract

Genes within the class II region of the major histocompatibility complex (MHC), including genes involved in antigen processing and presentation, have been reported to be associated with several autoimmune diseases. We report here that the LMP/TAP gene region is significantly associated with vitiligo, a disorder in which biochemical defects and/or autoimmune destruction cause melanocyte loss and resulting skin depigmentation. Case/control analyses revealed genetic association of vitiligo in Caucasian patients with an early age of onset with the transporter associated with antigen processing-1 (TAP1) gene. A family-based association method revealed biased transmission of specific alleles from heterozygous parents to affected offspring for the TAP1 gene, as well as for the closely linked LMP2 and LMP7 genes encoding subunits of the immunoproteasome. No association with vitiligo was found for the MECL1 gene, which encodes a third immunoproteasome subunit and is unlinked to the MHC class II region. These results suggest a possible role for the MHC class I antigen processing and/or presentation pathway in the antimelanocyte autoimmune response involved in vitiligo pathogenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Deng GY, Muir A, Maclaren NK, She JX . Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: Population family studies. Am J Hum Genet 1995; 56: 528–534.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Prahalad S, Kingsbury DJ, Griffin TA et al. Polymorphism in the MHC-encoded LMP7 gene: association with JRA without functional significance for immunoproteasome assembly. J Rheumatol 2001; 28: 2320–2325.

    CAS  PubMed  Google Scholar 

  3. Fraile A, Nieto A, Beraun Y, Martin J, Mataran L . Association of large molecular weight proteasome 7 gene polymorphism with ankylosing spondylitis. Arthritis Rheum 1998; 41: 560–562.

    Article  CAS  PubMed  Google Scholar 

  4. Djilali-Saiah I, Caillat-Zucman S, Schmitz J, Chaves-Vieira ML, Bach JF . Polymorphism of antigen processing (TAP, LMP) and HLA class II genes in celiac disease. Hum Immunol 1994; 40: 8–16.

    Article  CAS  PubMed  Google Scholar 

  5. Kumagai S, Kanagawa S, Morinobu A et al. Association of a new allele of the TAP2 gene, TAP2*Bky2 (Val577) with susceptibility to Sjögren's syndrome. Arthritis Rheum 1997; 40: 1685–1692.

    Article  CAS  PubMed  Google Scholar 

  6. Moins-Teisserance H, Semana G, Alizadeh M et al. TAP2 gene polymorphism contributes to genetic susceptibility to multiple sclerosis. Hum Immunol 1995; 42: 195–202.

    Article  Google Scholar 

  7. Tanaka K . Molecular biology of the proteasome. Biochem Biophys Res Commun 1998; 247: 537–541.

    Article  CAS  PubMed  Google Scholar 

  8. Pamer E, Cresswell P . Mechanisms of MHC class I-restricted antigen processing. Ann Rev Immunol 1998; 16: 323–358.

    Article  CAS  Google Scholar 

  9. Friedmann A . HLA and dermatological diseases. In: Lechler R, Warrens A (eds). HLA in Health and Disease. Academic Press: San Diego, 1999, pp 365–386.

    Google Scholar 

  10. Arcos-Burgos M, Parodi E, Salgar M et al. Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA. Hum Genet 2002; 110: 334–342.

    Article  CAS  PubMed  Google Scholar 

  11. Hann SK, Nordlund JJ (eds) . Vitiligo. Blackwell Science: Oxford, 2000.

    Book  Google Scholar 

  12. Le-Poole IC, van den Wijngaard RM, Westerhof W, Dutrieux RP, Das PK . Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 1993; 100: 816–822.

    Article  CAS  PubMed  Google Scholar 

  13. Tobin DJ, Swanson NN, Pittelkow MR, Peters EM, Schallreuter KU . Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 2000; 191: 407–416.

    Article  CAS  PubMed  Google Scholar 

  14. Das PK, van den Wijngaard RMJGJ, Wankowicz-Kalinska A, Le Poole IC . A symbiotic concept of autoimmunity and tumor immunity: lessons from vitiligo. Trends Immunol 2001; 22: 130–136.

    Article  CAS  PubMed  Google Scholar 

  15. Badri AM, Todd PM, Garioch JJ, Gudgeon JE, Stewart DG, Goudie RB . An immuno-histological study of cutaneous lymphocytes in vitiligo. J Pathol 1993; 170: 149–155.

    Article  CAS  PubMed  Google Scholar 

  16. Abdel-Naser MB, Kruger-Krasagakes S, Krasagakis K, Gollnick H, Orfanos CE . Further evidence for involvement of both cell mediated and humoral immunity in generalized vitiligo. Pigment Cell Res 1994; 7: 1–8.

    Article  CAS  PubMed  Google Scholar 

  17. Le Poole IC, van den Wijngaard RM, Westerhof W, Das PK . Presence of T cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Pathol 1996; 148: 1219–1228.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Harning R, Cui J, Bystryn JC . Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Dermatol 1991; 97: 1078–1080.

    Article  CAS  PubMed  Google Scholar 

  19. Song Y-H, Connor EL, Li Y, Zorovich B, Balducci P, Maclaren N . The role of tyrosinase in autoimmune vitiligo. Lancet 1994; 344: 1049–1052.

    Article  CAS  PubMed  Google Scholar 

  20. Kemp EH, Waterman EA, Gawkrodger DJ, Watson PF, Weetman AP . Autoantibodies to tyrosinase-related protein-1 detected in the sera of vitiligo patients using a quantitative radiobinding assay. Br J Dermatol 1998; 139: 798–805.

    Article  CAS  PubMed  Google Scholar 

  21. Bhatia PS, Mohan L, Pandey ON, Singh KK, Arora SK, Mukhija RD . Genetic nature of vitiligo. J Derm Sci 1992; 4: 180–184.

    Article  CAS  Google Scholar 

  22. Nath SK, Majumder PP, Nordlund JJ . Genetic epidemiology of vitiligo: multilocus recessivity cross-validated. Am J Hum Genet 1994; 55: 981–990.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Majumder PP, Nordlund JJ, Nath SK . Pattern of familial aggregation of vitiligo. Arch Dermatol 1993; 129: 994–998.

    Article  CAS  PubMed  Google Scholar 

  24. Alkhateeb A, Stetler GL, Old W et al. Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3–p32.2. Hum Mol Genet 2002; 11: 661–667.

    Article  CAS  PubMed  Google Scholar 

  25. Casp CB, She JX, McCormack WT . Genetic association of the catalase gene (CAT) with vitiligo susceptibility. Pigment Cell Res 2002; 15: 62–66.

    Article  CAS  PubMed  Google Scholar 

  26. Weir BS, Cockerham CC . Estimating F-statistics for the analysis of population structure. Evolution 1984; 38: 1358–1370.

    CAS  PubMed  Google Scholar 

  27. Spielman RS, Ewens WJ . The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 1996; 59: 983–989.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Orecchia G, Perfetti L, Malagoli P, Borghini F, Kipervag Y . Vitiligo is associated with a significant increase in HLA-A30, Cw6 and DQw3 and a decrease in C4AQ0 in northern Italian patients. Dermatology 1992; 185: 123–127.

    Article  CAS  PubMed  Google Scholar 

  29. Finco OM, Cuccia M, Martinetti G et al. Age of onset in vitiligo: relationship with HLA supratypes. Clin Genet 1991; 39: 48–54.

    Article  CAS  PubMed  Google Scholar 

  30. Djilali-Saiah I, Benini V, Daniel S, Assan R, Bach J-F, Caillat-Zucman S . Linkage disequilibrium between HLA class II (DR, DQ, DP) and antigen processing (LMP, TAP, DM) genes of the major histocompatibility complex. Tissue Antigens 1996; 48: 87–92.

    Article  CAS  PubMed  Google Scholar 

  31. Van Endert PM, Lopez MT, Patel SD, Monaco JJ, Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes. Proc Natl Acad Sci USA 1992; 89: 11594–11597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Carrington M, Stephens JC, Klitz W et al. Major histocompatibility complex class II haplotypes and linkage disequilibrium values observed in the CEPH families. Hum Immunol 1994; 41: 234–240.

    Article  CAS  PubMed  Google Scholar 

  33. Cullen M, Nobel J, Erlich H et al. Characterization of recombination in the HLA class II region. Am J Hum Genet 1997; 60: 397–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Jeffreys AJ, Ritchie A, Neumann R . High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. Hum Mol Genet 2000; 9: 725–733.

    Article  CAS  PubMed  Google Scholar 

  35. Cullen M, Perfetto SP, Klitz W, Nelson G, Carrington M . High-resolution patterns of meiotic recombination across the human major histocompatibility complex. Am J Hum Genet 2002; 71: 759–776.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Fu Y, Yan G, Shi L, Faustman D . Antigen processing and autoimmunity. Evaluation of mRNA abundance and function of HLA-linked genes. Ann NY Acad Sci 1998; 42: 138–155.

    Article  Google Scholar 

  37. Brooks P, Fuertes G, Murray RZ et al. Subcellular localization of proteasomes and their regulatory complexes in mammalian cells. Biochem J 2000; 346: 155–161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rock KL, Goldberg AL . Degradation of cell proteins and the generation of MHC class I-presented peptides. Ann Rev Immunol 1999; 17: 739–779.

    Article  CAS  Google Scholar 

  39. Rechsteiner M, Realini C, Ustrell V . The proteasome activator 11 S REG (PA28) and class I antigen presentation. Biochem J 2000; 345: 1–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Quadri SA, Singal DP . Peptide transport in human lymphoblastoid and tumor cells: effect of transporter associated with antigen presentation (TAP) polymorphism. Immunol Lett 1998; 61: 25–31.

    Article  CAS  PubMed  Google Scholar 

  41. Hayney MS, Poland GA, Dimanlig P et al. Polymorphisms of the TAP2 gene may influence antibody response to live measles vaccine virus. Vaccine 1997; 15: 3–6.

    Article  CAS  PubMed  Google Scholar 

  42. Obst R, Armandola EA, Nijenhuis M, Momburg F, Hammerling GJ . TAP polymorphism does not influence transport of peptide variants in mice and humans. Eur J Immunol 1995; 25: 2170–2176.

    Article  CAS  PubMed  Google Scholar 

  43. Daniel S, Caillat-Zucman S, Hammer J, Bach JF, van Endert PM . Absence of functional relevance of human transporter associated with antigen processing polymorphism for peptide selection. J Immunol 1997; 159: 2350–2357.

    CAS  PubMed  Google Scholar 

  44. Mishto M, Bonafe M, Salvioli S, Olivieri F, Franceschi C . Age dependent impact of LMP polymorphisms on TNFα-induced apoptosis in human peripheral blood mononuclear cells. Exp Gerontol 2002; 37: 301–308.

    Article  CAS  PubMed  Google Scholar 

  45. Sugimoto Y, Kuzushita N, Takehara T et al. A single nucleotide polymorphism of the low molecular mass polypeptide 7 gene influences the interferon response in patients with chronic hepatitis C. J Viral Hepat 2002; 9: 377–384.

    Article  CAS  PubMed  Google Scholar 

  46. Groettrup M, Khan S, Schwarz K, Schmidtke G . Interferon-γ inducible exchanges of 20S proteasome active site subunits: why? Biochimie 2001; 83: 367–372.

    Article  CAS  PubMed  Google Scholar 

  47. Wright KL, White LC, Kelly A et al. Coordinate regulation of the human TAP1 and LMP2 genes from a shared bi-directional promoter. J Exp Med 1995; 181: 1459–1471.

    Article  CAS  PubMed  Google Scholar 

  48. Pericak-Vance MA . Linkage disequilibrium and allelic association. In: Pericak-Vance MA, Haines JL, (eds). Approaches to Gene Mapping in Complex Human Diseases. Wiley-Liss: New York, 1998, pp 323–333.

    Google Scholar 

  49. Lewis PO, Zaykin D . Genetic Data Analysis: Computer Program for the Analysis of Allelic Data. 2001, Version 1.0 (d16c). Free program distributed by the authors over the internet from http://lewis.eeb.uconn.edu/lewishome/software.html.

Download references

Acknowledgements

We are grateful to the many vitiligo patients and family members who provided blood samples for this research. We thank Margaret R Wallace, Sally A Litherland and Susan P McGorray for helpful discussions and thoughtful critique of the manuscript. This work was supported by grants from the National Vitiligo Foundation and by Clinical Research Center Grant RR00082. CBC was supported by a training grant from the National Institutes of Health (T32 AR 07603), and by the UF Center for Immunology & Transplantation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W T McCormack.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Casp, C., She, JX. & McCormack, W. Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo. Genes Immun 4, 492–499 (2003). https://doi.org/10.1038/sj.gene.6364016

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364016

Keywords

This article is cited by

Search

Quick links