Beryllium binding to HLA-DP molecule carrying the marker of susceptibility to berylliosis glutamate β69

Amicosante, Massimo; Sanarico, Nunzia; Berretta, Floriana; Arroyo, Javier; Lombardi, Giovanna; Lechler, Robert I.; Colizzi, Vittorio; Saltini, Cesare

doi:10.1016/s0198-8859(01)00261-0

Cited by 60 publications

(56 citation statements)

References 30 publications

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“…When Be-reactive lung T cells are tested for an in vitro response to Be, the DP alleles implicated in disease susceptibility are the same as those shown to present Be to T cells (18,19). In addition, soluble HLA-DP molecules expressing βGlu69, but not HLA-DP molecules with a lysine at that position, can bind beryllium in vitro with high affinity (20,21). Thus, these findings strongly suggest that the ability to bind and present Be is the reason for the association of certain HLA-DP alleles and disease susceptibility.…”

mentioning

confidence: 99%

Crystal structure of HLA-DP2 and implications for chronic beryllium disease

Dai

Murphy

Crawford

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

148

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Chronic beryllium disease (CBD) is a fibrotic lung disorder caused by beryllium (Be) exposure and is characterized by granulomatous inflammation and the accumulation of Be-responsive CD4 + T cells in the lung. Genetic susceptibility to CBD has been associated with certain alleles of the MHCII molecule HLA-DP, especially HLA-DPB1*0201 and other alleles that contain a glutamic acid residue at position 69 of the β-chain (βGlu69). The HLA-DP alleles that can present Be to T cells match those implicated in the genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. The structure of HLA-DP2 and its interaction with Be are unknown. Here, we present the HLA-DP2 structure with its antigen-binding groove occupied by a self-peptide derived from the HLA-DR α-chain. The most striking feature of the structure is an unusual solvent exposed acidic pocket formed between the peptide backbone and the HLA-DP2 β-chain α-helix and containing three glutamic acids from the β-chain, including βGlu69. In the crystal packing, this pocket has been filled with the guanidinium group of an arginine from a neighboring molecule. This positively charged moiety forms an extensive H-bond/salt bridge network with the three glutamic acids, offering a plausible model for how Be-containing complexes might occupy this site. This idea is strengthened by the demonstration that mutation of any of the three glutamic acids in this pocket results in loss of the ability of DP2 to present Be to T cells.

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mentioning

confidence: 99%

Crystal structure of HLA-DP2 and implications for chronic beryllium disease

Dai

Murphy

Crawford

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

148

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“…The immunopathology of this disorder is dominated by the accumulation of CD4z CD45ROz T-helper (Th)-1 memory T-cells proliferating in response to Be in the lower respiratory tract [3][4][5]. Previously, the current authors have shown that allelic variants of the human leucocyte antigen (HLA)-DP molecule carrying a glutamate residue in position 69 of the HLA-DP b-chain (HLA-DPGlu69) [6][7][8] play a central role in disease pathogenesis by directly binding Be in the absence of antigen processing [9] and by restricting the response to Be of Th1 T-cell clones derived from patients with berylliosis [10]. In addition, the current authors have shown that the tumour necrosis factor (TNF)A2 allele of the cytokine gene TNF-a, which is expressed at exaggerated levels by lung and blood mononuclear cells from berylliosis patients in response to Be [11,12], is also associated with susceptibility to berylliosis and positively interacts with the HLA-DPGlu69 marker to increase berylliosis risk [13].…”

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confidence: 99%

HLA-DP-unrestricted TNF-α release in beryllium-stimulated peripheral blood mononuclear cells

Amicosante¹,

Berretta²,

Franchi³

et al. 2002

Eur Respir J

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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.

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“…Genetic counseling could be implicated in sensitized subjects for HLA-DPGlu69 mutation (27,39). Testing for carrier status in a pre-employment population, however, is problematic not only because of ethical issues but because HLA-DPGlu69 is a haplotype frequently encountered within the general population (40).With a CBD disease frequency of 5% in exposed workers, the positive predictive value of this test has been calculated to be only 8.3%-14.3% in different racial groups (40).…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis between CFSE flow cytometric and tritiated thymidine incorporation tests for beryllium sensitivity

Milovanova

2007

Cytometry Part B Clinical

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Background: In this study, we evaluated alternative possibility for CFSE beryllium flow cytometric test against beryllium blood lymphocyte proliferation test (BeLPT) as a standard radioactive clinical screening method to identify sensitization to beryllium.Methods: Delta PD (the ratio of divided cell population to the total number of cells with subtracted counts of unstimulated cells) of specific beryllium-induced pathogenic CD3 þ CD4 þ T-lymphocytes and stimulation index (SI) in CFSE proliferation test was compared with delta counts per minute (mean test CPM minus mean control CPM) and SI in radioactive blood BeLPT.Results: Comparison analysis of CFSE and BeLPT demonstrated excellent agreement between delta PD and delta CPM (j 5 0.845, P < < 0.0001). We determined 6.8% positive subjects in the berylliumexposed, Be-LPT-negative group. The decreased mean difference of these indexes to percentage of average and the long tail in the plot reflects increased sensitivity. CFSE/CD4 þ T-cell proliferation assay has 100% specificity, significantly higher sensitivity and efficiency than BeLPT.Conclusions: Both delta PD, measured by the precursor frequencies method in CFSE assay and delta CPM, defined by tritiated thymidine in BeLPT, can be used for the enumeration of beryllium specific CD41 T-cell proliferation and may substantially improve the quality of the early diagnosis of beryllium hypersensitivity. q 2007 Clinical Cytometry Society

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Beryllium binding to HLA-DP molecule carrying the marker of susceptibility to berylliosis glutamate β69

Cited by 60 publications

References 30 publications

Crystal structure of HLA-DP2 and implications for chronic beryllium disease

Crystal structure of HLA-DP2 and implications for chronic beryllium disease

HLA-DP-unrestricted TNF-α release in beryllium-stimulated peripheral blood mononuclear cells

Comparative analysis between CFSE flow cytometric and tritiated thymidine incorporation tests for beryllium sensitivity

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