Natural antibodies to factor VIII

Anti-factor VIII antibodies represent a unique model to study the relations hip between natural autoreactivity (natural antibodies to factor VIII of he althy individuals), disease-associated autoimmunity ("spontaneous" factor V III inhibitors of patients with anti-factor VIII autoimmune disease) and an tigen-driven immune responses (immune inhibitors in multitransfused patient s with hemophilia A) to a single human protein antigen. Although natural an d disease-associated anti-factor VIII antibodies are not readily distinguis hed based on the comparison of their isotypic distribution and epitope mapp ing, available studies of cross-reacting idiotypes suggest that factor VIII inhibitors in patient's plasma encompass two populations of anti-factor VI II antibodies. Some antibodies result from the clonal expansion of B lympho cytes that exist before treatment with factor VIII and secrete anti-factor VIII antibodies with properties similar to those of natural anti-factor VII I antibodies present in healthy individuals; other inhibitors are produced by B cell clones that have undergone affinity maturation and hypermutation of the V regions of the antibodies they produce. The implications for the t reatment of patients with anti-factor VIII inhibitors are discussed.