Chronic beryllium disease is characterized by the accumulation of helper/inducer T cells, macrophages, and granulomas in the lungs. To evaluate the hypothesis that the proliferation of CD4+ (helper/inducer) T cells in the lungs of patients with this disorder is maintained by local activation of beryllium-specific T-cell clones, we studied T cells obtained from peripheral blood and by bronchoalveolar lavage in eight patients and five healthy controls. The proliferation of T cells in response to beryllium in vitro was confined to the CD4+ T cells from the patients and was dependent on the presentation of antigen in the presence of both major histocompatibility complex class II antigens and functional interleukin-2 receptors. T cells from the patients' lungs had a significantly greater response to beryllium than did T cells from their peripheral blood (stimulation index, 103 vs. 5; P less than 0.01). Lines and clones of cells developed from T cells from the patients' lungs showed dose-dependent proliferation in response to beryllium but did not respond to recall antigens or to other metals. Although all beryllium-specific T-cell clones were CD4+ and none were CD8+ (suppressor/cytotoxic), all beryllium-specific clones studied had different rearrangements of T-cell antigen receptors, suggesting that the response to beryllium involved T cells with diverse specificities for beryllium. We conclude that in patients with chronic beryllium disease, beryllium acts as a class II-restricted antigen, stimulating local proliferation and accumulation in the lung of beryllium-specific CD4+ (helper/inducer) T cells. Hence, chronic beryllium disease is a hypersensitivity disease in which beryllium is the specific antigen.
Source Information
Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892.
This article has been cited by other articles:
Mack, D. G., Lanham, A. K., Palmer, B. E., Maier, L. A., Watts, T. H., Fontenot, A. P.
(2008). 4-1BB Enhances Proliferation of Beryllium-Specific T Cells in the Lung of Subjects with Chronic Beryllium Disease. J. Immunol.
181: 4381-4388
[Abstract][Full Text]
Rossman, M. D.
(2008). Justification for screening for chronic beryllium disease: closer to reality. Eur Respir J
32: 543-544
[Full Text]
Sawyer, R. T., Fontenot, A. P., Barnes, T. A., Parsons, C. E., Tooker, B. C., Maier, L. A., Gillespie, M. M., Gottschall, E. B., Silveira, L., Hagman, J., Newman, L. S.
(2007). Beryllium-Induced TNF-{alpha} Production Is Transcription-Dependent in Chronic Beryllium Disease. Am. J. Respir. Cell Mol. Bio.
36: 191-200
[Abstract][Full Text]
Simonian, P. L., Roark, C. L., Diaz del Valle, F., Palmer, B. E., Douglas, I. S., Ikuta, K., Born, W. K., O'Brien, R. L., Fontenot, A. P.
(2006). Regulatory Role of {gamma}{delta} T Cells in the Recruitment of CD4+ and CD8+ T Cells to Lung and Subsequent Pulmonary Fibrosis. J. Immunol.
177: 4436-4443
[Abstract][Full Text]
Fontenot, A. P., Keizer, T. S., McCleskey, M., Mack, D. G., Meza-Romero, R., Huan, J., Edwards, D. M., Chou, Y. K., Vandenbark, A. A., Scott, B., Burrows, G. G.
(2006). Recombinant HLA-DP2 Binds Beryllium and Tolerizes Beryllium-Specific Pathogenic CD4+ T Cells. J. Immunol.
177: 3874-3883
[Abstract][Full Text]
Chou, Y. K., Edwards, D. M., Weinberg, A. D., Vandenbark, A. A., Kotzin, B. L., Fontenot, A. P., Burrows, G. G.
(2005). Activation Pathways Implicate Anti-HLA-DP and Anti-LFA-1 Antibodies as Lead Candidates for Intervention in Chronic Berylliosis. J. Immunol.
174: 4316-4324
[Abstract][Full Text]
Santucci, M.B., Bocchino, M., Garg, S.K., Marruchella, A., Colizzi, V., Saltini, C., Fraziano, M.
(2004). Expansion of CCR5+ CD4+ T-lymphocytes in the course of active pulmonary tuberculosis. Eur Respir J
24: 638-643
[Abstract][Full Text]
Sawyer, R. T., Parsons, C. E., Fontenot, A. P., Maier, L. A., Gillespie, M. M., Gottschall, E. B., Silveira, L., Newman, L. S.
(2004). Beryllium-Induced Tumor Necrosis Factor-{alpha} Production by CD4+ T Cells Is Mediated by HLA-DP. Am. J. Respir. Cell Mol. Bio.
31: 122-130
[Abstract][Full Text]
Maier, L. A., McGrath, D. S., Sato, H., Lympany, P., Welsh, K., du Bois, R., Silveira, L., Fontenot, A. P., Sawyer, R. T., Wilcox, E., Newman, L. S.
(2003). Influence of MHC CLASS II in Susceptibility to Beryllium Sensitization and Chronic Beryllium Disease. J. Immunol.
171: 6910-6918
[Abstract][Full Text]
Wang, C., Mooney, J. L., Meza-Romero, R., Chou, Y. K., Huan, J., Vandenbark, A. A., Offner, H., Burrows, G. G.
(2003). Recombinant TCR Ligand Induces Early TCR Signaling and a Unique Pattern of Downstream Activation. J. Immunol.
171: 1934-1940
[Abstract][Full Text]
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: 1174-1178
[Abstract][Full Text]
Fontenot, A. P., Maier, L. A., Canavera, S. J., Hendry-Hofer, T. B., Boguniewicz, M., Barker, E. A., Newman, L. S., Kotzin, B. L.
(2002). Beryllium Skin Patch Testing to Analyze T Cell Stimulation and Granulomatous Inflammation in the Lung. J. Immunol.
168: 3627-3634
[Abstract][Full Text]
ROSSMAN, M. D., STUBBS, J., LEE, C. W., 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: 788-794
[Abstract][Full Text]
Saltini, C., Richeldi, L., Losi, M., Amicosante, M., Voorter, C., van den Berg-Loonen, E., Dweik, R.A., Wiedemann, H.P., Deubner, D.C., Tinelli, C.
(2001). Major histocompatibility locus genetic markers of beryllium sensitization and disease. Eur Respir J
18: 677-684
[Abstract][Full Text]
MAIER, L. A., SAWYER, R. T., BAUER, R. A., KITTLE, L. A., LYMPANY, P., MCGRATH, D., DUBOIS, R., DANILOFF, E., ROSE, C. S., NEWMAN, L. S.
(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: 1192-1199
[Abstract][Full Text]
Nemery, B., Bast, A., Behr, J., Borm, P.J.A., Bourke, S.J., Camus, Ph., De Vuyst, P., Jansen, H.M., Kinnula, V.L., Lison, D., Pelkonen, O., Saltini, C.
(2001). Interstitial lung disease induced by exogenous agents: factors governing susceptibility. Eur Respir J
18: 30S-42s
[Abstract][Full Text]
Maier, L.A., Sawyer, R.T., Tinkle, S.S., Kittle, L.A., Barker, E.A., Balkissoon, R., Rose, C., Newman, L.S.
(2001). IL-4 fails to regulate in vitro beryllium-induced cytokines in berylliosis. Eur Respir J
17: 403-415
[Abstract][Full Text]
Lombardi, G., Germain, C., Uren, J., Fiorillo, M. T., du Bois, R. M., 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: 3549-3555
[Abstract][Full Text]
Lee, J. Y., Atochina, O., King, B., Taylor, L., Elloso, M., Scott, P., Rossman, M. D.
(2000). Beryllium, an Adjuvant That Promotes Gamma Interferon Production. Infect. Immun.
68: 4032-4039
[Abstract][Full Text]
Wegner, R., Heinrich-Ramm, R., Nowak, D., Olma, K., Poschadel, B., Szadkowski, D.
(2000). Lung function, biological monitoring, and biological effect monitoring of gemstone cutters exposed to beryls. Occup. Environ. Med.
57: 133-139
[Abstract][Full Text]
Tinkle, S. S., Kittle, L. A., Newman, L. S.
(1999). Partial IL-10 Inhibition of the Cell-Mediated Immune Response in Chronic Beryllium Disease. J. Immunol.
163: 2747-2753
[Abstract][Full Text]
Wang, Z., White, P. S., Petrovic, M., Tatum, O. L., Newman, L. S., Maier, L. A., Marrone, B. L.
(1999). Differential Susceptibilities to Chronic Beryllium Disease Contributed by Different Glu69 HLA-DPB1 and -DPA1 Alleles. J. Immunol.
163: 1647-1653
[Abstract][Full Text]
Fontenot, A. P., Falta, M. T., Freed, B. M., Newman, L. S., Kotzin, B. L.
(1999). Identification of Pathogenic T Cells in Patients with Beryllium-Induced Lung Disease. J. Immunol.
163: 1019-1026
[Abstract][Full Text]
COMHAIR, S. A. A., LEWIS, M. J., BHATHENA, P. R., HAMMEL, J. P., ERZURUM, S. C.
(1999). Increased Glutathione and Glutathione Peroxidase in Lungs of Individuals with Chronic Beryllium Disease. Am. J. Respir. Crit. Care Med.
159: 1824-1829
[Abstract][Full Text]
MALIARIK, M. J., CHEN, K. M., MAJOR, M. L., SHEFFER, R. G., POPOVICH, J. Jr., RYBICKI, B. A., IANNUZZI, M. C.
(1998). Analysis of HLA-DPB1 Polymorphisms in African-Americans with Sarcoidosis. Am. J. Respir. Crit. Care Med.
158: 111-114
[Abstract][Full Text]
Fontenot, A. P., Kotzin, B. L., Comment, C. E., Newman, L. S.
(1998). Expansions of T-cell Subsets Expressing Particular T-cell Receptor Variable Regions in Chronic Beryllium Disease. Am. J. Respir. Cell Mol. Bio.
18: 581-589
[Abstract][Full Text]
ZISSEL, G., BÄUMER, I., FLEISCHER, B., SCHLAAK, M., MÜLLER-QUERNHEIM, J.
(1997). TCR Vbeta Families in T Cell Clones from Sarcoid Lung Parenchyma, BAL, and Blood. Am. J. Respir. Crit. Care Med.
156: 1593-1600
[Abstract][Full Text]
MAPP, C. E., BALBONI, A., BARICORDI, R., FABBRI, L. M.
(1997). Human Leukocyte Antigen Associations in Occupational Asthma Induced by Isocyanates. Am. J. Respir. Crit. Care Med.
156: S139-S143
[Abstract][Full Text]
Inoue, Y., Barker, E., Daniloff, E., Kohno, N., Hiwada, K., Newman, L. S.
(1997). Pulmonary Epithelial Cell Injury and Alveolar-Capillary Permeability in Berylliosis. Am. J. Respir. Crit. Care Med.
156: 109-115
[Abstract][Full Text]
Richeldi, L, Sorrentino, R, Saltini, C
(1993). HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science
262: 242-244
[Abstract]
Fontenot, A. P., Torres, M., Marshall, W. H., Newman, L. S., Kotzin, B. L.
(2000). Beryllium presentation to CD4+ T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease. Proc. Natl. Acad. Sci. USA
97: 12717-12722
[Abstract][Full Text]
Previous
