Inserm U. 430, institut des Cordeliers, 15, rue de l'École-de-Médecine, 75006 Paris, France.
Antibodies with hydrolytic activity have been described in human in several pathological situations: lupus erythematosus, autoimmune thyroiditis, asthma and Bence-Jones disease. Although the target molecules hydrolyzed by the antibodies are self antigens (DNA, thyroglobulin, vasoactif instestinal peptide), a direct implication of the hydrolysis of the self-antigen in the etiology of the disease has never been demonstrated. We have described the presence of IgG antibodies able to hydrolyse F VIII in patients with severe hemophilia A who have developed F VIII inhibitors following administration of therapeutic F VIII. The kinetic parameters of the clivage of F VIII by the anti-F VIII antibodies are in the range of that of catalytic antibodies previously described. We have further demonstrated that catalytic antibodies are present in more than 50% of inhibitor-positive patients with severe haemophilia A. Catalytic antibodies to F VIII are the first example where the hydrolysis of the target molecule by proteolytic antibodies may be directly relevant to the etiology of the disease. The identification of F VIII inhibitors as proteases will open the way to novel therapeutic approaches aimed at eliminating F VIII inhibitors in haemophilia A patients.