Genetic susceptibility and immune-mediated destruction in beryllium-induced disease

Fontenot, Andrew P.; Maier, Lisa A.

doi:10.1016/j.it.2005.08.004

Cited by 67 publications

(55 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, we understand little about the nature of the T-cell ligands that form when small chemical moieties, such as plant urushiols or penicillin (27,28) or metal cations (15), attach to self-peptide-MHC complexes to , mediating the widespread hypersensitivity to nickelcontaining jewelry (16), to Be ++ , which causes the rarer, but much more serious, fulminating lung inflammation seen in chronic beryllium disease (CBD) (29). At present, we do not know the structure of the MHC-peptide-cation complex ligand involved in any of these diseases.…”

Section: Discussionmentioning

confidence: 99%

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

Yin

Crawford

Marrack

et al. 2012

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

View full text Add to dashboard Cite

T cell-mediated allergy to Ni++ is one of the most common forms of allergic contact dermatitis, but how the T-cell receptor (TCR) recognizes Ni ++ is unknown. We studied a TCR from an allergic patient that recognizes Ni ++ bound to the MHCII molecule DR52c containing an unknown self-peptide. We identified mimotope peptides that can replace both the self-peptide and Ni ++ in this ligand. They share a p7 lysine whose εNH 2 group is surface-exposed when bound to DR52c. Whereas the TCR uses germ-line complementary-determining region (CDR)1/2 amino acids to dock in the conventional diagonal mode on the mimotope-DR52c complex, the interface is dominated by the TCR Vβ CDR3 interaction with the p7 lysine. Mutations in the TCR CDR loops have similar effects on the T-cell response to either the mimotope or Ni ++ ligand. We suggest that the mimotope p7 lysine mimics Ni ++ in the natural TCR ligand and that MHCII β-chain flexibility in the area around the peptide p7 position forms a common site for cation binding in metal allergies.antigen presentation | hypersensitivity | peptide display library | crystal structure | metal recognition T -cell receptors (TCRs) made up of α-and β-chains have a very large number of ligands, including self-and foreign peptides, superantigens, lipids, small organic haptens, and metal ions. These ligands usually react with TCRs when they are bound to major histocompatibility complex (MHC) proteins. TCRs usually bind MHC/peptide combinations in similar orientations such that the TCR is aligned diagonally across the MHC/peptide, with the Vβ region of the TCR placed over the α1 α-helix of the MHCI heavy chain or of the MHCII α-chain and the Vα region placed over the α2 α-helix of the MHCI heavy chain or the β1 α-helix of the MHCII β-chain (1, 2). We (1, 3-5) and others (6-8) have suggested that germ line-encoded residues in the complementary-determining region (CDR)1 and CDR2 loops of the TCR variable regions are evolutionarily conserved for interaction with the MHC. These residues are also involved when natural killer T (NKT) cells recognize glycolipids bound to the nonclassical MHCI protein CD1d, and even when T cells recognize the non-MHC protein CD155 (9).It is noteworthy, however, that the presence of these evolutionarily conserved amino acids does not assure the conventional diagonal docking mode for TCRs on MHC molecules. For example, the NKT TCRs have a unique docking mode on CD1d (10, 11): Protein superantigens bridge TCRs to MHCII in a manner that prevents conventional TCR-MHCII interaction (12), and TCRs often dock to autoantigen peptides bound to MHCII in unusual orientations (13,14). Thus, in cases in which the structural details of the interaction between the TCR and its target are not known, we cannot be certain that the interaction will occur with the TCR in its usual orientation on MHC or not. Such is the case for the recognition of metal ions by TCRs (15 ++ when a particular unknown peptide(s) is bound to DR52c (18). Here, using a display library method we have previously describe...

show abstract

Section: Discussionmentioning

confidence: 99%

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

Yin

Crawford

Marrack

et al. 2012

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

View full text Add to dashboard Cite

show abstract

“…C hronic beryllium disease (CBD) 3 is characterized by the accumulation of memory CD4 ϩ T lymphocytes and granulomatous inflammation in the lungs of berylliumexposed individuals (1,2). When stimulated with beryllium salts, a large percentage of bronchoalveolar lavage (BAL) CD4 ϩ T cells from CBD patients respond vigorously by producing proinflammatory cytokines such as IFN-␥ and TNF-␣ (3,4).…”

Section: Up-regulation Of Programmed Death-1 Expression Onmentioning

confidence: 99%

Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease

Palmer¹,

Mack²,

Martin³

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

Chronic beryllium disease (CBD) is caused by workplace exposure to beryllium and is characterized by the accumulation of memory CD4+ T cells in the lung. These cells respond vigorously to beryllium salts in culture by producing proinflammatory Th1-type cytokines. The presence of these inflammatory cytokines leads to the recruitment of alveolar macrophages, alveolitis, and subsequent granuloma development. It has been shown that chronic exposure to conventional Ags leads to up-regulation in the expression of negative regulators of T cells such as programmed death-1 (PD-1). Due to the persistence of beryllium in the lung after the cessation of exposure, aberrant regulation of the PD-1 pathway may play an important role in CBD development. In the present study, PD-1 expression was measured on blood and bronchoalveolar lavage (BAL) CD4+ T cells from beryllium-sensitized and CBD subjects. PD-1 expression was significantly higher on BAL CD4+ T cells compared with those cells in blood, with the highest expression on the beryllium-specific T cell subset. In addition, the expression of PD-1 on BAL CD4+ T cells directly correlated with the severity of the T cell alveolitis. Increased expression of the PD-1 ligands, PD-L1 and PD-L2, on BAL CD14+ cells compared with blood was also seen. The addition of anti-PD-1 ligand mAbs augmented beryllium-induced CD4+ T cell proliferation, and an inverse correlation was seen between PD-1 expression on beryllium-specific CD4+ T cells and beryllium-induced proliferation. Thus, the PD-1 pathway is active in beryllium-induced disease and plays a key role in controlling beryllium-induced T cell proliferation.

show abstract

“…metal hypersensitivity | MHC presentation | genetic susceptibility C hronic beryllium disease (CBD) is a granulomatous lung disorder that occurs in susceptible individuals exposed to beryllium (Be) in the workplace (1). Genetic susceptibility to CBD has been linked to major histocompatibility complex class II (MHCII) alleles, particularly HLA-DP.…”

mentioning

confidence: 99%

Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease

Mack¹,

Falta²,

McKee³

et al. 2014

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

View full text Add to dashboard Cite

Susceptibility to chronic beryllium disease (CBD) is linked to certain HLA-DP molecules, including HLA-DP2. To elucidate the molecular basis of this association, we exposed mice transgenic (Tg) for HLA-DP2 to beryllium oxide (BeO) via oropharyngeal aspiration. As opposed to WT mice, BeO-exposed HLA-DP2 Tg mice developed mononuclear infiltrates in a peribronchovascular distribution that were composed of CD4 + T cells and included regulatory T (T reg ) cells. Beryllium-responsive, HLA-DP2-restricted CD4 + T cells expressing IFN-γ and IL-2 were present in BeO-exposed HLA-DP2 Tg mice and not in WT mice. Using Be-loaded HLA-DP2-peptide tetramers, we identified Be-specific CD4 + T cells in the mouse lung that recognize identical ligands as CD4 + T cells derived from the human lung. Importantly, a subset of HLA-DP2 tetramer-binding CD4 + T cells expressed forkhead box P3, consistent with the expansion of antigen-specific T reg cells. Depletion of T reg cells in BeO-exposed HLA-DP2 Tg mice exacerbated lung inflammation and enhanced granuloma formation. These findings document, for the first time to our knowledge, the development of a Be-specific adaptive immune response in mice expressing HLA-DP2 and the ability of T reg cells to modulate the beryllium-induced granulomatous immune response.metal hypersensitivity | MHC presentation | genetic susceptibility

show abstract

Genetic susceptibility and immune-mediated destruction in beryllium-induced disease

Cited by 67 publications

References 70 publications

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy

Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease

Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease

Contact Info

Product

Resources

About