Immune response to FVIII in patients with hemophilia A. (A) The primary immune response is initiated by the internalization of the therapeutically administered FVIII by professional antigen presenting cells (APCs; eg, dendritic cells) and its subsequent presentation to naive FVIII-specific (FVIII-sp) CD4⁺ T cells. Activated CD4⁺ T cells in turn activate FVIII-specific naive B cells, which proliferate and differentiate either into plasmocytes (or antibody-secreting cells, ASCs) or into FVIII-specific memory B cells. (B) During the secondary immune response, FVIII-specific memory B cells generated during the primary immune response act as APCs and activate FVIII-specific CD4⁺ T cells. With the help of CD4⁺ T cells, FVIII-specific memory B cells further differentiate into ASCs. In parallel, uptake of FVIII by professional APCs results in activation of T cells that in turn activate new FVIII-specific B cells and thus generate additional ASCs and memory B cells.