Natural autoantibodies and anti-idiotypes

Natural antibodies to factor VIII are present in the normal antibody repert oire as other self-reactive antibodies to soluble proteins. The question as to whether they represent just a chance occurrence linked to the huge dive rsification of the antibody repertoire or whether these antibodies have an actual physiological relevance is not entirely settled. Evidence is in favo r of a role in the maintenance of immune homeostasis, however, namely self- reactive antibodies are required to maintain the capacity of the immune sys tem 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 propert y is neutralized at least in part by the production of corresponding anti-i diotypic antibodies. Normal homeostasis can therefore be viewed as a networ k of interacting molecules, idiotypes, and anti-idiotypes; disruption of th is 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 autoimm une reactions. This would mean either passive administration of anti-idioty pic 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 produ cing inhibitors. This essentially requires that an analysis of the anti-fac tor VIII immune response be carried out at the clonal level. Such work is o ngoing in our laboratory.