HLA-DP-unrestricted TNF-α 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 β-chain (HLA-DPGlu69), can bind Be directly and present it to interferon (IFN)-γ releasing Th1 T-cell clones from patients with berylliosis; and 2) the cytokine gene tumour necrosis factor (TNF)-α which has been shown to increase berylliosis risk independent of HLA-DPGlu69.In order to determine whether TNF-α 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-γ, TNF-α, 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-γ 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-α 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-α production in healthy control subjects not exposed to Be in the absence of T-cell proliferation and IFN-γ production.In conclusion, these data suggest that the tumour necrosis factor-α 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.

Cytokine profiles in human exposure to metals (IUPAC Technical Report)

“…Antibodies to HLA-DPglu69 were able to suppress proliferation and IFN-γ release by T-cells from patients with beryllosis, but not secretion of TNF-α, indicating different mechanisms stimulating release [82]. Increased numbers of T-cells producing IL-2 and IFN-γ have been reported in blood of patients with chronic Be disease [84] .…”

“…Beryllium sulfate stimulates IL-2, IL-6, IL-10, IFN-γ, and TNF-α production in bronchoalveolar lavage cells from patients with chronic Be disease [81], and activates TH1 cell clones from such patients [82]. In one mechanism, R. KLEIN et al…”

Beryllium-Induced TNF-α Production Is Transcription-Dependent in Chronic Beryllium Disease

“…Future studies will include sufficient patient numbers to perform a more detailed analysis using nuclear run-on transcription assays or RNA Pol II ChIP assays to provide formal biochemical proof that Be-stimulation induces TNF-␣ gene transcription. Due to this limitation, it is reasonable to suggest that some, or all, of these transcription factors could mediate the activation of genes encoding other Be-stimulated proteins produced by CBD BAL CD4 ϩ T cells-for example, IFN-␥, IL-2, IL-6, and IL-10 (7,(24)(25)(26)(27)(28).…”

An industrial risk: Beryllium

“…Yine, normal bireylerden faklı olarak HLA-DR β zincirinin 47. pozisyonunda fenilalanin bulunmasının da 47,48 HLA-DPGlu69-negatif kişilerdeki berilyum hipersensitivitesi ile ilişkili olduğu düşünülmektedir. 49 Benzer olarak, HLA-DPGlu69-negatif kişilerde berilyum hipersensitivitesi ile HLA-DR*13 allellerinin ilişkili olduğu gösterilmiştir. 48 HLA-DR*13 allellerinde, DR β-zincirinin 47. pozisyonunda fenilalanin ve 71. pozisyonunda bir glutamik asit (HLA-DP 69. pozisyonundaki glutamik asitin karşılığı olan) yer almaktadır.…”