B-cell memory against factor VIII

The development of persistent neutralizing antibodies against factor VIII (FVIII) is the most severe complication in the treatment of congenital hemophilia A patients with FVIII replacement therapies. Recently, we presented data which indicate that neutralizing antibodies are high-affinity antibodies which are mostly of the IgG1 and IgG4 subclasses. However, there are also FVIII-specific antibodies of low to moderate affinity which are found in some patients without neutralizing antibodies and in some healthy individuals. The underlying immune mechanisms which regulate the development of these different populations of FVIII-specific antibodies are poorly understood. In this review, we discuss potential mechanisms for the development of low-affinity and high-affinity antibodies. In particular, we discuss the role of memory B cells which are essential in maintaining long-lasting antibody responses and in driving the rapid anamnestic antibody response after re-exposure to the same antigen. We also present available data on the potential role of FVIII-specific memory B cells in the maintenance of neutralizing antibodies against FVIII.