Immune mechanisms in lead induced neurotoxicity

Lead (Pb) exposure induces the production of autoantibodies (AuAb) against several neural proteins, including myelin basic protein (MBP), glial fibrillary acidic protein (GFAP) and neurofilament (NF) protein. However, it is not known whether Pb-induced neural damage must precede the AuAb response. This thesis addressed this question by comparing the kinetics of Pb-induced AuAb production and interleukin production vs. changes in brain GFAP levels, a marker of CNS neurotoxicity. In addition, gender differences for any Pb-induced autoimmune response were determined. Male and female mice were exposed in vivo to 1300 ppm PbOAc in the drinking water. Serum AuAb titers against 5 nervous system proteins (MBP, GFAP, NF68, NF160, NF200) and the levels of IL-2 and IL-6 from supernatants of lectin-stimulated splenocytes were measured and compared to changes in brain GFAP levels. GFAP levels were elevated in the hippocampus and cerebellum of male mice at day 5 but recovered to baseline afterward. In males, serum AuAbs against nervous system proteins were of the IgM isotype, were mostly directed against the NFs and peaked predominately around day 10. These AuAb changes were accompanied by IL-6 elevations (day 10), followed by IL-2 elevations (day 14). Analogous effects were not seen in female mice. These results suggest that Pb-induced nervous system damage precedes AuAb production in male mice and also confirm the sensitivity of males to Pb toxicity since Pb consumption did not differ between the genders.; Some heavy metals are believed involved in the pathogenesis of several nervous system diseases. In these disorders, AuAb against neural proteins are evident at some stage. We hypothesize that Pb aggravates neurological disease by enhancing the immunogenicity of nervous system proteins such as MBP, GFAP and NF. This hypothesis was addressed by inoculating mice with either saline, Pb alone, one of the above proteins, or Pb-altered versions of the protein. In all cases, the sera of mice treated with the one of the Pb-altered proteins had statistically higher antibody titers than both controls (Pb and saline) and native protein-immunized mice. IL-6 production was increased in mice immunized with Pb-altered MBP but not with Pb-altered GFAP or Pb-altered NF. IL-2 levels were unchanged in all cases. These results demonstrate that Pb does enhance the immunogenicity of the 3 nervous system proteins and suggest an immunologically-mediated component for Pb-induced neurotoxicity. The IL-6 results suggest that Pb-altered proteins may induce AuAb production through different mechanisms.