Genetic Factors Modify the Risk of Developing Beryllium Disease

Sally S. Tinkle; Ainsley Weston; Melanie S. Flint

doi:10.1055/s-2003-39016

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2003; 24(2): 169-178
DOI: 10.1055/s-2003-39016

Genetic Factors Modify the Risk of Developing Beryllium Disease

Sally S. Tinkle, Ainsley Weston, Melanie S. Flint

Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia

Abstract

ABSTRACT

Chronic beryllium disease (CBD) is a debilitating, granulomatous lung disease that occurs in 1 to 5% of exposed workers. Beryllium stimulates a major histocompatibility Class II-restricted, TH1, CD4+ T cell-mediated immune response. The immunological component of the illness, coupled with the small subset of beryllium workers who develop disease, led researchers to hypothesize that genetic factors modify risk of disease. Analysis of human leukocyte antigen (HLA) genes, the T cell receptor, and tumor necrosis factor (TNF)-α focused on three critical steps in the development of beryllium specific immunity. Molecular epidemiological analysis of the association of HLA-DP, -DR, and -DQ has implicated HLA-DPB1 ^E69 allelic variants in disease; however, its role in sensitization is unclear. A single report suggested association between HLA-DQB1 ^G86 and progression from sensitization to disease. A beryllium-specific binding motif was identified in CBD-derived T cell clones. Beryllium-stimulated proliferation using HLA-DPB1¹0201 and TCRAV22S1/TCRBVb3 T cell receptors (TCRs) confirmed beryllium specificity of these molecules. The G/A transition at -308 in the TNF-α promoter was associated with high concentrations of TNF-α in bronchoalveolar lavage and to disease severity. Although these studies are continuing, the data confirm the role of genetic factors in the cellular response to beryllium.

KEYWORDS

Beryllium disease - risk factors - HLA - T cell receptor - TNF-α

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References

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