In vitro restimulation of FVIII-specific memory B cells in the presence of FVIII and CpG-ODN. (A) In vitro restimulation of FVIII-specific memory B cells at low concentrations of FVIII results in differentiation into antibody-secreting cells (ASC). Low concentrations of FVIII combined with TLR9 ligand CpG-ODN results in an increased number of ASCs. (B) High concentrations of FVIII induce apoptosis of FVIII-specific memory B cells. CpG-ODN is able to overcome the apoptotic effect induced by high-concentration doses of FVIII. (C) Low concentrations of CpG-ODN alone induce no or very limited numbers of ASCs. (D) High concentrations of CpG-ODN severely reduce the FVIII-induced formation of ASCs. (Professional illustration by Kenneth X. Probst.)