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Involvement of T-cell receptor-β alterations in the development of otosclerosis linked to OTSC2

Genes & Immunity volume 11, pages 246–253 (2010)Cite this article

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Abstract

Otosclerosis is a common form of hearing loss, characterized by disordered bone remodeling in the otic capsule. Within the otosclerotic foci, several immunocompetent cells and immune-modulating factors can be found. Different etiological theories involving the immune system have been suggested. However, a genetic component is clearly present. In large otosclerosis families, seven autosomal-dominant loci have been found, but none of the disease-causing genes has been identified. This study focused on the exploration of the second otosclerosis locus on chromosome 7q34-36 (OTSC2), holding the T-cell receptor beta locus (TRB locus). A significantly lower T-cell receptor-β (TCR-β) mRNA expression and percentage of blood circulating TCR-αβ+ T cells was detected in OTSC2 patients compared with controls and patients with the complex form of the disease. Further analysis illustrated more significant disturbances in specific T-cell subsets, including an increased CD28null cell population, suggesting a disturbed T-cell development and ageing in OTSC2 patients. These disturbances could be associated with otosclerotic bone remodeling, given the known effects of immunocompetent cells on bone physiology. These data implicate the TRB locus as the causative gene in the OTSC2 region and represent an important finding in the elucidation of the disease pathology.

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References

  1. Declau F, Van Spaendonck M, Timmermans JP, Michaels L, Liang J, Qiu JP et al. Prevalence of otosclerosis in an unselected series of temporal bones. Otol Neurotol 2001; 22: 596–602.

    Article  CAS  Google Scholar 

  2. Tomek MS, Brown MR, Mani SR, Ramesh A, Srisailapathy CR, Coucke P et al. Localization of a gene for otosclerosis to chromosome 15q25-q26. Hum Mol Genet 1998; 7: 285–290.

    Article  CAS  Google Scholar 

  3. Van Den Bogaert K, Govaerts PJ, Schatteman I, Brown MR, Caethoven G, Offeciers FE et al. A second gene for otosclerosis, OTSC2, maps to chromosome 7q34-36. Am J Hum Genet 2001; 68: 495–500.

    Article  CAS  Google Scholar 

  4. Chen W, Campbell CA, Green GE, Van Den Bogaert K, Komodikis C, Manolidis LS et al. Linkage of otosclerosis to a third locus (OTSC3) on human chromosome 6p21.3-22.3. J Med Genet 2002; 39: 473–477.

    Article  CAS  Google Scholar 

  5. Brownstein Z, Goldfarb A, Levi H, Frydman M, Avraham KB . Chromosomal mapping and phenotypic characterization of hereditary otosclerosis linked to the OTSC4 locus. Arch Otolaryngol Head Neck Surg 2006; 132: 416–424.

    Article  Google Scholar 

  6. Van Den Bogaert K, De Leenheer EM, Chen W, Lee Y, Nurnberg P, Pennings RJ et al. A fifth locus for otosclerosis, OTSC5, maps to chromosome 3q22-24. J Med Genet 2004; 41: 450–453.

    Article  CAS  Google Scholar 

  7. Thys M, Van Den Bogaert K, Iliadou V, Vanderstraeten K, Dieltjens N, Schrauwen I et al. A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13-16.1. Eur J Hum Genet 2007; 15: 362–368.

    Article  CAS  Google Scholar 

  8. Bel Hadj Ali I, Thys M, Beltaief N, Schrauwen I, Hilgert N, Vanderstraeten K et al. A new locus for otosclerosis, OTSC8, maps to the pericentromeric region of chromosome 9. Hum Genet 2008; 123: 267–272.

    Article  Google Scholar 

  9. Thys M, Schrauwen I, Vanderstraeten K, Janssens K, Dieltjens N, Van Den Bogaert K et al. The coding polymorphism T263I in TGF-beta1 is associated with otosclerosis in two independent populations. Hum Mol Genet 2007; 16: 2021–2030.

    Article  CAS  Google Scholar 

  10. Schrauwen I, Thys M, Vanderstraeten K, Fransen E, Dieltjens N, Huyghe JR et al. Association of bone morphogenetic proteins with otosclerosis. J Bone Miner Res 2008; 23: 507–516.

    Article  CAS  Google Scholar 

  11. Schrauwen I, Ealy M, Huentelman MJ, Thys M, Homer N, Vanderstraeten K et al. A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis. Am J Hum Genet 2009; 84: 328–338.

    Article  CAS  Google Scholar 

  12. Schrauwen I, Thys M, Vanderstraeten K, Fransen E, Ealy M, Cremers CW et al. No evidence for association between the renin-angiotensin-aldosterone system and otosclerosis in a large Belgian-Dutch population. Otol Neurotol 2009; 30: 1079–1083.

    Article  Google Scholar 

  13. Yoo TJ . Etiopathogenesis of otosclerosis: a hypothesis. Ann Otol Rhinol Laryngol 1984; 93: 28–33.

    Article  CAS  Google Scholar 

  14. Reshetnikov NN, Popova TI . IgA, IgM and IgG levels and antibodies to native DNA and collagen type II in the perilymph of patients with otosclerosis. Vestn Otorinolaringol 1992; 1: 14–16.

    Google Scholar 

  15. Yoo TJ, Tomoda K, Stuart JM, Kang AH, Townes AS . Type II collagen-induced autoimmune otospongiosis. A preliminary report. Ann Otol Rhinol Laryngol 1983; 92: 103–108.

    Article  CAS  Google Scholar 

  16. Lolov SR, Edrev GE, Kyurkchiev SD, Kehayov IR . Elevated autoantibodies in sera from otosclerotic patients are related to the disease duration. Acta Otolaryngol 1998; 118: 375–380.

    Article  CAS  Google Scholar 

  17. Solvsten Sorensen M, Nielsen LP, Bretlau P, Jorgensen MB . The role of type II collagen autoimmunity in otosclerosis revisited. Acta Otolaryngol 1988; 105: 242–247.

    Article  CAS  Google Scholar 

  18. Harris JP, Woolf NK, Ryan AF . A reexamination of experimental type II collagen autoimmunity: middle and inner ear morphology and function. Ann Otol Rhinol Laryngol 1986; 95: 176–180.

    Article  CAS  Google Scholar 

  19. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A et al. Association scan of 14 500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007; 39: 1329–1337.

    Article  CAS  Google Scholar 

  20. Gregoriadis S, Zervas J, Varletzidis E, Toubis M, Pantazopoulos P, Fessas P . HLA antigens and otosclerosis. A possible new genetic factor. Arch Otolaryngol 1982; 108: 769–771.

    Article  CAS  Google Scholar 

  21. Singhal SK, Mann SB, Datta U, Panda NK, Gupta AK . Genetic correlation in otosclerosis. Am J Otolaryngol 1999; 20: 102–105.

    Article  CAS  Google Scholar 

  22. Pedersen U, Madsen M, Lamm LU, Elbrond O . HLA-A, -B, -C antigens in otosclerosis. J Laryngol Otol 1983; 97: 1095–1097.

    Article  CAS  Google Scholar 

  23. Arnold W, Friedmann I . Immunohistochemistry of otosclerosis. Acta Otolaryngol Suppl 1990; 470: 124–128; discussion 128–129.

    CAS  PubMed  Google Scholar 

  24. Altermatt HJ, Gerber HA, Gaeng D, Muller C, Arnold W . Immunohistochemical findings in otosclerotic lesions. Hno 1992; 40: 476–479.

    CAS  PubMed  Google Scholar 

  25. Arnold W, Friedmann I . Otosclerosis—an inflammatory disease of the otic capsule of viral aetiology? J Laryngol Otol 1988; 102: 865–871.

    Article  CAS  Google Scholar 

  26. Bodo M, Carinci P, Venti G, Giammarioli M, Donti E, Stabellini G et al. Glycosaminoglycan metabolism and cytokine release in normal and otosclerotic human bone cells interleukin-1 treated. Connect Tissue Res 1997; 36: 231–240.

    Article  CAS  Google Scholar 

  27. Karosi T, Jokay I, Konya J, Szabo LZ, Pytel J, Jori J et al. Detection of osteoprotegerin and TNF-alpha mRNA in ankylotic stapes footplates in connection with measles virus positivity. Laryngoscope 2006; 116: 1427–1433.

    Article  CAS  Google Scholar 

  28. Niedermeyer HP, Arnold W . Otosclerosis and measles virus—association or causation? ORL J Otorhinolaryngol Relat Spec 2008; 70: 63–69; discussion 69–70.

    Article  CAS  Google Scholar 

  29. Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E et al. The influence of age on T cell generation and TCR diversity. J Immunol 2005; 174: 7446–7452.

    Article  CAS  Google Scholar 

  30. Haynes BF, Denning SM, Singer KH, Kurtzberg J . Ontogeny of T-cell precursors: a model for the initial stages of human T-cell development. Immunol Today 1989; 10: 87–91.

    Article  CAS  Google Scholar 

  31. Jiang H, Chess L . Regulation of immune responses by T cells. N Engl J Med 2006; 354: 1166–1176.

    Article  CAS  Google Scholar 

  32. Venken K, Hellings N, Hensen K, Rummens JL, Medaer R, D’Hooghe MB et al. Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression. J Neurosci Res 2006; 83: 1432–1446.

    Article  CAS  Google Scholar 

  33. Vallejo AN, Brandes JC, Weyand CM, Goronzy JJ . Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J Immunol 1999; 162: 6572–6579.

    CAS  PubMed  Google Scholar 

  34. Thewissen M, Somers V, Venken K, Linsen L, van Paassen P, Geusens P et al. Analyses of immunosenescent markers in patients with autoimmune disease. Clin Immunol 2007; 123: 209–218.

    Article  CAS  Google Scholar 

  35. Raffeiner B, Dejaco C, Duftner C, Kullich W, Goldberger C, Vega SC et al. Between adaptive and innate immunity: TLR4-mediated perforin production by CD28null T-helper cells in ankylosing spondylitis. Arthritis Res Ther 2005; 7: R1412–R1420.

    Article  CAS  Google Scholar 

  36. Thewissen M, Somers V, Hellings N, Fraussen J, Damoiseaux J, Stinissen P . CD4+CD28null T cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation. J Immunol 2007; 179: 6514–6523.

    Article  CAS  Google Scholar 

  37. Lorenzo J, Horowitz M, Choi Y . Osteoimmunology: interactions of the bone and immune system. Endocr Rev 2008; 29: 403–440.

    Article  CAS  Google Scholar 

  38. Milroy CM, Michaels L . Pathology of the otic capsule. J Laryngol Otol 1990; 104: 83–90.

    Article  CAS  Google Scholar 

  39. Goodnow CC . Multistep pathogenesis of autoimmune disease. Cell 2007; 130: 25–35.

    Article  CAS  Google Scholar 

  40. Mombaerts P, Clarke AR, Rudnicki MA, Iacomini J, Itohara S, Lafaille JJ et al. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature 1992; 360: 225–231.

    Article  CAS  Google Scholar 

  41. Joachims ML, Chain JL, Hooker SW, Knott-Craig CJ, Thompson LF . Human alpha beta and gamma delta thymocyte development: TCR gene rearrangements, intracellular TCR beta expression, and gamma delta developmental potential—differences between men and mice. J Immunol 2006; 176: 1543–1552.

    Article  CAS  Google Scholar 

  42. Bouvier G, Watrin F, Naspetti M, Verthuy C, Naquet P, Ferrier P . Deletion of the mouse T-cell receptor beta gene enhancer blocks alphabeta T-cell development. Proc Natl Acad Sci USA 1996; 93: 7877–7881.

    Article  CAS  Google Scholar 

  43. Gruver AL, Hudson LL, Sempowski GD . Immunosenescence of ageing. J Pathol 2007; 211: 144–156.

    Article  CAS  Google Scholar 

  44. Colella S, Yau C, Taylor JM, Mirza G, Butler H, Clouston P et al. QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res 2007; 35: 2013–2025.

    Article  CAS  Google Scholar 

  45. Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 2007; 17: 1665–1674.

    Article  CAS  Google Scholar 

  46. Rowen L, Koop BF, Hood L . The complete 685-kilobase DNA sequence of the human beta T cell receptor locus. Science 1996; 272: 1755–1762.

    Article  CAS  Google Scholar 

  47. van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–2317.

    Article  CAS  Google Scholar 

  48. Hellemans J, Mortier G, De Paepe A, Speleman F, Vandesompele J . qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol 2007; 8: R19.

    Article  Google Scholar 

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Acknowledgements

We thank all family members and other participants of this study. We also thank Geert Vandeweyer and Edwin Reyniers for the technical assistance with CNV analysis and Kris Van Den Bogaert for help with this project. This work was supported by EuroHear by grants from the European Commission (FP6 Integrated project EuroHear LSHG-CT-20054-512063), the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) (grant G.0138.07), the University of Antwerp (TOP grant) and the Belgian Charcot foundation. IS has a predoctoral position with the FWO. KV was financed by the Hasselt University.

Author information

Author notes

  1. K Venken

    Present address: 5Current address: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.,

  2. J-J Hendrickx

    Present address: 6Current address: Department of Otolaryngology & Head and Neck Surgery, UZ Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090 Brussel, Belgium.,

  3. L Van Laer

    Present address: 7Current address: Center for Medical Genetics Ghent, Ghent University, De Pintelaan 185—9000 Ghent, Belgium.,

  4. I Schrauwen and K Venken: The authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

    I Schrauwen, K Vanderstraeten, M Thys, J-J Hendrickx, E Fransen, L Van Laer & G Van Camp

  2. Hasselt University, Biomedisch Onderzoeksinstituut and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium

    K Venken, P Stinissen & N Hellings

  3. The Eargroup, Antwerp-Deurne, Belgium

    P J Govaerts

  4. University Department of Otolaryngology, St-Augustinus Hospital Antwerp, Antwerp, Belgium

    M Verstreken & I Schatteman

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Correspondence to G Van Camp.

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Schrauwen, I., Venken, K., Vanderstraeten, K. et al. Involvement of T-cell receptor-β alterations in the development of otosclerosis linked to OTSC2. Genes Immun 11, 246–253 (2010). https://doi.org/10.1038/gene.2010.3

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