Identification of pathogenic T cells in patients with beryllium-induced lung disease.
Chronic beryllium disease (CBD) is caused by beryllium exposure and is characterized by granulomatous inflammation with accumulation of CD4+ T cells in the lung. We analyzed TCR beta-chain and alpha-chain genes expressed by these CD4+ T cells. In the lungs of individual patients, as well as among four of five CBD patients studied, different oligoclonal expansions within the Vbeta3 subset were found to express homologous or even identical CDR3 amino acid sequences. These related expansions were specific for CBD patients, were compartmentalized to lung, and persisted at high frequency in patients with active disease. Limiting dilution cloning and analysis of coexpressed TCR alpha-chain genes confirmed that these TCRs were selectively expanded by a common Ag involving beryllium. Overall, homologous TCR beta- and alpha-chains showed identical V regions and invariant charged residues within the CDR3 but considerable variability in TCRJ usage. Remarkably, CBD patients expressing nearly identical TCRs did not share common HLA-DRB1 or DQ alleles. These results implicate particular CD4+ cells in the pathogenesis of CBD and provide insight into how beryllium is recognized in human disease.
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
A P
AP
Fontenot
M T
MT
Falta
B M
BM
Freed
L S
LS
Newman
B L
BL
Kotzin
D000595:Amino Acid Sequence; D001608:Beryllium / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002999:Clone Cells; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000187:drug effects; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000187:drug effects; D019673:Genes, T-Cell Receptor alpha / Q000187:drug effects; D019674:Genes, T-Cell Receptor beta / Q000187:drug effects; D015769:Granuloma, Respiratory Tract / Q000139:chemically induced* / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced* / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics
D016693:Receptors, Antigen, T-Cell, alpha-beta; D001608:Beryllium