Structural basis of metal hypersensitivity

Abstract

Metal hypersensitivity is a common immune disorder. Human immune systems mount the allergic attacks on metal ions through skin contacts, lung inhalation and metal-containing artificial body implants. The consequences can be simple annoyances to life-threatening systemic illness. Allergic hyper-reactivities to nickel (Ni) and beryllium (Be) are the best-studied human metal hypersensitivities. Ni-contact dermatitis affects 10 % of the human population, whereas Be compounds are the culprits of chronic Be disease (CBD). αβ T cells (T cells) play a crucial role in these hypersensitivity reactions. Metal ions work as haptens and bind to the surface of major histocompatibility complex (MHC) and peptide complex. This modifies the binding surface of MHC and triggers the immune response of T cells. Metal-specific αβ T cell receptors (TCRs) are usually MHC restricted, especially MHC class II (MHCII) restricted. Numerous models have been proposed, yet the mechanisms and molecular basis of metal hypersensitivity remain elusive. Recently, we determined the crystal structures of the Ni and Be presenting human MHCII molecules, HLA-DR52c (DRA*0101, DRB3*0301) and HLA-DP2 (DPA1*0103, DPB1*0201). These structures revealed unusual features of MHCII molecules and shed light on how metal ions are recognized by T cells.

Fig. 1

Ribbon representations of the MHCII/peptide complexes. View is from the top looking down the α1 helix and β1 helix of MHCII (the potential metal-binding residues are shown with coloring: oxygen, red; nitrogen, blue). The α1 domain is shown in cyan and the β1 domain in magenta. The peptide is colored in yellow. The figures are prepared with program, Pymol. The amino acid names and the peptide anchoring residues are labeled. The four peptide anchoring pockets are labeled with P1, P4, P6 and P9 in all figures a The DR52c/Tu peptide complex, b The DP2/DRA peptide complex

Fig. 2

Ribbon representation of the HLA-DR52c/Tu peptide is viewed as Fig. 1. The model is color coded by B-factor. Blue indicates a low B-factor through to yellow indicating a high B-factor

Fig. 3

The unusual features of HLA-DP2 a The DP2/DRa peptide complex is viewed as Fig. 1. The water accessible surface of the DP2 molecule (without bound pDRA) is shown. The HLA-DP2 β-chain α-helix colored by the relative charge of the surface atoms (red, negative and blue, positive). The acidic pocket is located in the area between p5Pro and the DP2 β-chain α-helix. b A hypothetic Be compound is modeled in the acidic pocket. View of the acidic pocket looking down the peptide binding groove from the top. Wireframe representations of the side chains of β26Glu, β68Glu and β69Glu are colored in magenta. A wireframe representation of P4 to P6 of pDRA is shown with white carbon, red oxygen and blue nitrogen. Also, shown is a blue circle as a hypothetic Be compound

Fig. 4

Models of metal presentation to CD4⁺ T cells in the context of MHCII molecules. Four models of metal presentation have been hypothesized. The schematic drawings of TCR and MHCII are colored as cyan (top) and blue (bottom). A metal ion is showed as a red circle. A peptide is showed as a magenta ellipse. The conformationally changed peptide is showed as a square and a ellipse, a shows the schematic model for the direct binding of a metal to the MHCII molecule only, b depicts the model of interaction where the metal binds to the antigenic peptide and the MHC molecule, c shows that the metal only interacts with peptide, d shows metal induced the change of peptide or MHC as neoantigens