Redox-reactive autoantibodies in cerebrospinal fluids

The oxidative stress associated with increased transitional metal concentrations in neurodegenerative diseases served as the impetus for our testing the status of redox-reactive autoantibodies in the cerebrospinal fluids from autopsy-confirmed Alzheimer's patients. Here we describe a novel family of autoantibodies capable of recognizing autoantigens subsequent to in vitro oxidation-reduction (redox) reactions in the blood and spinal fluids of all normal individuals tested. Redox autoantibodies are not detected in conventional immunoassays, thereby differentiating them from natural and hidden autoantibodies described by others. Whereas blood-borne redox autoantibodies can be IgG, IgM, and/or IgA, in spinal fluid the antibody isotype is limited to IgG. Autoantibodies in certain patients are reversible and disappear when exposed to oxidizing agents in vitro. One mechanism proposed to modulate the autoantibody unmasking-masking reactions relies upon redox-driven nitrosylation of an amino acid-containing aromatic ring, which is found within the complementarity-determining regions (CDR) of the antibodies' antigen-binding sites. The evolutionary persistence of this novel antoantibody family indicates that they are important for immunological homeostasis and suggests that they perform necessary physiological functions. The dramatic difference in the presence of such antibodies in normal versus Alzheimer's disease (AD) suggests an important immune system dysfunction in AD.