Metal-derivatized Major Histocompatibility Complex

One of the prices we pay for our love of jewelry is allergic contact hypersensitivity to metal, an autoimmune condition that variably afflicts around 10% of all Caucasians (1). Contact hypersensitivity is a classic type IV DTH (delayed type hypersensitivity) response, involving primed T cells that are specific for metal modified antigens generated at a local site in the body (most commonly the epidermal layer of the skin). The T cells respond by producing proinflammatory mediators that result in local redness, swelling, and itching (2). In many cases nickel is found to be the culprit and unfortunately for sensitive people, nickel is one of the most common metals in the environment, which makes it particularly difficult to avoid. Being a ubiquitous component of metal alloys, nickel is found not only in catheters, needles, dental braces, and many other medical devices, but also in everyday items such as jewelry, watches, coins, and even in some foods. Cases can range in severity from a mild localized swelling, redness, and itchiness to a much more debilitating reaction involving larger areas (e.g., the entire mouth in some patients with hypersensitivity to the metal of their dental braces). Ni2+ reactive T cell clones have been isolated from patients and found to display varying degree of MHC class II restriction (some are more promiscuous than others) and two models have been advanced to explain what might be happening at the molecular level (3). The first model (Fig. 1) proposes that Ni2+ derivatized self-proteins are naturally processed and presented as Ni2+/peptides by the APC resident in the skin (e.g., Langerhan cells). The second model proposes a processing independent pathway where the metal directly derivatizes MHC peptide complexes on the surface of the APC. While both mechanisms seem feasible, firm evidence for either has been elusive … until now. In this issue, Lu et al. (4), present direct evidence for the formation of a preformed HLA-DR/Ni2+ complex that stimulates a Ni2+ reactive human T cell clone called ANi-2.3. ANi-2.3 is a CD4+ T cell with a Vβ17/Vα1 T cell receptor and is restricted by HLA-DR52c pretreated with soluble Ni2+. Using mutagenesis, they localize the Ni2+ binding site to histidine 81 on top of MHC class II β-chain. His81 is familiar to anyone who has worked with bacterial superantigens because it's the same residue targeted by a subset of bacterial superantigens using a Zn2+ atom to bind tightly to MHC class II (5). His81 is one of only a few conserved residues on the top of the MHC class II and plays an important role in stabilizing bound peptide through a hydrogen bond to the peptide backbone (6). The important feature of Zn2+ in superantigen binding is the stability it provides the MHC class II/Sag complex, so the analogy between stable superantigen binding and metal-mediated TCR binding is clear and important. The Lu paper reveals for the first time, a possible molecular structure that might explain how normally tolerant, self-reactive T cells are stimulated into action through the addition of a single metal atom on the top of the MHC class II molecule. Figure 1. Two hypothetical pathways for nickel presentation. (1) Processing-dependent pathway. Nickel ions bind to self proteins which are then processed and presented by MHC on Langerhan cells. (2) Processing-independent pathway. Nickel ions enter through the .