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Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus

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Abstract

Cytokines play key roles in immune responses, inflammation and fibrosis. The balance between levels of cytokines, their receptors and specific inhibitors controls inflammatory reactions in tissues. The pathogenesis of lichen sclerosus is unknown but probably involves cytokine mediators such as interleukin 1 (IL-1) and interleukin 1 receptor antagonist (IL-1ra). The IL-1ra is a competitive inhibitor of IL-1α and IL-1β, and therefore is a powerful endogenous anti-inflammatory molecule. The gene encoding IL-1ra (designated IL-1RN) has a variable number tandem repeat polymorphism in intron 2. There are five alleles of the gene corresponding to 2, 3, 4, 5 and 6 repeats of an 86-bp sequence. We have determined allele frequencies in a control population and a group of 78 patients with lichen sclerosus. The frequency of one of the alleles is related to increasing disease severity. Thus, IL-1RN may be a candidate gene or severity factor for lichen sclerosus or may possibly be a linked marker to another, as yet undefined, gene.

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References

  • Alcocer-Varela J, Martine-Cordero E, Alarcon-Segovia D (1985) Spontaneous production of and defective response to interleukin 1 by peripheral blood mononuclear cells from patients with scleroderma. Clin Exp Immunol 59: 666–672

    Google Scholar 

  • Bigler CF, Norris DA, Weston WL, Arend WP (1992) Interleukin 1 receptor antagonist production by human keratinocytes. J Invest Dermatol 98: 38–44

    Google Scholar 

  • Blakemore AIF, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff GW (1993) Interelukin 1 receptor antagonist gene polymorphism in systemic lupus erythematosus (abstract). Br J Rheum 32: 162

    Google Scholar 

  • Blakemore AIF, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff GW (1994) IL-1 receptor antagonist gene polymorphism as a severity factor in SLE. Arthritis Rheum (in press)

  • Camp R, Fincham N, Ross J, Bird C, Gearing A (1990) Potent inflammatory properties in human skin of interleukin 1 alpha like material isolated from normal skin. J Invest Dermatol 94: 735–741

    Google Scholar 

  • Carli P, Cattaneo A, Piminelli N, Cozza A, Bracco G, Giannotti B (1991) Immunohistochemical evidence of skin immune system involvement in vulvar lichen sclerosus et atrophicus. Dermatologica 182: 18–22

    Google Scholar 

  • Cork MJ, Mee JB, Tarlow JK, Blakemore AIF, Giovine FS di, Bleehen SS, Duff GW (1992) Induction pathway of cytokine gene expression across the active edge of psoriatic plaques (abstract). Br J Dermatol 127: 428

    Google Scholar 

  • Cork MJ, Tarlow JK, Blakemore AIF, Mee JB, Crane AM, Stierle C, Bleehen SS, Duff GW (1993) Psoriasis and interleukin 1. J R Coll Physicians Lond 27: 366

    Google Scholar 

  • Dickie RJ, Home CHW, Sutherland HW, Bewsher PD, Stankler L (1982) Direct evidence of localised immunological damage in vulvar lichen sclerosus et atrophicus. J Clin Pathol 35: 1395–1397

    Google Scholar 

  • Dinarello CA (1991) Interleukin 1 and interleukin 1 receptor antagonism. Blood 77: 1627–1652

    Google Scholar 

  • Dinarello CA, Thompson RC (1991) Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today 12: 404–410

    Google Scholar 

  • Duff GW (1989) Peptide regulatory factors in non-malignant disease. Lancet 1: 1432–1435

    Google Scholar 

  • Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC (1990) Primary structure and functional expression from complementary DNA of a human interleukin 1 receptor antagonist. Nature 343: 341–346

    Google Scholar 

  • Friedrich Jr EG, MacLaren NK (1984) Genetic aspects of vulvar lichen sclerosus. Am J Obstet Gynecol 150: 161–166

    Google Scholar 

  • Giovine FS di, Takhash E, Blakemore AIF, Duff GW (1992) Single base polymorphism at -511 in the human interleukin-1 β gene (IL-1β). Hum Mol Genet 1: 450

    Google Scholar 

  • Hammerberg C, Arend WP, Fisher GJ, Chan LS, Berger AE, Haskill JS, Voorhees JJ, Cooper KD (1992) Interleukin 1 receptor antagonist in normal and psoriatic epidermis. J Clin Invest 90: 571–583

    Google Scholar 

  • Haskill JS, Martin G, Van Le L, Morris J, Peace A, Bigler CF, Jaffe GJ, Hammerberg C, Sporn SA, Fong S, Arend WP, Ralph P (1991) cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Proc Natl Acad Sci USA 88: 3681–3685

    Google Scholar 

  • Jinks DC, Minter M, Tarver DA, Vanderford M, Hejtmancik JF, McCabe ERB (1989) Molecular genetic diagnosis of sickle cell disease using dried blood specimens on blotters used for newborn screening. Hum Genet 81: 363–366

    Google Scholar 

  • Kristensen M, Deleuran B, Eedy DJ, Feldmann M, Breathnach SM, Brennan FM (1992) Distribution of interleukin 1 receptor antagonist protein (IRAP) interleukin 1 receptor and interleukin 1α in normal and psoriatic skin. Decreased expression of IRAP in psoriatic lesional epidermis. Br J Dermatol 127: 305–311

    Google Scholar 

  • Kupper TS (1990) Immunophysiology: the role of cells and cytokines in immunity and inflammation. Oxford University Press, New York, pp 285–305

    Google Scholar 

  • Kutsch CL, Norris DA, Arend WP (1993) Tumour necrosis factor α induces interleukin 1 α and interleukin 1 receptor antagonist production by cultured human keratinocytes. J Invest Dermatol 101: 79–85

    Google Scholar 

  • Lennard A, Gorman P, Carrier M, Griffiths S, Scotney H, Sheer D, Solari R (1992) Cloning and chromosome mapping of the human interleukin 1 receptor antagonist gene. Cytokine 4: 83–89

    Google Scholar 

  • Mansfield JC, Holden H, Tarlow JK, Giovine FS di, McDowell TL, Wilson AG, Holdsworth CD, Duff GW (1994) Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin 1 receptor antagonist. Gastroenterology 106: 637

    Google Scholar 

  • Marren P, Yell J, Poskitt K, Wojinarowska F (1993) The immunogenetic basis for lichen sclerosus (abstract). Br J Dermatol 129: 23

    Google Scholar 

  • McIntyre KW, Stepan GJ, Kolinsky KD, Benjamin WR, Plocinski JM, Kaffka KL, Campen CA, Chizzonite RA, Kilian PL (1991) Inhibition of interleukin 1 (IL-1) at binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 173: 931–939

    Google Scholar 

  • Meyrick-Thomas RH, Ridley CM, McGibbon DH, Black MM (1988) Lichen sclerosus et atrophicus and autoimmunity, a study of 350 women. Br J Dermatol 118: 41–46

    Google Scholar 

  • Mizutani H, Black R, Kupper TS (1991) Human keratinocytes produce but do not process pro-interleukin 1 beta. Different strategies of IL-1 production and processing in monocytes and keratinocytes. J Clin Invest 87: 1066–1071

    Google Scholar 

  • Nickiin MJH, Weith A, Duff GW (1994) A physical map of the reion encompassing the human interleukin-1α, β and the interleukin-1 receptor antagonist genes. Genomics 19: 382–384

    Google Scholar 

  • Purcell KG, Spencer LV, Simpson PM, Helman SW, Oldfather JW, Fowler Jr JF (1990) HLA antigens in lichen sclerosus et atrophicus. Arch Dermatol 126: 1043–1045

    Google Scholar 

  • Ridley CM (1992) Lichen sclerosus. Dermatol Clin 10: 309–323

    Google Scholar 

  • Ridley CM (1993) Genital lichen sclerosus (lichen sclerosus el atrophicus) in childhood and adolescence. J R Soc Med 86: 69–75

    Google Scholar 

  • Schempp C, Bocklage H, Lange R, Kolmel HW, Orfanos CE, Gollnick H (1993) Further evidence for Borrelia burgdorferi infection in morphea and lichen sclerosus et atrophicus confirmed by DNA amplification. J Invest Dermatol 100: 717–720

    Google Scholar 

  • Schwartz BD (1992) The major histocompatibility complex and disease susceptibility. In: Wyngaarden JB, Smith Jr LH, Bennett JC (eds) Cecil textbook of medicine. Saunders, Philadelphia, pp 1470–1479

    Google Scholar 

  • Sideri M, Parazzini F, Rognoni MT, La Vecchia C, Negri E, Garsia S, Arnoletti E, Cecchetti G (1989) Risk factors for vulvar lichen sclerosus. Am J Obstet Gynecol 161: 38–42

    Google Scholar 

  • Steinkasserer A, Spurr NK, Cox S, Jeggo P, Sim RB (1992) The human IL-1 receptor antagonist gene (IL-1RN) maps to chromosome 2q14-q21 in the region of the IL-1α and IL-1β loci. Genomics 13: 654–657

    Google Scholar 

  • Tarlow JK, Blakemore AIF, Lennard A, Solari R, Hughes HN, Steinkasserer A, Duff GW (1993a) Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 91: 403–404

    Google Scholar 

  • Tarlow JK, Blakemore AIF, Cork MJ, Messenger A, McDonagh A, Bleehen SS, Gordon C, Emery P, Duff GW (1993b) Association between interelukin I receptor antagonist (IL-1ra) gene polymorphism and chronic inflammatory skin diseases (abstract). Br J Dermatol 129: 480

    Google Scholar 

  • Tarlow JK, Clay FE, Cork MJ, Blakemore AIF, McDonagh AJG, Messenger AG, Duff GW (1994) Severity of Alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene. J Invest Dermatol (in press)

  • Umehara H, Kumagai S, Murakami M, Suginoshita T, Tanaka K, Hashida S, Ishikawa E, Imura H (1990) Enhanced production of interleukin 1 and tumour necrosis factor a by cultured peripheral blood monocytes from patients with scleroderma. Arthritis Rheum 33: 893–897

    CAS  PubMed  Google Scholar 

  • Wilson AG, Giovine FS di, Blakemore AIF, Duff GW (1992) Single base polymorphism in the human tumour necrosis factor alpha (TNFα) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1: 353

    CAS  Google Scholar 

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Authors and Affiliations

  1. Section of Molecular Medicine, Royal Hallamshire Hospital, S10 2JF, Sheffield, UK

    Frances E. Clay, Michael J. Cork, Joanna K. Tarlow, Alexandra I. F. Blakemore & Gordon W. Duff

  2. Section of Dermatology, Royal Hallamshire Hospital, S10 2JF, Sheffield, UK

    Christine I. Harrington & Fiona Lewis

Authors
  1. Frances E. Clay
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  2. Michael J. Cork
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  3. Joanna K. Tarlow
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  4. Alexandra I. F. Blakemore
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  5. Christine I. Harrington
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  6. Fiona Lewis
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  7. Gordon W. Duff
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Clay, F.E., Cork, M.J., Tarlow, J.K. et al. Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus. Hum Genet 94, 407–410 (1994). https://doi.org/10.1007/BF00201602

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  • DOI: https://doi.org/10.1007/BF00201602

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