Steady-state interaction of FVIII with the immune system under physiologic conditions. At the humoral level, tolerance to FVIII under physiologic conditions relies on an equilibrium between the recognition of FVIII by naturally occurring potentially inhibitory anti-FVIII antibodies and their control by neutralizing anti-idiotypic antibodies. Neutralizing anti-idiotypic antibodies may also regulate the B-cell clones that secrete the FVIII-specific autoantibodies. At the T-cell level, natural FVIII-reactive T cells may be down-regulated by natural regulatory T cells (Tregs; ie, CD4⁺CD25⁺FoxP3⁺ Tregs) and/or by induced transforming growth factor β (TGF-β)–secreting Tregs.