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PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

Genes & Immunity volume 6, pages 430–437 (2005)Cite this article

Abstract

Variation in genes encoding costimulatory molecules expressed on lymphocytes has been expected to contribute to the genetic component of inflammatory disease, but only the gene encoding the inhibitory protein, CTLA-4, seems consistently to confer disease susceptibility. Studies in murine models implicate the inhibitory product of the pd1 gene, programmed death-1, in the maintenance of peripheral tolerance to self-antigens. We identify 22 single-nucleotide polymorphisms (SNPs) in the equivalent human gene, PDCD1, a number of which show significant associations with the specific immunoglobulin E response to grass allergens in atopic individuals. Stepwise analyses indicate that four of the disease-associated SNPs have independent effects. The two most common haplotypes show positive and negative associations but rarer haplotypes are also likely to be of influence. In a case–control study, multiple regression analysis of genotypic data implies that PDCD1 also confers susceptibility to rheumatoid arthritis. Along with work linking PDCD1 with susceptibility to another autoimmune condition, systemic lupus erythematosus, our data identify PDCD1 as a second immunomodulatory gene with pleiotropic effects in human disease. Genes encoding negative regulators may generally confer a significant fraction of the genetic risk associated with inherited inflammatory disorders.

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References

  1. Chen L . Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 2004; 8: 336–347.

    Article  Google Scholar 

  2. Acuto O, Michel F . CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 2003; 3: 939–951.

    Article  CAS  Google Scholar 

  3. Kristiansen OP, Larsen ZM, Pociot F . CTLA-4 in autoimmune diseases—a general susceptibility gene to autoimmunity? Genes Immun 2000; 1: 170–184.

    Article  CAS  Google Scholar 

  4. Ahmed S, Ihara K, Kanemitsu S et al. Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population. Rheumatology 2001; 40: 662–667.

    Article  CAS  Google Scholar 

  5. Teutsch SM, Booth DR, Bennetts BH, Heard RN, Stewart GJ . Association of common T cell activation gene polymorphisms with multiple sclerosis in Australian patients. J Neuroimmunol 2004; 148: 218–230.

    Article  CAS  Google Scholar 

  6. Milicic A, Brown MA, Wordsworth BP . Polymorphism in codon 17 of the CTLA-4 gene (+49 A/G) is not associated with susceptibility to rheumatoid arthritis in British Caucasians. Tissue Antigens 2001; 58: 50–54.

    Article  CAS  Google Scholar 

  7. Nishimura H, Agata Y, Kawasaki A et al. Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol 1996; 8: 773–780.

    Article  CAS  Google Scholar 

  8. Okazaki T, Iwai Y, Honjo T . New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 2002; 14: 779–782.

    Article  CAS  Google Scholar 

  9. Hutloff A, Dittrich AM, Beier KC et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1999; 397: 263–266.

    Article  CAS  Google Scholar 

  10. Watanabe N, Gavrieli M, Sedy JR et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 2003; 4: 670–679.

    Article  CAS  Google Scholar 

  11. Carreno BM, Collins M . The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 2002; 20: 29–53.

    Article  CAS  Google Scholar 

  12. Nishimura H, Nose M, Hiai H, Minato N, Honjo T . Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11: 141–151.

    Article  CAS  Google Scholar 

  13. Nishimura H, Okazaki T, Tanaka Y et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001; 291: 319–322.

    Article  CAS  Google Scholar 

  14. Prokunina L, Castillejo-Lopez C, Oberg F et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002; 32: 666–669.

    Article  CAS  Google Scholar 

  15. Daniels SE, Bhattacharrya S, James A et al. A genome-wide search for quantitative trait loci underlying asthma. Nature 1996; 383: 186–194.

    Article  Google Scholar 

  16. CSGA. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet 1997; 15: 389–392.

  17. Ober C, Cox NJ, Abney M et al. Genome-wide search for asthma susceptibility loci in a founder population. Hum Mol Genet 1998; 7: 1393–1398.

    Article  CAS  Google Scholar 

  18. Koppelman GH, Stine OC, Xu J et al. Genome-wide search for atopy susceptibility genes in Dutch families with asthma. J Allergy Clin Immunol. 2002; 109: 498–506.

    Article  CAS  Google Scholar 

  19. Heinzmann A, Plesnar C, Kuehr J, Forster J, Deichmann KA . Common polymorphisms in the CTLA-4 and CD28 genes at 2q33 are not associated with asthma or atopy. Eur J Immunogen 2000; 27: 57–61.

    Article  CAS  Google Scholar 

  20. Howard TD, Postma DS, Hawkins GA et al. Fine mapping of an IgE-controlling gene on chromosome 2q: analysis of CTLA4 and CD28. J Allergy Clin Immunol 2002; 110: 743–751.

    Article  CAS  Google Scholar 

  21. Hizawa N, Yamaguchi E, Jinushi E, Konno S, Kawakami Y, Nishimura M . Increased total serum IgE levels in patients with asthma and promoter polymorphisms at CTLA4 and FCER1B. J Allergy Clin Immunol 2001; 108: 74–79.

    Article  CAS  Google Scholar 

  22. Lee SY, Lee YH, Shin C et al. Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene. Chest 2002; 122: 171–176.

    Article  CAS  Google Scholar 

  23. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.

    Article  CAS  Google Scholar 

  24. Romagnani S . Lymphokine production by human T cells in disease states. Annu Rev Immunol 1994; 12: 227–257.

    Article  CAS  Google Scholar 

  25. Sekigawa I, Yoshiike T, Iida N, Hashimoto H, Ogawa H . Allergic disorders in systemic lupus erythematosus: prevalence and family history. Lupus 2002; 11: 426–429.

    Article  CAS  Google Scholar 

  26. Matsushita M, Hayashi T, Ando S et al. Changes of CD4/CD8 ratio and interleukin-16 in systemic lupus erythematosus. Clin Rheumatol 2000; 19: 270–274.

    Article  CAS  Google Scholar 

  27. Sekigawa I, Matsushita M, Lee S et al. A possible pathogenic role of CD8+ T cells and their derived cytokine, IL-16, in SLE. Autoimmunity 2000; 33: 37–44.

    Article  CAS  Google Scholar 

  28. Sekigawa I, Ogasawara H, Kaneko H, Hishikawa T, Hashimoto H . Retroviruses and autoimmunity. Intern Med 2001; 40: 80–86.

    Article  CAS  Google Scholar 

  29. Joffe MI, Kew M, Rabson AR . Lymphocyte subtypes in patients with atopic eczema, protein calorie malnutrition, SLE and liver disease. J Clin Lab Immunol 1982; 10: 97–101.

    Google Scholar 

  30. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T . PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 2001; 98: 13866–13871.

    Article  CAS  Google Scholar 

  31. Dong H, Zhu G, Tamada K, Chen L . B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999; 5: 1365–1369.

    Article  CAS  Google Scholar 

  32. Tseng SY, Otsuji M, Gorski K et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001; 193: 839–846.

    Article  CAS  Google Scholar 

  33. Sidorenko SP, Clark EA . The dual-function CD150 receptor subfamily: the viral attraction. Nat Immunol 2003; 4: 19–24.

    Article  CAS  Google Scholar 

  34. Freeman GJ, Long AJ, Iwai Y et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192: 1027–1034.

    Article  CAS  Google Scholar 

  35. Latchman Y, Wood CR, Chernova T et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2: 261–268.

    Article  CAS  Google Scholar 

  36. Nishimura H, Honjo T, Minato N . Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000; 191: 891–898.

    Article  CAS  Google Scholar 

  37. Sears MR, Herbison GP, Holdaway MD, Hewitt CJ, Flannery EM, Silva PA . The relative risks of sensitivity to grass pollen, house dust mite and cat dander in the development of childhood asthma. Clin Exp Allergy 1989; 19: 419–424.

    Article  CAS  Google Scholar 

  38. Cookson WO, De Klerk NH, Ryan GR, James AL, Musk AW . Relative risks of bronchial hyper-responsiveness associated with skin-prick test responses to common antigens in young adults. Clin Exp Allergy 1991; 21: 473–479.

    Article  CAS  Google Scholar 

  39. Ober C, Moffatt M . Contributing factors to the pathobiology. The genetics of asthma. Clin Chest Med 2000; 21: 245–261.

    Article  CAS  Google Scholar 

  40. Ueda H, Howson JMM, Esposito L et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423: 506–511.

    Article  CAS  Google Scholar 

  41. Prokunina L, Padyukov L, Bennet A et al. Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope. Arthritis Rheum 2004; 50: 1770–1773.

    Article  CAS  Google Scholar 

  42. Lin SC, Yen JH, Tsai JJ . Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus. Arthritis Rheum 2004; 50: 770–775.

    Article  CAS  Google Scholar 

  43. Ferreiros-Vidal I, Gomez-Reino JJ, Barros F et al. Association of PDCD1 with susceptibility to systemic lupus erythematosus: evidence of population-specific effects. Arthritis Rheum 2004; 50: 2590–2597.

    Article  CAS  Google Scholar 

  44. Dermitzakis ET, Reymond A, Scamuffa N et al. Evolutionary discrimination of mammalian conserved non-genic sequences (CNGs). Science 2003; 302: 1033–1035.

    Article  CAS  Google Scholar 

  45. Ravetch JV, Lanier LL . Immune inhibitory receptors. Science 2000; 290: 84–89.

    Article  CAS  Google Scholar 

  46. Freitas AA, Rocha B . Peripheral T cell survival. Curr Opin Immunol 1999; 11: 152–156.

    Article  CAS  Google Scholar 

  47. Kruglyak L, Nickerson DA . Variation is the spice of life. Nat Genet 2001; 27: 234–236.

    Article  CAS  Google Scholar 

  48. Moffatt MF, Hill MR, Cornelius F et al. Genetic linkage of T-cell receptor alpha/delta complex to specific IgE responses. Lancet 1994; 343: 1597–1600.

    Article  CAS  Google Scholar 

  49. Hill MR, James AL, Faux JA et al. Fc epsilon RI-beta polymorphism and risk of atopy in a general population sample. BMJ 1995; 311: 776–779.

    Article  CAS  Google Scholar 

  50. Zhang L, Cui X, Schmitt K, Hubert R, Navidi W, Arnheim N . Whole genome amplification from a single cell: implications for genetic analysis. Proc Natl Acad Sci USA 1992; 89: 5847–5851.

    Article  CAS  Google Scholar 

  51. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

    Article  CAS  Google Scholar 

  52. Abecasis GR, Cardon LR, Cookson WO . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–292.

    Article  CAS  Google Scholar 

  53. Monks SA, Kaplan NL, Weir BS . A comparative study of sibship tests of linkage and/or association. Am J Hum Genet 1998; 63: 1507–1516.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was funded by the Arthritis Research Campaign and by The Wellcome Trust.

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Authors and Affiliations

  1. Nuffield Department of Clinical Medicine, The University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK

    E S James & S J Davis

  2. Rheumatoid Arthritis Genetics Group, Institute of Musculoskeletal Sciences, The University of Oxford, The Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK

    S Harney & B P Wordsworth

  3. Asthma Genetics Group, The Henry Wellcome Building for Genomic Medicine, The University of Oxford, Roosevelt Drive, Headington, Oxford, UK

    E S James, W O C M Cookson & M F Moffatt

  4. MRC Human Immunology Unit, The University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK

    S J Davis

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  1. E S James
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Correspondence to S J Davis.

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Supplementary information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene).

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James, E., Harney, S., Wordsworth, B. et al. PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders. Genes Immun 6, 430–437 (2005). https://doi.org/10.1038/sj.gene.6364223

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