Redox-reactive autoantibodies: Detection and physiological relevance

We recently described a hitherto unrecognized family of autoantibodies that become unmasked (detectable) subsequent to oxidation–reduction (redox) reactions. These masked redox-reactive autoantibodies are not detectable by using conventional immunoassays. Additional experimentation has demonstrated that autoantibodies in the blood of patients with autoimmune diseases can be masked (become undetectable) by exposure to oxidizing agents. Simultaneous masking and unmasking of different autoantibodies in a given patient's serum or plasma is evidence that immune complexes are not the source of redox-reactive autoantibodies. We propose that a mechanism responsible for unmasking–masking antibody specificities requires nitrosylation of tyrosine residues in the hypervariable or complementarity determining regions of the antibodies' antigen-binding sites. Other laboratories, selected by us for their respective expertise, have studied our redox-reacted and control serum and/or antibody preparations and have found an expanding array of autoantibody specificities. The gathering data suggest that certain autoimmune diseases may involve redox disorders rather than a failure to deplete, suppress, tolerate or divert self-directed B cell activity. The persistence and fluctuation of redox-reactive autoantibodies suggest that they are manifestations of an as yet undefined natural selective pressure on the evolution of the immunological system. We propose that they are the “contrivances” suggested by Paul Ehrlich more than a hundred years ago, and that these antibodies perform important physiological and pathophysiological functions.