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HLA-DP Allele-Specific T Cell Responses to Beryllium Account for DP-Associated Susceptibility to Chronic Beryllium Disease

2001; American Association of Immunologists; Volume: 166; Issue: 5 Linguagem: Inglês

10.4049/jimmunol.166.5.3549

1550-6606

Giovanna Lombardi, Conrad Germain, Julia Uren, Maria Teresa Fiorillo, Ronald M. du Bois, W. Jones-Williams, Cesare Saltini, Rosa Sorrentino, Robert I. Lechler,

Immunodeficiency and Autoimmune Disorders

Abstract Occupational exposure to small molecules, such as metals, is frequently associated with hypersensitivity reactions. Chronic beryllium (Be) disease (CBD) is a multisystem granulomatous disease that primarily affects the lung, and occurs in ∼3% of individuals exposed to this element. Immunogenetic studies have demonstrated a strong association between CBD and possession of alleles of HLA-DP containing glutamic acid (Glu) at position 69 in the HLA-DPβ-chain. T cell clones were raised from three patients with CBD in whom exposure occurred 10 and 30 years previously. Of 25 Be-specific clones that were obtained, all were restricted by HLA-DP alleles with Glu at DPβ69. Furthermore, the proliferative responses of the clones were absolutely dependent upon DPβ Glu69 in that a single amino acid substitution at this position abolished the response. As befits a disease whose pathogenesis involves a delayed type hypersensitivity response, the large majority of Be-specific clones secreted IFN-γ (Th1) and little or no IL-4 (Th2) cytokines. This study provides insights into the molecular basis of DP2-associated susceptibility to CBD.