Figure 3.

CH in PNH. (A-B) A schematic of the relationship between immune-mediated BMF and the development of PNH. (A) In immune-mediated BMF, such as AA, HSPCs (dark gray circles) undergo immune-mediated attack by cytotoxic T lymphocytes (CTLs), which recognize AA autoantigen presented in the context of an HLA molecule (red lines, HLA:peptide) via a T-cell receptor (TCR). Effective CTL activation requires the presence of a costimulatory signal (blue line). (B) PNH HSPCs (light gray circles) are believed to evade autoimmune T-cell recognition by 1 or more mechanisms, which include lack of a GPI-anchored autoantigen, lack of a costimulatory interaction that may involve GPI-anchored proteins, or relative resistance to T-cell–mediated cell death. (C) The evasion of the CTL-mediated immune attack leads to clonal expansion by the PNH HSPCs. Ongoing autoimmune selective pressure may lead to the emergence of additional somatic mutations (depicted by colored circles) both in the ancestral, previously normal HSPCs and in the PNH HSPCs. (D) With long-term follow-up, stepwise accumulation of additional genetic events, either in the ancestral HSPCs or in the PNH clone, can lead to secondary MDS-AML in 3% to 6% of PNH patients.