title: HLA-DP-unrestricted TNF-alpha release in beryllium-stimulated peripheral blood mononuclear cells.
abstract: Berylliosis is a granulomatous disorder of the lung caused by inhalation of beryllium (Be) and dominated by the accumulation of CD4+ T-helper (Th)1 memory T-cells proliferating in response to Be in the lower respiratory tract. Two gene markers have been associated with susceptibility to berylliosis: 1) the human leucocyte antigen (HLA)-DP gene whose allelic variants, carrying glutamate in position 69 of the beta-chain (HLA-DPGlu69), can bind Be directly and present it to interferon (IFN)-gamma releasing Th1 T-cell clones from patients with berylliosis; and 2) the cytokine gene tumour necrosis factor (TNF)-alpha which has been shown to increase berylliosis risk independent of HLA-DPGlu69. In order to determine whether TNF-alpha release was triggered by Th1 T-cell activation by Be stimulation in the context of HLA-DPGlu69 molecules, the proliferation of BeSO4-stimulated blood mononuclear cells and the release of IFN-gamma, TNF-alpha, RANTES (regulated on activation normal T-cell expressed and secreted), granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4, IL-6, IL-8, IL-10 and IL-12 by BeSO4-stimulated blood mononuclear cells was quantified in 11 individuals with berylliosis using an anti-HLA-DP antibody as a probe for HLA-DP restricted T-cell activation. While proliferation and IFN-gamma release were completely abrogated by HLA-DP inhibition (inhibition with anti-HLA-DP monoclonal antibody (mAb): 88+/-16 and 77+/-16%, respectively; anti-HLA-DR: 29+/-38 and 14+/-10%, respectively), the release of TNF-alpha was not (inhibition with anti-HLA-DP mAb: 8.9+/-7.8%). No other cytokine was detected at significant levels. Moreover, Be was able to induce TNF-alpha production in healthy control subjects not exposed to Be in the absence of T-cell proliferation and IFN-gamma production. In conclusion, these data suggest that the tumour necrosis factor-alpha response of mononuclear cells is independent of the activation of beryllium-specific human leucocyte anitgen-DP restricted T-cells, which is consistent with the finding that the tumour necrosis factorA2 and the human leucocyte anitgen-DPGlu69 genetic markers are independently interacting in increasing berylliosis risk.
authors.affiliation: amicosante@inmi.it
authors.forename: M
authors.initials: M
authors.lastname: Amicosante
authors.forename: F
authors.initials: F
authors.lastname: Berretta
authors.forename: A
authors.initials: A
authors.lastname: Franchi
authors.forename: P
authors.initials: P
authors.lastname: Rogliani
authors.forename: C
authors.initials: C
authors.lastname: Dotti
authors.forename: M
authors.initials: M
authors.lastname: Losi
authors.forename: R
authors.initials: R
authors.lastname: Dweik
authors.forename: C
authors.initials: C
authors.lastname: Saltini
mesh_terms: D000328:Adult; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001607:Berylliosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001608:Beryllium / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006682:HLA-DP Antigens / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D006682:HLA-DP Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D001608:Beryllium