Journal of Molecular Medicine

, Volume 83, Issue 5, pp 397–405 | Cite as

Function associated transforming growth factor-β gene polymorphism in chronic beryllium disease

  • Karoline I. Gaede
  • Massimo Amicosante
  • Manfred Schürmann
  • Elisabeth Fireman
  • Cesare Saltini
  • Joachim Müller-Quernheim
Original Article


Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP β chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) β1 genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-β1 (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (−308) PM. The most significant results were found for the TGF-β1 (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-β1 (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-β1 (codon 25) PM genotype frequency associated with a low TGF-β release suggests that immunoregulatory cytokines such as TGF-β are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-α and TGF-β1, with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.


Chronic beryllium disease TGF-β gene polymorphism TNFA-HLA 



Bronchoalveolar lavage


Beryllium hypersensitivity


Chronic beryllium disease


Transforming growth factor


Tumor necrosis factor



The authors thank Stefanie Adam and Carmen Schöne for expert technical assistance. This study was supported in part by the German Research Council (DFG, Mu 692-3/3), the United States Department of Energy (grant DE-FG02-93ER61714 and DE-FG02-ER63416), and a grant from the Guzzini Foundation. Major parts of this study were performed in the Medical Hospital of the Research Center, Borstel, Germany.


  1. 1.
    Saltini C, Markham TN, Williams WJ (1999) Berylliosis. In: James DG (ed) The granulomatous disorders. Cambridge University Press, Cambridge, pp 336–351Google Scholar
  2. 2.
    Newman LS, Kreiss K, King TE Jr, Seay S, Campbell PA (1989) Pathologic and immunologic alterations in early stages of beryllium disease. Re-examination of disease definition and natural history. Am Rev Respir Dis 139:1479–1486Google Scholar
  3. 3.
    Richeldi L, Kreiss K, Mroz MM, Zhen B, Tartoni P, Saltini C (1997) Interaction of genetic and exposure factors in the prevalence of berylliosis. Am J Ind Med 32:337–340Google Scholar
  4. 4.
    Richeldi L, Sorrentino R, Saltini C (1993) HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science 262:242–244PubMedGoogle Scholar
  5. 5.
    Wang Z, White PS, Petrovic M, Tatum OL, Newman LS, Maier LA, Marrone BL (1999) Differential susceptibilities to chronic beryllium disease contributed by different Glu69 HLA-DPB1 and -DPA1 alleles. J Immunol 163:1647–1653Google Scholar
  6. 6.
    Saltini C, Richeldi L, Losi M, Amicosante M, Voorter C, van den Berg-Loonen E, Dweik RA, Wiedemann HP, Deubner DC, Tinelli C (2001) Major histocompatibility locus genetic markers of beryllium sensitization and disease. Eur Respir J 18:677–684CrossRefGoogle Scholar
  7. 7.
    Wang Z, Farris GM, Newman LS, Shou Y, Maier LA, Smith HN, Marrone BL (2001) Beryllium sensitivity is linked to HLA-DP genotype. Toxicology 165:27–38CrossRefGoogle Scholar
  8. 8.
    Rossman MD, Stubbs J, Lee CW, Argyris E, Magira E, Monos D (2002) Human leukocyte antigen Class II amino acid epitopes: susceptibility and progression markers for beryllium hypersensitivity. Am J Respir Crit Care Med 165:788–794Google Scholar
  9. 9.
    Maier LA, McGrath DS, Sato H, Lympany P, Welsh K, Du Bois R, Silveira L, Fontenot AP, Sawyer RT, Wilcox E, Newman LS (2003) Influence of MHC CLASS II in susceptibility to beryllium sensitization and chronic beryllium disease. J Immunol 171:6910–6918Google Scholar
  10. 10.
    Amicosante M, Sanarico N, Berretta F, Arroyo J, Lombardi G, Lechler R, Colizzi V, Saltini C (2001) Beryllium binding to HLA-DP molecule carrying the marker of susceptibility to berylliosis glutamate beta 69. Hum Immunol 62:686–693CrossRefGoogle Scholar
  11. 11.
    Lombardi G, Germain C, Uren J, Fiorillo MT, du Bois RM, Jones-Williams W, Saltini C, Sorrentino R, Lechler R (2001) HLA-DP allele-specific T cell responses to beryllium account for DP-associated susceptibility to chronic beryllium disease. J Immunol 166:3549–3555Google Scholar
  12. 12.
    Fontenot AP, Torres M, Marshall WH, Newman LS, Kotzin BL (2000) Beryllium presentation to CD4+ T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease. Proc Natl Acad Sci USA 97:12717–12722CrossRefGoogle Scholar
  13. 13.
    Newman LS (1996) Immunology, genetics, and epidemiology of beryllium disease. Chest 109:40S-43SGoogle Scholar
  14. 14.
    Maier LA (2002) Genetic and exposure risks for chronic beryllium disease. Clin Chest Med 23:827–839Google Scholar
  15. 15.
    Maier LA, Sawyer RT, Bauer RA, Kittle LA, Lympany P, McGrath D, Dubois R, Daniloff E, Rose CS, Newman LS (2001) High beryllium-stimulated TNF-alpha is associated with the −308 TNF-alpha promoter polymorphism and with clinical severity in chronic beryllium disease. Am J Respir Crit Care Med 164:1192–1199Google Scholar
  16. 16.
    Dotti C, D’Apice MR, Rogliani P, Novelli G, Saltini C, Amicosante M (2004) Analysis of TNF-alpha promoter polymorphisms in the susceptibility to beryllium hypersensitivity. Sarcoidosis Vasc Diffuse Lung Dis 21:29–34Google Scholar
  17. 17.
    Zissel G, Homolka J, Schlaak J, Schlaak M, Muller-Quernheim J (1996) Anti-inflammatory cytokine release by alveolar macrophages in pulmonary sarcoidosis. Am J Respir Crit Care Med 154:713–719Google Scholar
  18. 18.
    Li B, Khanna A, Sharma V, Singh T, Suthanthiran M, August P (1999) TGF-beta1 DNA polymorphisms, protein levels, and blood pressure. Hypertension 33:271–275Google Scholar
  19. 19.
    Begovich AB, McClure GR, Suraj VC, Helmuth RC, Fildes N, Bugawan TL, Erlich HA, Klitz W (1992) Polymorphism, recombination, and linkage disequilibrium within the HLA class II region. J Immunol 148:249–258Google Scholar
  20. 20.
    Seitzer U, Swider C, Stuber F, Suchnicki K, Lange A, Richter E, Zabel P, Muller-Quernheim J, Flad HD, Gerdes J (1997) Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis. Cytokine 9:787–790CrossRefGoogle Scholar
  21. 21.
    Meyer KC (1994) Beryllium and lung disease. Chest 106:942–946Google Scholar
  22. 22.
    Stokes RF, Rossman MD (1991) Blood cell proliferation response to beryllium: analysis by receiver-operating characteristics. J Occup Med 33:23–28Google Scholar
  23. 23.
    Newman LS (1995) Beryllium disease and sarcoidosis: clinical and laboratory links. Sarcoidosis 12:7–19Google Scholar
  24. 24.
    Schürmann M, Bein G, Kirsten D, Schlaak M, Müller-Quernheim J, Schwinger E (1998) HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis. Respir Med 92:649–652CrossRefGoogle Scholar
  25. 25.
    Lario S, Inigo P, Campistol JM, Poch E, Rivera F, Oppenheimer F (1999) Restriction enzyme-based method for transforming growth factor-beta (1) genotyping: nonisotopic detection of polymorphisms in codons 10 and 25 and the 5’-flanking region. Clin Chem 45:1290–1292Google Scholar
  26. 26.
    Somoskövi A, Zissel G, Seitzer U, Gerdes J, Schlaak M, Muller Quernheim J (1999) Polymorphisms at position −308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis. Cytokine 11:882–887CrossRefGoogle Scholar
  27. 27.
    Stüber F, Petersen M, Bokelmann F, Schade U (1996) A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 24:381–384Google Scholar
  28. 28.
    Rozas J, Rozas R (1995) DnaSP, DNA sequence polymorphism: an interactive program for estimating population genetics parameters from DNA sequence data. Comput Appl Biosci 11:621–625Google Scholar
  29. 29.
    Amicosante M, Berretta F, Franchi A, Rogliani P, Dotti C, Losi M, Dweik R, Saltini C (2002) HLA-DP-unrestricted TNF-alpha release in beryllium-stimulated peripheral blood mononuclear cells. Eur Respir J 20:1174–1178CrossRefGoogle Scholar
  30. 30.
    Infante PF, Newman LS (2004) Beryllium exposure and chronic beryllium disease. Lancet 363:415–416CrossRefGoogle Scholar
  31. 31.
    Muraközy G, Gaede KI, Zissel G, Schlaak M, Müller-Quernheim J (2001) Analysis of gene polymorphisms in interleukin-10 and transforming growth factor-beta 1 in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 18:165–169Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Karoline I. Gaede
    • 1
    • 2
  • Massimo Amicosante
    • 3
  • Manfred Schürmann
    • 4
  • Elisabeth Fireman
    • 5
  • Cesare Saltini
    • 3
  • Joachim Müller-Quernheim
    • 1
  1. 1.Medical University Hospital FreiburgDepartment of PneumologyFreiburgGermany
  2. 2.Research Center BorstelBorstelGermany
  3. 3.Department of Internal MedicineUniversity of Rome Tor VergataRomeItaly
  4. 4.Institute of Human GeneticsUniversity LübeckLübeckGermany
  5. 5.Tel Aviv Sourasky Medical CenterDepartment of Pulmonary and Allergic Diseases

Personalised recommendations