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The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

Autoimmunity Highlights volume 1, pages 73–81 (2010)Cite this article

Abstract

CTLA-4, initially described as a membranebound molecule, is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence shows the CTLA-4 gene to be an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T-lymphocyte-associated antigen-4 (sCTLA-4) has been established and shown to possess CD80/CD86 binding activity and in vitro immunoregulatory functions. sCTLA-4 is generated by alternatively spliced mRNA. Whereas low levels of sCTLA-4 are detected in normal human serum, increased serum levels are observed in several autoimmune diseases (e.g. Graves’ disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, coeliac disease, autoimmune pancreatitis and primary biliary cirrhosis). The biological significance of increased sCTLA-4 serum levels is not fully clarified yet. On the one hand, it can be envisaged that sCTLA-4 specifically inhibits early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could compete for the binding of the membrane form of CTLA-4 with CD80/CD86 in the later phases of T-lymphocyte activation, causing a reduction in inhibitory signalling. This double-edged nature of sCTLA-4 to block the binding of CD28 to CD80/CD86 may result in different outcomes during the clinical course of an autoimmune disease.

References

  1. Lenschow DJ, Walunas TL, Blueston JA (1996) CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233–258

    Article  PubMed  Google Scholar 

  2. Bocko D, Kosmaczewska A, Ciszak L et al (2002) CD28 costimulatory molecule — expression, structure and function. Arch Immunol Ther Exp 50:169–177

    Google Scholar 

  3. Shapiro VS, Truitt KE, Imboden JB et al (1997) CD28 mediates transcriptional upregulation of the interleukin-2 (IL-2) promoter through a composite element containing the CD28RE and NF-IL-2B AP-1 sites. Mol Cell Biol 17:4051–4058

    Article  PubMed  PubMed Central  Google Scholar 

  4. Walunas TL, Lenschow DJ, Bakker CY et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413

    Article  PubMed  Google Scholar 

  5. Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459–465

    Article  PubMed  Google Scholar 

  6. Saverino D, Tenca C, Zarcone D et al (1999) CTLA-4 (CD152) inhibits the specific lysis mediated by human cytolytic T lymphocytes in a clonally distributed fashion. J Immunol 162:651–658

    PubMed  Google Scholar 

  7. Merlo A, Tenca C, Fais F et al (2005) Inhibitory receptors CD85j, LAIR-1, and CD152 down-regulate immunoglobulin and cytokine production by human B lymphocytes. Clin Diagn Lab Immunol12:705–712

    Google Scholar 

  8. Laurent S, Carrega P, Saverino D et al CTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions. Hum Immunol. DOI: http://dx.doi.org/10.1016/j.humi-mm.2010.07.007

  9. Saverino D, Merlo A, Bruno S et al (2002) Dual effect of CD85/leukocyte Ig-like receptor-1/Ig-like transcript 2 and CD152 (CTLA-4) on cytokine production by antigen-stimulated human T cells. J Immunol 168:207–215

    Article  PubMed  Google Scholar 

  10. Oaks MK, Hallett KM, Penwell RT et al (2000) A native soluble form of CTLA-4. Cell Immunol 201:144–153

    Article  PubMed  Google Scholar 

  11. Simone R, Saverino D (2009) The soluble CTLA-4 receptor and its emerging role in autoimmune diseases. Curr Immunol Rev 5:54–68

    Article  Google Scholar 

  12. Wong CK, Lun SWM, Ko FW et al (2005) Increased expression of plasma and cell surface co-stimulatory molecules CTLA-4, CD28 and CD86 in adult patients with allergic asthma. Clin Exp Immunol 141:122–129

    Article  PubMed  PubMed Central  Google Scholar 

  13. Saverino D, Riccio AM, Rogkakou A et al (2009) Serum CTLA-4 in Hymenoptera venom allergy end its modulation by specific immunotherapy. J Allergy Clin Immunol 123:258–260

    Article  PubMed  Google Scholar 

  14. Sakthivel P, Wermeling F, Elmgren A et al (2010) Circulating soluble CTLA-4 is related to inflammatory markers in the 70 year old population. Scand J Clin Lab Invest 70:237–243

    Article  PubMed  Google Scholar 

  15. Tunbridge WM, Evered DC, Hall R et al (1997) The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol 7:481–493

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  17. Awata T, Kurihara S, Iitaka M et al (1998) Association of CTLA-4 gene A-G polymorphism (IDDM12 locus) with acute-onset and insulin-depleted IDDM as well as autoimmune thyroid disease (Graves’ disease and Hashimoto’s thyroiditis) in the Japanese population. Diabetes 47:128–129

    Article  PubMed  Google Scholar 

  18. Kouki T, Sawai Y, Gardine CA et al (2000) CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves’ disease. J Immunol 165:6606–6611

    Article  PubMed  Google Scholar 

  19. Mochizuki M, Amemiya S, Kobayashi K et al (2003) Association of the CTLA-4 gene 49 A/G polymorphism with type 1 diabetes and autoimmune thyroid disease in Japanese children. Diabetes Care 26:843–847

    Article  PubMed  Google Scholar 

  20. Oaks MK, Hallett KM (2000) A soluble form of CTLA-4 in patients with autoimmune thyroid disease. J Immunol 164:5015–5018

    Article  PubMed  Google Scholar 

  21. Lafage-Pochitaloff M, Costello R, Couez D et al (1990) Human CD28 and CTLA-4 Ig superfamily genes are located on chromosome 2 at bands q33–q34. Immunogenetics 31:198–201

    Article  PubMed  Google Scholar 

  22. Harper K, Balzano C, Rouvier E et al (1991) CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal localization. J Immunol 147:1037–1044

    PubMed  Google Scholar 

  23. Linsley PS, Greene JL, Brady WH et al (1994) Human B.7-1(CD80) and B.7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1:793–801

    Article  PubMed  Google Scholar 

  24. Nisticò L, Buzzetti R, Pritchard LE et al (1996) The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Hum Mol Genet 5:1075–1080

    Article  PubMed  Google Scholar 

  25. Deichmann K, Heinzmann A, Brüggenolte et al (1996) An Mse I RFLP in the human CTLA4 promotor. Biochem Biophys Res Commun 225:817–818

    Article  PubMed  Google Scholar 

  26. Davies TF (1996) The pathogenesis of Graves’ disease. In: Braverman LE, Utiger RD (eds) The thyroid, 7th edn. Lippincott-Raven, Philadelphia, pp 525–536

    Google Scholar 

  27. Tomer Y, Huber A (2009) The etiology of autoimmune thyroid disease: a story of genes and environment. J Autoimmun 32:231–239

    Article  PubMed  PubMed Central  Google Scholar 

  28. Weetman AP, McGregor AM (1994) Autoimmune thyroid disease: further developments in our understanding. Endocr Rev 15:788–830

    PubMed  Google Scholar 

  29. Yanagawa T, Hidaka Y, Guimaraes V et al (1995) CTLA-4 gene polymorphism associated with Graves’ disease in a Caucasian population. J Clin Endocrinol Metab 80:41–45

    PubMed  Google Scholar 

  30. Zhao SX, Pan CM, Cao HM et al (2010) Association of the CTLA4 gene with Graves’ disease in the Chinese Han population. PLoS One 5:e9821

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gu LQ, Zhu W, Zhao SX et al (2010) Clinical associations of the genetic variants of CTLA-4, Tg, TSHR, PTPN22, PTPN12 and FCRL3 in patients with Graves’ disease. Clin Endocrinol 72:248–255

    Article  Google Scholar 

  32. Yin X, Latif R, Bahn R et al (2008) Influence of the TSH receptor gene on susceptibility to Graves’ disease and Graves’ ophthalmopathy. Thyroid 18:1201–1206

    Article  PubMed  PubMed Central  Google Scholar 

  33. Daroszewski J, Pawlak E, Karabon L et al (2009) Soluble CTLA-4 receptor an immunological marker of Graves’ disease and severity of ophthalmopathy is associated with CTLA-4 Jo31 and CT60 gene polymorphisms. Eur J Endocrinol 161:787–793

    Article  PubMed  Google Scholar 

  34. Dallos T, Avbelj M, Barák L et al (2008) CTLA-4 gene polymorphisms predispose to autoimmune endocrinopathies but not to celiac disease. Neuro Endocrinol Lett 9:334–340

    Google Scholar 

  35. Douroudis K, Prans E, Kisand K et al (2009) Cytotoxic Tlymphocyte antigen 4 gene polymorphisms are associated with latent autoimmune diabetes in adults. Clin Chim Acta 403:226–228

    Article  PubMed  Google Scholar 

  36. Saleh HM, Rohowsky N, Leski M (2008) The CTLA4 -819 C/T and +49 A/G dimorphisms are associated with Type 1 diabetes in Egyptian children. Indian J Hum Genet 14:92–98

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  38. Fritze D, Herrman C, Naeim F et al (1974) HL-A antigens in myasthenia gravis. Lancet 1:240–242

    Article  PubMed  Google Scholar 

  39. Fernández-Mestre M, Sánchez K, Balbás O et al (2009) Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases. Hum Immunol 70:532–535

    Article  PubMed  Google Scholar 

  40. Wray BN, Stankovich J, Whittock L et al (2008) CTLA-4 and multiple sclerosis: the A49G single nucleotide polymorphism shows no association with multiple sclerosis in a Southern Australian population. J Neuroimmunol 196:139–142

    Article  PubMed  Google Scholar 

  41. Muñoz-Valle JF, Valle Y, Padilla-Gutiérrez JR et al (2010) The +49A>G CTLA-4 polymorphism is associated with rheumatoid arthritis in Mexican population. Clin Chim Acta 411:725–728

    Article  PubMed  Google Scholar 

  42. Holopainen P, Naluai AT, Moodie S et al; Members of the European Genetics Cluster on Coeliac Disease (2004) Candidate gene region 2q33 in European families with coeliac disease. Tissue Antigens 63:212–222

    Article  PubMed  Google Scholar 

  43. Talwalkar JA, Lindor KD (2003) Primary biliary cirrhosis. Lancet 362:53–61

    Article  PubMed  Google Scholar 

  44. Gershwin ME, Mackay IR (2008) The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 47:737–745

    Article  PubMed  Google Scholar 

  45. Invernizzi P, Selmi C, Poli F et al (2008) Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls. Hepatology 48:1906–1912

    Article  PubMed  PubMed Central  Google Scholar 

  46. Donaldson PT, Baragiotta A, Heneghan MA et al (2006) HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study. Hepatology 44:667–674

    Article  PubMed  Google Scholar 

  47. Shimoda S, Nakamura M, Ishibashi H et al (1995) HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med 181:1835–1845

    Article  PubMed  Google Scholar 

  48. Joshita S, Umemura T, Yoshizawa K et al; Shinshu PBC Study Group (2010) Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients. J Hepatol 53:537–541

    Article  PubMed  Google Scholar 

  49. Saverino D, Brizzolara R, Simone R et al (2007) Soluble CTLA-4 in autoimmune thyroid diseases: relationship with clinical status and possible role in the immune response dysregulation. Clin Immunol 123:190–198

    Article  PubMed  Google Scholar 

  50. Wang XB, Kakoulidou M, Giscombe R et al (2002) Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence. J Neuroimmunol 130:224–232

    Article  PubMed  Google Scholar 

  51. Simone R, Brizzolara R, Chiappori A et al (2009) A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury and tTG antibody production. Int Immunol 21:1037–1045

    Article  PubMed  Google Scholar 

  52. Wang XB, Giscombe R, Yan Z et al (2002) Expression of CTLA-4 by human monocytes. Scand J Immunol 55:53–60

    Article  PubMed  Google Scholar 

  53. Liu MF, Wang CR, Chen PC et al (2003) Increased of expression of soluble cytotoxic T-lymphocyte-associated antigen-4 molecule in patients with systemic lupus erythematosus. Scand J Immunol 57:568–572

    Article  PubMed  Google Scholar 

  54. Sato S, Fujimoto M, Hasegawa M et al (2004) Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis. Rheumatology 43:1261–1266

    Article  PubMed  Google Scholar 

  55. Wong CK, Lit LCW, Tam LS et al (2005) Aberrant production of soluble costimulatory molecules CTLA-4, CD28, CD80 and CD86 in patients with systemic lupus erythematosus. Rheumatology 44:989–994

    Article  PubMed  Google Scholar 

  56. Bergholdt R, Taxvig C, Eising S et al (2005) BLB variants in type 1 diabetes and their genetic interaction with CTLA4. J Leukoc Biol 77:579–585

    Article  PubMed  Google Scholar 

  57. Brunet JF, Denizot F, Luciani MF et al (1987) A new member of the immunoglobulin superfamily — CTLA-4. Nature 328:267–270

    Article  PubMed  Google Scholar 

  58. Dariavach P, Mattei MG, Golstein P et al (1988) Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human cytoplasmic domains. Eur J Immunol 18:1901–1905

    Article  PubMed  Google Scholar 

  59. Ligers A, Xu C, Saarinen S et al (1999) The CTLA-4 gene is associated with multiple sclerosis. J Neuroimmunol 97:182–190

    Article  PubMed  Google Scholar 

  60. Toussirot E, Saas P, Deschamps M et al (2009) Increased production of soluble CTLA-4 in patients with spondylarthropathies correlates with disease activity. Arthritis Res Ther 11:R101

    Article  PubMed  PubMed Central  Google Scholar 

  61. Tector M, Khatri BO, Kozinski K et al (2009) Biochemical analysis of CTLA-4 immunoreactive material from human blood. BMC Immunol 10:51–60

    Article  PubMed  PubMed Central  Google Scholar 

  62. Umemura T, Ota M, Hamano H et al (2008) Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol 103:588–594

    Article  PubMed  Google Scholar 

  63. Lowe RM, Graham J, Sund G et al (2000) The length of the CTLA-4 microsatellite (AT)N-repeat affects the risk for type 1 diabetes. Autoimmunity 32:173–180

    Article  PubMed  Google Scholar 

  64. Chang M-C, Chang Y-T, Tien Y-W et al (2007) T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. Clin Chemi 53:1700–1705

    Article  Google Scholar 

  65. Grohmann U, Orabona C, Fallarino F et al (2002) CTLA-4-Ig regulates catabolism in vivo. Nat Immunol 3:1097–1101

    Article  PubMed  Google Scholar 

  66. Mellor AL, Munn DH (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20:469–473

    Article  PubMed  Google Scholar 

  67. Kawa S, Ota M, Yoshizawa K et al (2002) HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology 122:1264–1269

    Article  PubMed  Google Scholar 

  68. Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17:875–904

    Article  PubMed  Google Scholar 

  69. Andreevski TV, Sudomoina MA, Gusev EI et al (2002) Polymorphism A/G in position +49 of CTLA4 exon 1 in multiple sclerosis in Russians. Mol Biol 36:643–648

    Article  Google Scholar 

  70. Djilali-Saiah I, Schmitz J, Harfouch-Hammoud E et al (1998) CTLA-4 gene polymorphism is associated with predisposition to celiac disease. Gut 43:187–189

    Article  PubMed  PubMed Central  Google Scholar 

  71. Orozco G, Torres B, Nunez-Roldan A et al (2004) Cytotoxic Tlymphocyte antigen-4-CT60 polymorphism in rheumatoid arthritis. Tissue Antigens 64:667–670

    Article  PubMed  Google Scholar 

  72. Vaidya B, Pearce S (2004) The emerging role of the CTLA-4 gene in autoimmune endocrinopathies. Eur J Endocrinol 150:619–626

    Article  PubMed  Google Scholar 

  73. Giorelli M, Livera P, Defazio G et al (2001) IFN-beta1a modulates the expression of CTLA-4 and CD28 splice variants in human mononuclear cells: induction of soluble isoforms. J Interferon Cytokine Res 21:809–812

    Article  PubMed  Google Scholar 

  74. Finger EB, Bluestone JA (2002) When ligand becomes receptor — tolerance via B7 signaling on DCs. Nat Immunol 3:1056–1057

    Article  PubMed  Google Scholar 

  75. Kaartinen T, Lappalainen J, Haimila K et al (2007) Genetic variation in ICOS regulates mRNA levels of ICOS and splicing isoforms of CTLA4. Mol Immunol 447:1644–1651

    Article  Google Scholar 

  76. Swain SL, Huston G, Tonkonogy S et al (1991) Transforming growth factor-beta and IL-4 cause helper T cell precursors to develop into distinct effector helper cells that differ in lymphokine secretion pattern and cell surface phenotype. J Immunol 147:2991–3000

    PubMed  Google Scholar 

  77. Catassi C, Fasano A (2010) Celiac disease diagnosis: simple rules are better than complicated algorithms. Am J Med 123:691–693

    Article  PubMed  Google Scholar 

  78. Sugai E, Moreno ML, Hwang HJ et al (2010) Celiac disease serology in patients with different pretest probabilities: is biopsy avoidable? World J Gastroenterol 16:3144–315

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Section of Human Anatomy, Department of Experimental Medicine, University of Genova, Genova, Italy

    Daniele Saverino & Rita Simone

  2. Medical and Radiometabolic Therapy Unit, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132, Genova, Italy

    Marcello Bagnasco & Giampaola Pesce

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  1. Daniele Saverino
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  2. Rita Simone
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  3. Marcello Bagnasco
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Correspondence to Marcello Bagnasco.

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Saverino, D., Simone, R., Bagnasco, M. et al. The soluble CTLA-4 receptor and its role in autoimmune diseases: an update. Autoimmun Highlights 1, 73–81 (2010). https://doi.org/10.1007/s13317-010-0011-7

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Autoimmunity Highlights

ISSN: 2038-3274

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