Allergic manifestations as the results of a conditional autoimmune response.
By means of repertoire cloning we have isolated human anti-IgE antibodies as well as human anti-FcepsilonRI antibodies. Whether the naturally occurring anti-IgE autoantibodies play a pathophysiological role may be disputed, but the beneficial role of recombinant anti-IgE antibodies as a therapeutic agent has been shown. On the other hand, the natural antibodies isolated from an antibody library of a nonallergic individual against the FcepsilonRI alpha-chain are anaphylactogenic, if FcepsilonRI was not occupied. Thus, anti-FcepsilonRI autoantibodies may be part of a conditional autoimmune reaction, leading to urticaria if local IgE is consumed, e.g. after an immediate reaction. Thus, anti-FcepsilonRI antibodies may represent an amplification arm of the late reaction. The normal occurrence of anti-IgE and anti-IgE receptor autoantibodies may suggest that it might also be feasible to induce such autoantibodies by vaccination. In a monkey model using a mimotope of human IgE it was possible to induce a beneficial anti- IgE autoimmune response. The actual epitope of the IgE molecule was then also molecularly reconstructed by generating recombinant anti-idiotypic antibodies. These antibodies also induced effectively an anti-IgE response in monkeys, suggesting that not only mimotopes but also anti-idiotypic antibodies may be used to generate an autoimmune response. Both of our projects suggest that active immunization may be a new form of immunomodulation for the treatment of allergic disease.