Widespread evidence indicates that exposures to heavy metals can induce toxic reponses in various organs, particularly in the kidney and the nervous and immune systems. We recently discovered that certain metals can induce an autoimmune response against native protein comprising the cells targeted by the metals. In particular, we found that Pb alters the immunogenicity of three types of neurotypic proteins leading to autoantibody production against native neurotypic protein and that Cd alters the immunogenicity of laminin leading to autoantibody production against native laminin and native collagen IV. Therefore, we speculate that this is one mechanism by which metals induce their toxic effects in targeted tissue, which in turn, led us to the following related hypotheses:1) Toxic metals react with native proteins altering their tertiary structures and rendering them antigenic; 2) for a given protein subtrate, the degree of antigenicity induced by a metal directly correlated with the nucleophilic reactivity of the metal; and 3) at least some toxocity from the metals is due to their inducement of autoantibody production against native proteins by the above-described mechanism.

Our current work addresses these hyphotheses. For example, we asses the antigenic potential of proteins incubated with metal ions covering a broad range of nucleophilic reactivity. Also, we will determine the relative abilities of these metal ions to alter teritary protein structure. Moreover, we will quantitate autoantibodies and specific cytikines, i.e., IL-2, IL-6, and TNFx, produced by spleen cells isolated from animals exposed to these metaland determine whether supernatants produced by these spleen cells are toxic to targeted organ cells. Our results should expand the understanding of the mechanisms by which metals induce their toxic responses.