Figure 1.

Mechanisms of anti-FVIII alloantibody development. Infused factor VIII (FVIII) is endocytosed by antigen-presenting cells (APC) and degraded into small peptides. FVIII-derived peptides are presented through major histocompatibility complex (MHC) class II molecules to naïve FVIII-specific CD4+ T-helper (Th) that get activated. Co-stimulatory signals are needed to elicit the immune response and release immune-regulatory molecules (cytokines). The activated T cell then interacts with B cells, which will differentiate into inhibitory antibody-secreting plasma cells. Memory T and B cells of importance for subsequent exposures are formed. Tfh, T follicular helper cells; TCR, T-cell receptor; CD40L, CD40 ligand; IL, interleukin; TNF-α, tumor necrosis factor-alpha; IFNγ, interferon-γ; TGF-β, transforming growth factor beta; IgG, immunoglobulin G.