Factor VIII Inhibitors. Natural autoantibodies and anti-idiotypes

Natural antibodies to factor VIII are present in the normal antibody repertoire as other self-reactive antibodies to soluble proteins. The question as to whether they represent just a chance occurrence linked to the huge diversification of the antibody repertoire or whether these antibodies have an actual physiological relevance is not entirely settled. Evidence is in favor of a role in the maintenance of immune homeostasis, however, namely self-reactive antibodies are required to maintain the capacity of the immune system to distinguish self from nonself. Anti-factor VIII antibodies pose an interesting case in point because they exhibit the capacity to inhibit the function of factor VIII. Such a property is neutralized at least in part by the production of corresponding anti-idiotypic antibodies. Normal homeostasis can therefore be viewed as a network of interacting molecules, idiotypes, and anti-idiotypes; disruption of this equilibrium leads to the development of autoimmunity. A question that remains open for the time being is whether this network of interactions can be modulated in a defined way for the treatment of autoimmune reactions. This would mean either passive administration of anti-idiotypic antibodies or active immunization with idiotypes. The former has proved to be efficient, and the latter has still to be demonstrated. Further, and probably most importantly, is the question of the possible application of the idiotypic network concept to the treatment of hemophilia patients producing inhibitors. This essentially requires that an analysis of the anti-factor VIII immune response be carried out at the clonal level. Such work is ongoing in our laboratory.