T cell cross-reactivity to heavy metals: identical cryptic peptides may be presented from protein exposed to different metals

Abstract

The mechanisms by which metals induce activation of T cells and thus produce allergic and/ or autoimmune reactions are still obscure, and the same is true for the mechanisms that underly T cell cross-reactivity to different heavy metal ions. In the present study, we investigated induction by metals of T cell reactions to cryptic peptides of bovine RNase A. Murine CD4+ T cell hybridomas specific for cryptic RNase peptides presented from Au(III)-treated RNase were used as detection probes. We showed that in vitro treatment of RNase with Pd(II), Pd(IV), Ni(IV), and partially Pt(IV), but not Au(I), Ni(II), or Pt(II), induced presentation of the same cryptic peptides as those presented from Au(III)-treated RNase. That the former heavy metal ions, but not the latter, were able to alter the antigenicity of RNase was reflected by their ability to induce conformational changes of RNase, as detected by circular dichroism spectroscopy. Furthermore, upon immunization against RNase pretreated with these metals, CD4+ T cell hybridomas specific for unidentified cryptic peptides were obtained. In conclusion, "metal-specific" T cell reactions may be directed against cryptic peptides, and metal cross-reactivity in allergic individuals might be due to metal-induced presentation of overlapping, but not identical, panels of cryptic peptides.

Proteolytic Cleavage of a Self-Antigen Following Xenobiotic-Induced Cell Death Produces a Fragment with Novel Immunogenic Properties

“…In recent studies Griem and colleagues (17,18) have used bovine RNase A as a model Ag to examine how metals might influence T cell recognition of protein Ags. Immunization of mice with unaltered RNase A or gold-altered RNase A (RNase A/Au(III)) led to a number of T cell hybridomas of varying antigenic specificities (17).…”

“…Treatment of RNase A with a number of other metal ions failed to produce material reactive with the RNase A/Au(III)-specific T cell clones. However a more recent study (18) showed that lead-, platinum-, or nickel-treated bovine RNase A could serve as an Ag for RNase A/Au(III)-specific T cell clones. Although immunization with lead-, platinum-, or nickel-treated bovine RNase A resulted in metal-RNase A specific clones; only one clone, following lead-RNase A immunization, could recognize the cryptic peptide 94 -108.…”

“…As mercury-protein interaction has been shown to alter protease sensitivity (16), it is possible that mercury modification of fibrillarin may influence Ag processing, leading to the production of cryptic T cell determinants. Abnormal Ag processing of metal-modified protein is supported by recent studies that have identified cryptic peptides that stimulate IL-2 production by T cell hybridomas obtained from mice immunized with bovine RNase A complexed to gold (17,18). The cryptic nature of these determinants has been suggested by studies showing that T cell hybridomas from mice immunized with bovine RNase alone do not respond to the same peptides (17,18).…”

“…Abnormal Ag processing of metal-modified protein is supported by recent studies that have identified cryptic peptides that stimulate IL-2 production by T cell hybridomas obtained from mice immunized with bovine RNase A complexed to gold (17,18). The cryptic nature of these determinants has been suggested by studies showing that T cell hybridomas from mice immunized with bovine RNase alone do not respond to the same peptides (17,18). Although these studies did not elucidate the process of peptide generation from a metal-modified Ag, APCs are involved as the presence of metal-exposed macrophages contributed to T cell activation (17).…”

CORR Insights®: Do Patients With a Failed Metal-on-metal Hip Implant With a Pseudotumor Present Differences in Their Peripheral Blood Lymphocyte Subpopulations?

“…Case and group studies [4,5] indicate that once locally activated, adaptive immune inflammation to metal contributes to (if not, mediates) the pathogenesis of poor implant performance. Metal DTH reactivity is a lymphocyte mediated response, similar to a Type IV DTH reaction.…”