, Volume 24, Issue 1, pp 1–17 | Cite as

Chronic beryllium disease: an updated model interaction between innate and acquired immunity

  • Richard T. Sawyer
  • Lisa A. MaierEmail author


During the last decade, there have been concerted efforts to reduce beryllium (Be) exposure in the workplace and thereby reduce potential cases of this occupational lung disorder. Despite these efforts, it is estimated that there are at least one million Be-exposed individuals in the U.S. who are potentially at risk for developing chronic beryllium disease (CBD). Previously, we reviewed the current CBD literature and proposed that CBD represents a model interaction between innate and acquired immunity (Sawyer et al., Int Immunopharmacol 2:249–261, 2002). We closed this review with a section on “future directions” that identified key gaps in our understanding of the pathogenesis of CBD. In the intervening period, progress has been made to fill in some of these gaps, and the current review will provide an update on that progress. Based on recent findings, we provide a new hypothesis to explain how Be drives sustained chronic inflammation and granuloma formation in CBD leading to progressive compromised lung function in CBD patients. This paradigm has direct implications for our understanding of the development of an immune response to Be, but is also likely applicable to other immune-mediated lung diseases of known and unknown etiology.


Beryllium Chronic beryllium disease Granuloma Innate immunity Acquired immunity 


  1. Amicosante M, Fontenot AP (2006) T cell recognition in chronic beryllium disease. Clin Immunol 121:134–143PubMedCrossRefGoogle Scholar
  2. 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 62:686–693PubMedCrossRefGoogle Scholar
  3. 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 20:1174–1178PubMedCrossRefGoogle Scholar
  4. Amicosante M, Berretta F, Dweik R, Saltini C (2009) Role of high-affinity HLA-DP specific CLIP-derived peptides in beryllium binding to the HLA-DPGlu69 berylliosis-associated molecules and presentation to beryllium-sensitized T cells. Immunology 128:e462–e470PubMedCrossRefGoogle Scholar
  5. Bailey RL, Thomas CA, Deubner DC, Kent MS, Kreiss K, Schuler CR (2010) Evaluation of a preventive program to reduce sensitization at a beryllium metal, oxide, and alloy production plant. J Occup Environ Med 52:505–512PubMedCrossRefGoogle Scholar
  6. Balkissoon RC, Newman LS (1999) Beryllium copper alloy (2%) causes chronic beryllium disease. J Occup Environ Med 41:304–308PubMedCrossRefGoogle Scholar
  7. Barna BP, Dweik RA, Farver CF, Culver D, Yen-Lieberman B, Thomassen MJ (2002) Nitric oxide attenuates beryllium-induced IFN gamma responses in chronic beryllium disease: evidence for mechanisms independent of IL-18. Clin Immunol 103:169–175PubMedCrossRefGoogle Scholar
  8. Batista FD, Harwood NE (2009) The who, how and where of antigen presentation to B cells. Nat Rev Immunol 9:15–27PubMedCrossRefGoogle Scholar
  9. Bekris LM, Viernes HM, Farin FM, Maier LA, Kavanagh TJ, Takaro TK (2006) Chronic beryllium disease and glutathione biosynthesis genes. J Occup Environ Med 48:599–606PubMedCrossRefGoogle Scholar
  10. Berretta F, Butler RH, Diaz G, Sanarico N, Arroyo J, Fraziano M, Aichinger G, Wucherpfennig KW, Colizzi V, Saltini C, Amicosante M (2003) Detailed analysis of the effects of Glu/Lys beta69 human leukocyte antigen-DP polymorphism on peptide-binding specificity. Tissue Antigens 62:459–471PubMedCrossRefGoogle Scholar
  11. Bill JR, Mak DG, Falta MT, Maier LA, Sullivan AK, Joslin FG, Martin AK, Freed BM, Kotzin BL, Fontenot AP (2005) Beryllium presentation to DC4+T cells is dependent on a single amino acid residue in the MHC class II β-chain. J Immunol 175:7029–7037PubMedGoogle Scholar
  12. Burgdorf S, Kautz A, Bohnert V, Knolle PA, Kurts C (2007) Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science 316:612–616PubMedCrossRefGoogle Scholar
  13. Butnor KJ, Sporn TA, Ingram P, Gunasegaram S, Pinto JF, Roggli VL (2003) Beryllium detection in human lung tissue using electron probe X-ray microanalysis. Mod Pathol 16:1171–1177PubMedCrossRefGoogle Scholar
  14. Chaudhary A, Sauer NN, Gupta G (2004) Beryllium-specific immune response in primary cells from healthy individuals. Toxicology 201:9–19PubMedCrossRefGoogle Scholar
  15. Chen X, Jensen PE (2008) The role of B lymphocytes as antigen-presenting cells. Arch Immunol Ther Exp (Warsz) 56:77–83CrossRefGoogle Scholar
  16. Chen TT, Li L, Chung DH, Allen CD, Torti SV, Torti FM, Cyster JG, Chen CY, Brodsky FM, Niemi EC, Nakamura MC, Seaman WE, Daws MR (2005) TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med 202:955–965PubMedCrossRefGoogle Scholar
  17. Chou YK, Edwards DM, Weinberg AD, Vandenbark AA, Kotzin BL, Fontenot AP, Burrows GG (2005) Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis. J Immunol 174:4316–4324PubMedGoogle Scholar
  18. Coates SS, Lehnert BE, Sharma S, Kindell SM, Gary RK (2007) Beryllium induces premature senescence in human fibroblasts. J Pharmacol Exp Ther 322:70–79PubMedCrossRefGoogle Scholar
  19. Comhair SA, Lewis MJ, Bhathena PR, Hammel JP, Erzurum SC (1999) Increased glutathione and glutathione peroxidase in lungs of individuals with chronic beryllium disease. Am J Respir Crit Care Med 159:1824–1829PubMedGoogle Scholar
  20. Cummings KJ, Stefaniak AB, Virji MA, Kreiss K (2009) A reconsideration of acute beryllium disease. Environ Health Perspect 117:1250–1256PubMedGoogle Scholar
  21. Dai S, Murphy GA, Crawford F, Mack DG, Falta MT, Marrack P, Kappler JW, Fontenot AP (2010) Crystal structure of HLA-DP2 and implications for chronic beryllium disease. Proc Natl Acad Sci 107:7425–7430PubMedCrossRefGoogle Scholar
  22. Day GA, Hoover MD, Stefaniak AB, Dickerson RM, Peterson EJ, Esmen NA, Scripsick RC (2005) Bioavailability of beryllium oxide particles: an in vitro study in the murine J774A.1 macrophage cell line model. Exp Lung Res 31:341–360PubMedCrossRefGoogle Scholar
  23. Day GA, Stefaniak AB, Weston A, Tinkle SS (2006) Beryllium exposure: dermal and immunological considerations. Int Arch Occup Environ Health 79:161–164PubMedCrossRefGoogle Scholar
  24. Day GA, Dufresne A, Stefaniak AB, Schuler CR, Stanton ML, Miller WE, Kent MS, Deubner DC, Kreiss K, Hoover MD (2007) Exposure pathway assessment at a copper–beryllium alloy facility. Ann Occup Hyg 51:67–80PubMedCrossRefGoogle Scholar
  25. Dobis DR, Sawyer RT, Gillespie MM, Huang J, Newman LS, Maier LA, Day BJ (2008) Modulation of lymphocyte proliferation by antioxidants in chronic beryllium disease. Am J Respir Crit Care Med 177:1002–1011PubMedCrossRefGoogle Scholar
  26. Dobis DR, Sawyer RT, Gillespie MM, Newman LS, Maier LA, Day BJ (2010) Sulfasalazine and mesalamine modulate beryllium-specific lymphocyte proliferation and inflammatory cytokine production. Am J Respir Cell Mol Biol. doi: 10.1165/rcmb.2009-0150OC
  27. Dudziak D, Kamphorst AO, Heidkamp GF, Bucholz VR, Trumpfheller C, Yamazaki S, Cheong C, Liu K, Lee HW, Park CG, Steinman RM, Nussenzweig MC (2007) Differential antigen processing by dendritic cell subsets in vivo. Science 315:107–111PubMedCrossRefGoogle Scholar
  28. Everest DA (1964) The chemistry of beryllium. In: Robinson RL (ed) Topics in inorganic and general chemistry. Elsevier, AmsterdamGoogle Scholar
  29. Fontenot AP, Kotzin BL (2003) Chronic beryllium disease: immune-mediated destruction with implications for organ-specific autoimmunity. Tissue Antigens 62:449–458PubMedCrossRefGoogle Scholar
  30. Fontenot AP, Falta MT, Freed BM, Newman LS, Kotzin BL (1999) Identification of pathogenic T cells in patients with beryllium-induced lung disease. J Immunol 163:1019–1026PubMedGoogle Scholar
  31. Fontenot AP, Newman LS, Kotzin BL (2001) Chronic beryllium disease: T cell recognition of a metal presented by HLA-DP. Clin Immunol 100:4–14PubMedCrossRefGoogle Scholar
  32. Fontenot AP, Canavera SJ, Gharavi L, Newman LS, Kotzin BL (2002) Target organ localization of memory CD4+ T cells in patients with chronic beryllium disease. J Clin Invest 110:1473–1482PubMedGoogle Scholar
  33. Fontenot AP, Gharavi L, Bennett SR, Canavera SJ, Newman LS, Kotzin BL (2003) CD28 costimulation independence of target organ versus circulating memory antigen-specific CD4+ T cells. J Clin Invest 112:776–784PubMedGoogle Scholar
  34. Fontenot AP, Palmer BE, Sullivan AK, Joslin FG, Wilson CC, Maier LA, Newman LS, Kotzin BL (2005) Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response. J Clin Invest 115:2886–2893PubMedCrossRefGoogle Scholar
  35. Fontenot AP, Edwards DM, Chou YK, Mack DG, LaTocha D, Vandenbark AA, Burrows GG (2006a) Self-presentation of beryllium by BAL CD4+ T cells: T cell–T cell interactions and their potential role in chronic beryllium disease. Eur J Immunol 36:930–939PubMedCrossRefGoogle Scholar
  36. Fontenot AP, Keizer TS, McCleskey M, Mack DG, Meza-Romero R, Huan J, Edwards DM, Chou YK, Vandenbark AA, Scott B, Burrows GG (2006b) Recombinant HLA-DP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells. J Immunol 177:3874–3883PubMedGoogle Scholar
  37. Gelin C, Sloma I, Charron D, Mooney N (2009) Regulation of MHC II and CD1 antigen presentation: from ubiquity to security. J Leukoc Biol 85:215–224PubMedCrossRefGoogle Scholar
  38. Gorjala P, Gary RK (2010) Beryllium sulfate induces p21CDKN1A expression and a senescence-like cell cycle arrest in susceptible cancer cell types. Biometals. doi: 10.1007/s10534-010-9352-y [ahead of print]
  39. Hamerlinck FF (1999) Neopterin: a review. Exp Dermatol 8:167–176PubMedCrossRefGoogle Scholar
  40. Harris J, Bartelson BB, Barker E, Balkissoon R, Kreiss K, Newman LS (1997) Serum neopterin in chronic beryllium disease. Am J Ind Med 32:21–26PubMedCrossRefGoogle Scholar
  41. Hasejima N, Kobayashi H, Takezawa S, Yamato K, Kadoyama C, Kawano Y (1995) Chronic beryllium disease after exposure to low-beryllium-content copper. Nihon Kyobu Shikkan Gakkai Zasshi 33:1105–1110PubMedGoogle Scholar
  42. Henneberger PK, Cumro D, Duebner DD, Kent MS, McCawley M, Kreiss K (2001) Beryllium sensitization and disease among long-term and short-term workers in a beryllium ceramics plant. Int Arch Occup Environ Health 74(3):167–176Google Scholar
  43. Henneberger PK, Goe SK, Miller WE, Doney B, Groce DW (2004) Industries in the United States with airborne beryllium exposure and estimates of the number of current workers potentially exposed. J Occup Environ Hyg 1:648–659PubMedCrossRefGoogle Scholar
  44. Holt PG, Haining S, Nelson DJ, Sedgwick JD (1994) Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. J Immunol 153:256–261PubMedGoogle Scholar
  45. Hong-Geller E (2009) A role for cell adhesion in beryllium-mediated lung disease. J Occup Environ Hyg 6:727–731PubMedCrossRefGoogle Scholar
  46. Hong-Geller E, Pardington PE, Cary RB, Sauer NN, Gupta G (2006) Chemokine regulation in response to beryllium exposure in human peripheral blood mononuclear and dendritic cells. Toxicology 218:216–228PubMedCrossRefGoogle Scholar
  47. Hume DA (2008) Macrophages as APC and the dendritic cell myth. J Immunol 181:5829–5835PubMedGoogle Scholar
  48. Infante PF, Newman LS (2004) Beryllium exposure and chronic beryllium disease. Lancet 363:415–416PubMedCrossRefGoogle Scholar
  49. Jonth AC, Silveira L, Fingerlin TE, Sato H, Luby JC, Welsh KI, Rose CS, Newman LS, du Bois RM, Maier LA (2007) TGF-beta 1 variants in chronic beryllium disease and sarcoidosis. J Immunol 179:4255–4262PubMedGoogle Scholar
  50. Keizer TS, Sauer NN, McCleskey TM (2005) Beryllium binding at neutral pH: the importance of the Be-O-Be motif. J Inorg Biochem 99:1174–1181PubMedCrossRefGoogle Scholar
  51. Kittle LA, Sawyer RT, Fadok VA, Maier LA, Newman LS (2002) Beryllium induces apoptosis in human lung macrophages. Sarcoidosis Vasc Diffuse Lung Dis 19:101–113PubMedGoogle Scholar
  52. Kokturk N, Sabag M, Stark M, Grief J, Fireman E (2009) High extracellular induced sputum haem oxygenase-1 in sarcoidosis and chronic beryllium disease. Eur J Clin Invest 39:584–590PubMedCrossRefGoogle Scholar
  53. Kreisel D, Krupnick AS, Balsara KR, Riha M, Gelman AE, Popma SH, Szeto WY, Turka LA, Rosengard BR (2002) Mouse vascular endothelium activates CD8+T lymphocytes in a B7-dependent fashion. J Immunol 169:6154–6161PubMedGoogle Scholar
  54. Li L, Fang CJ, Ryan JC, Niemi EC, Lebron JA, Bjorkman PJ, Arase H, Torti FM, Torti SV, Nakamura MC, Seaman WE (2010) Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci 107:3505–3510PubMedCrossRefGoogle Scholar
  55. Limper AH, Colby TV, Sanders MS, Asakura S, Roche PC, DeRemee RA (1994) Immunohistochemical localization of transforming growth factor-beta 1 in the nonnecrotizing granulomas of pulmonary sarcoidosis. Am J Respir Crit Care Med 149:197–204PubMedGoogle Scholar
  56. Mack DG, Lanham AK, Palmer BE, Maier LA, Watts TH, Fontenot AP (2008) 4-1BB enhances proliferation of beryllium-specific T cells in the lung of subjects with chronic beryllium disease. J Immunol 181:4381–4388PubMedGoogle Scholar
  57. Mack DG, Lanham AM, Palmer BE, Maier LA, Fontenot AP (2009) CD27 expression on CD4+ T cells differentiates effector from regulatory T cell subsets in the lung. J Immunol 182:7317–7324PubMedCrossRefGoogle Scholar
  58. Mack DG, Lanham AM, Falta MT, Palmer BE, Maier LA, Fontenot AP (2010) Deficient and dysfunctional regulatory T cells in the lungs of chronic beryllium disease subjects. Am J Respir Crit Care Med 181:1241–1249PubMedCrossRefGoogle Scholar
  59. Maier LA, Sawyer RT, Bauer RA, Kittle LA, Lympany P, McGrath D, Dubois R, Daniloff E, Rose CS, Newman LS (2001a) 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 164:1192–1199PubMedGoogle Scholar
  60. Maier LA, Sawyer RT, Tinkle SS, Kittle LA, Barker EA, Balkissoon R, Rose C, Newman LS (2001b) IL-4 fails to regulate in vitro beryllium-induced cytokines in berylliosis. Eur Respir J 17:403–415PubMedCrossRefGoogle Scholar
  61. Maier LA, Kittle LA, Mroz MM, Newman LS (2003a) Beryllium-stimulated neopterin as a diagnostic adjunct in chronic beryllium disease. Am J Ind Med 43:592–601PubMedCrossRefGoogle Scholar
  62. Maier LA, McGrath DS, Sato H, Lympany P, Welsh K, Du Bois R, Silveira L, Fontenot AP, Sawyer RT, Wilcox E, Newman LS (2003b) Influence of MHC class II in susceptibility to beryllium sensitization and chronic beryllium disease. J Immunol 171:6910–6918PubMedGoogle Scholar
  63. Marchal-Somme J, Uzunhan Y, Marchand-Adam S, Kambouchner M, Valeyre D, Crestani B, Soler P (2007) Dendritic cells accumulate in human fibrotic interstitial lung disease. Am J Respir Crit Care Med 176:1007–1014PubMedCrossRefGoogle Scholar
  64. Marchand-Adam S, El Khatib A, Guillon F, Brauner MW, Lamberto C, Lepage V, Naccache JM, Valeyre D (2008) Short- and long-term response to corticosteroid therapy in chronic beryllium disease. Eur Respir J 32:687–693PubMedCrossRefGoogle Scholar
  65. McCanlies EC, Ensey JS, Schuler CR, Kreiss K, Weston A (2004) The association between HLA-DPB1Glu69 and chronic beryllium disease and beryllium sensitization. Am J Ind Med 46:95–103PubMedCrossRefGoogle Scholar
  66. McCanlies EC, Schuler CR, Kreiss K, Frye BL, Ensey JS, Weston A (2007) TNF-alpha polymorphisms in chronic beryllium disease and beryllium sensitization. J Occup Environ Med 49:446–452PubMedCrossRefGoogle Scholar
  67. McCleskey TM, Buchner V, Field RW, Scott BL (2009) Recent advances in understanding the biomolecular basis of chronic beryllium disease: a review. Rev Environ Health 24:75–115PubMedGoogle Scholar
  68. McKeehan LW (1922) The crystal structure of beryllium and of beryllium oxide. Proc Natl Acad Sci USA 8:270–274PubMedCrossRefGoogle Scholar
  69. Mestas J, Hughes CC (2001) Endothelial cell costimulation of T cell activation through CD58–CD2 interactions involves lipid raft aggregation. J Immunol 167:4378–4385PubMedGoogle Scholar
  70. Mroz MM, Kreiss K, Lezotte DC, Campbell PA, Newman LS (1991) Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic beryllium disease. J Allergy Clin Immunol 88:54–60PubMedCrossRefGoogle Scholar
  71. Mroz MM, Maier LA, Strand M, Silviera L, Newman LS (2009) Beryllium lymphocyte proliferation test surveillance identifies clinically significant beryllium disease. Am J Ind Med 52:762–773PubMedCrossRefGoogle Scholar
  72. Newman LS, Mroz MM, Balkissoon R, Maier LA (2005) Beryllium sensitization progresses to chronic beryllium disease: a longitudinal study of disease risk. Am J Respir Crit Care Med 171:54–60PubMedCrossRefGoogle Scholar
  73. Nilsen AM, Vik R, Behrens C, Drablos PA, Espevik T (2010) Beryllium sensitivity among workers at a Norwegian aluminum smelter. Am J Ind Med 53:724–732PubMedGoogle Scholar
  74. Palmer BE, Mack DG, Martin AK, Maier LA, Fontenot AP (2007) CD57 expression correlates with alveolitis severity in subjects with beryllium-induced disease. J Allergy Clin Immunol 120:184–191PubMedCrossRefGoogle Scholar
  75. Palmer BE, Mack DG, Martin AK, Gillespie MM, Mroz MM, Maier LA, Fontenot AP (2008) Up-regulation of programmed death-1 expression on beryllium-specific CD4+T cell sin chronic beryllium disease. J Immunol 180:2704–2712PubMedGoogle Scholar
  76. Pappas GP, Newman LS (1993) Early pulmonary physiologic abnormalities in beryllium disease. Am Rev Respir Dis 148:661–666PubMedGoogle Scholar
  77. Perrigoue JG, Saenz SA, Siracusa MC, Allenspach EJ, Taylor BC, Giacomin PR, Nair MG, Du Y, Zaph C, van Rooijen N, Comeau MR, Pearce EJ, Laufer TM, Artis D (2009) MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity. Nat Immunol 10:697–705PubMedCrossRefGoogle Scholar
  78. Pott GB, Palmer BE, Sullivan AK, Silviera L, Maier LA, Newman LS, Kotzin BL, Fontenot AP (2005) Frequency of beryllium-specific, TH1-type cytokine-expressing CD4+ T cells in patients with beryllium-induced disease. J Allergy Clin Immunol 115:1036–1042PubMedCrossRefGoogle Scholar
  79. Price DJ, Joshi JG (1983) Ferritin: binding of beryllium and other divalent metal ions. J Biol Chem 258:10873–10880PubMedGoogle Scholar
  80. Reichardt P, Dornbach B, Rong S, Beissert S, Gueler F, Loser K, Gunzer M (2007) Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse. Blood 110:1519–1529PubMedCrossRefGoogle Scholar
  81. Rossman MD (2001) Chronic beryllium disease: a hypersensitivity disorder. Appl Occup Environ Hyg 16:615–618PubMedCrossRefGoogle Scholar
  82. Rossman MD, Kern JA, Elias JA, Cullen MR, Epstein PE, Preuss OP, Markham TN, Daniele RP (1988) Proliferative response of bronchoalveolar lymphocytes to beryllium. A test for chronic beryllium disease. Ann Intern Med 108:687–693PubMedGoogle Scholar
  83. 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 165:788–794PubMedGoogle Scholar
  84. Rouleau M, Dion C, Plamondon P, Kennedy G, L’Esperance G, Zayed J (2005) Physical and chemical characterization of beryllium particles from several workplaces in Quebec, Canada—part A: determining methods for the analysis of low levels of beryllium. J Toxicol Environ Health A 68:1889–1905PubMedCrossRefGoogle Scholar
  85. Rybicki BA, Walewski JL, Maliarik MJ, Kian H, Iannuzzi MC (2005) The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet 77:491–499PubMedCrossRefGoogle Scholar
  86. Sackett HM, Maier LA, Silveira LJ, Mroz MM, Ogden LG, Murphy JR, Newman LS (2004) Beryllium medical surveillance at a former nuclear weapons facility during cleanup operations. J Occup Environ Med 46:953–961PubMedCrossRefGoogle Scholar
  87. Salehi F, Zayed J, Audusseau S, Muller C, Truchon G, Plamondon P, L’Esperance G, Chevalier G, Mazer B (2009) Immunological responses in C3H/HeJ mice following nose-only inhalation exposure to different sizes of beryllium metal particles. J Appl Toxicol 29:61–68PubMedCrossRefGoogle Scholar
  88. Samuel G, Maier LA (2008) Immunology of chronic beryllium disease. Curr Opin Allergy Clin Immunol 8:126–134PubMedCrossRefGoogle Scholar
  89. Sato H, Silveira L, Fingerlin T, Dockstader K, Gillespie M, Lagan AL, Lympany P, Sawyer RT, du Bois RM, Welsh KI, Maier LA (2007a) TNF polymorphism and bronchoalveolar lavage cell TNF-alpha levels in chronic beryllium disease and beryllium sensitization. J Allergy Clin Immunol 119:687–696PubMedCrossRefGoogle Scholar
  90. Sato H, Spagnolo P, Silveira L, Welsh KI, du Bois RM, Newman LS, Maier LA (2007b) BTNL2 allele associations with chronic beryllium disease in HLA-DPB1*Glu69-negative individuals. Tissue Antigens 70:480–486PubMedCrossRefGoogle Scholar
  91. Sawyer RT, Fadok VA, Kittle LA, Maier LA, Newman LS (2000) Beryllium-stimulated apoptosis in macrophage cell lines. Toxicology 149:129–142PubMedCrossRefGoogle Scholar
  92. Sawyer RT, Maier LA, Kittle LA, Newman LS (2002) Chronic beryllium disease: a model interaction between innate and acquired immunity. Int Immunopharmacol 2:249–261PubMedCrossRefGoogle Scholar
  93. Sawyer RT, Day BJ, Fadok VA, Chiarappa-Zucca M, Maier LA, Fontenot AP, Silveira L, Newman LS (2004a) Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease. Am J Respir Cell Mol Biol 31:470–477PubMedCrossRefGoogle Scholar
  94. Sawyer RT, Fontenot AP, Barnes TA, Parsons CE, Tooker BC, Maier LA, Gillespie MM, Gottschall EB, Silveira L, Hagman J, Newman LS (2004b) Beryllium-induced tumor necrosis factor-alpha production by CD4+ T cells is mediated by HLA-DP. Am J Respir Cell Mol Biol 31:122–130PubMedCrossRefGoogle Scholar
  95. Sawyer RT, Abraham JL, Daniloff E, Newman LS (2005a) Secondary ion mass spectroscopy demonstrates retention of beryllium in chronic beryllium disease granulomas. J Occup Environ Med 47:1218–1226PubMedCrossRefGoogle Scholar
  96. Sawyer RT, Dobis DR, Goldstein M, Velsor L, Maier LA, Fontenot AP, Silveira L, Newman LS, Day BJ (2005b) Beryllium-stimulated reactive oxygen species and macrophage apoptosis. Free Radic Biol Med 38:928–937PubMedCrossRefGoogle Scholar
  97. Sawyer RT, Fontenot AP, Barnes TA, Parsons CE, Tooker BC, Maier LA, Gillespie MM, Gottschall EB, Silveira L, Hagman J, Newman LS (2007) Beryllium-induced TNF-alpha production is transcription-dependent in chronic beryllium disease. Am J Respir Cell Mol Biol 36:191–200PubMedCrossRefGoogle Scholar
  98. Schon-Hegrad MA, Oliver J, McMenamin PG, Holt PG (1991) Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways. J Exp Med 173:1345–1356PubMedCrossRefGoogle Scholar
  99. Scott BL, Wang Z, Marrone BL, Sauer NN (2003) Potential binding modes of beryllium with the class II major histocompatibility complex HLA-DP: a combined theoretical and structural database study. J Inorg Biochem 94:5–13PubMedCrossRefGoogle Scholar
  100. Shortman K, Liu YJ (2002) Mouse and human dendritic cell subtypes. Nat Rev Immunol 2:151–161PubMedCrossRefGoogle Scholar
  101. Shortman K, Naik SH (2007) Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7:19–30PubMedCrossRefGoogle Scholar
  102. Silva S, Ganguly K, Fresquez TM, Gupta G, McCleskey TM, Chaudhary A (2009) Beryllium alters lipopolysaccharide-mediated intracellular phosphorylation and cytokine release in human peripheral blood mononuclear cells. J Occup Environ Hyg 6:775–782PubMedCrossRefGoogle Scholar
  103. Simonian PL, Roark CL, Diaz del Valle F, Palmer BE, Douglas IS, Ikuta K, Born WK, O’Brien RL, Fontenot AP (2006) Regulatory role of gammadelta T cells in the recruitment of CD4+ and CD8+ T cells to lung and subsequent pulmonary fibrosis. J Immunol 177:4436–4443PubMedGoogle Scholar
  104. Simonian PL, Roark CL, Wehrmann F, Lanham AK, Diaz del Valle F, Born WK, O’Brien RL, Fontenot AP (2009) Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol 182:657–665PubMedCrossRefGoogle Scholar
  105. Snyder JA, Weston A, Tinkle SS, Demchuk E (2003) Electrostatic potential on human leukocyte antigen: implications for putative mechanism of chronic beryllium disease. Environ Health Perspect 111:1827–1834PubMedCrossRefGoogle Scholar
  106. Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R (2009) Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol 10:713–720PubMedCrossRefGoogle Scholar
  107. Stefaniak AB, Guilmette RA, Day GA, Hoover MD, Breysse PN, Scripsick RC (2005) Characterization of phagolysosomal simulant fluid for study of beryllium aerosol particle dissolution. Toxicol In Vitro 19:123–134PubMedCrossRefGoogle Scholar
  108. Taiwo OA, Slade MD, Cantley LF, Fiellin MG, Wesdock JC, Bayer FJ, Cullen MR (2008) Beryllium sensitization in aluminum smelter workers. J Occup Environ Med 50:157–162PubMedCrossRefGoogle Scholar
  109. Taiwo OA, Slade MD, Cantley LF, Kirsche SR, Wesdock JC, Cullen MR (2010) Prevalence of beryllium sensitization among aluminum smelter workers. Occup Med. doi: 10.1093/occmed/kqq097 [ahead of print]
  110. Tarantino-Hutchison LM, Sorrentino C, Nadas A, Zhu Y, Rubin EM, Tinkle SS, Weston A, Gordon T (2009) Genetic determinants of sensitivity to beryllium in mice. J Immunotoxicol 6:130–135PubMedCrossRefGoogle Scholar
  111. Tinkle SS, Newman LS (1997) Beryllium-stimulated release of tumor necrosis factor-alpha, interleukin-6, and their soluble receptors in chronic beryllium disease. Am J Respir Crit Care Med 156:1884–1891PubMedGoogle Scholar
  112. Tinkle SS, Kittle LA, Schumacher BA, Newman LS (1997) Beryllium induces IL-2 and IFN-gamma in berylliosis. J Immunol 158:518–526PubMedGoogle Scholar
  113. Tinkle SS, Kittle LA, Newman LS (1999) Partial IL-10 inhibition of the cell-mediated immune response in chronic beryllium disease. J Immunol 163:2747–2753PubMedGoogle Scholar
  114. Tinkle SS, Antonini JM, Rich BA, Roberts JR, Salmen R, DePree K, Adkins EJ (2003) Skin as a route of exposure and sensitization in chronic beryllium disease. Environ Health Perspect 111:1202–1208PubMedCrossRefGoogle Scholar
  115. Wang HB, Ghiran I, Matthaei K, Weller PF (2007) Airway eosinophils: allergic inflammation recruited professional antigen-presenting cells. J Immunol 179:7585–7592PubMedGoogle Scholar
  116. Wearsch PA, Cresswell P (2008) The quality control of MHC class I peptide loading. Curr Opin Cell Biol 20:624–631PubMedCrossRefGoogle Scholar
  117. Welch L, Ringen K, Bingham E, Dement J, Takaro T, McGowan W, Chen A, Quinn P (2004) Screening for beryllium disease among construction trade workers at Department of Energy nuclear sites. Am J Ind Med 46:207–218PubMedCrossRefGoogle Scholar
  118. Woo HA, Yim SH, Shin DH, Kang D, Yu DY, Rhee SG (2010) Inactivation of peroxiredoxin I by phosphorylation allows localized H2O2 accumulation for cell signaling. Cell 140:517–528PubMedCrossRefGoogle Scholar
  119. Yazdanpanah B, Wiegmann K, Tchikov V, Krut O, Pongratz C, Schramm M, Kleinridders A, Wunderlich T, Kashkar H, Utermohlen O, Bruning JC, Schutze S, Kronke M (2009) Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature 460:1159–1163PubMedCrossRefGoogle Scholar
  120. Yoshimoto T, Yasuda K, Tanaka H, Nakahira M, Imai Y, Fujimori Y, Nakanishi K (2009) Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat Immunol 10:706–712PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  1. 1.Asthma, Allergy and Inflammation Branch, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious DiseaseNational Institutes of HealthBethesdaUSA
  2. 2.Robert H. Hollis Laboratory of Environmental and Occupational Health Sciences, Division of Environmental and Occupational Health Science, Department of MedicineNational Jewish HealthDenverUSA
  3. 3.Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, School of MedicineUniversity of Colorado DenverDenverUSA
  4. 4.Department of Environmental & Occupational Health, Colorado School of Public HealthUniversity of Colorado DenverDenverUSA

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