Pure and Applied Chemistry

Abstract: A project is underway within IUPAC to evaluate and harmonize the use of various biomarkers for immunosensitization to metals. This present review summarizes our knowledge of the mechanisms by which certain trace elements evoke allergenicity. Some physiological electrolytes (e.g., Na⁺, K⁺) and macronutrients (e.g., Ca²⁺, Fe³⁺) are immunologically inactive. However, some trace elements essential for cell function (e.g., Co²⁺, Cu²⁺, Cr³⁺), as well as nonessential elements generally considered toxic (e.g., Hg species) or in use as therapeutic agents (e.g., some species of Pt and Au), can give rise to adverse immune reactions. Specific immunological responses to Ni, Co, Cr, Hg, Be, Cu, Pt, Pd, Ir, In, and Au are discussed. In general, these elements can activate T or B cells by specific receptor interactions, resulting in clonal expansion of a metal-specific lymphocyte and an immune response (typically dermatitis) upon re-exposure. Compelling evidence points to the primary role of the T cell in responding to the metal. T-cell activation occurs when a protein of the major histocompatibility complex (MHC) binds to a T-cell receptor in the presence of an MHC binding peptide. Many antigenic substances result in presentation of MHC bound antigenic peptides to the T-cell receptor; metal ions appear to act as haptens that directly or indirectly cause structural changes in MHC molecule-peptide complexes that result in recognition of these complexes by specific T-cell subsets. Nickel and gold are particularly instructive in understanding mechanisms, and are used to discuss models in which the metal may bind to the antigenic peptide (i) before or (ii) after its association with the MHC/T-cell receptor complex, (iii) may bind to the MHC/receptor complex prior to recruitment of the antigenic peptide, or (iv) may bind to the formed peptide/MHC/receptor complex through ligands contributed by one or more of the components.