paroxysmal nocturnal hemoglobinuria (PNH)

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare blood disease in which blood cells are destroyed, leading to anemia, fatigue, and increased risk of blood clots. While several effective therapies can prevent the destruction of PNH red blood cells by blocking abnormal activation of a part of the immune system called “complement”, these treatments are life-long, extremely costly and do not lead to cure. In many places around the world, access to PNH treatments is limited. The main barrier to developing curative therapies for PNH has been a poor understanding of why PNH patients develop large outgrowths (“clones”) of PNH cells. Interestingly, most healthy individuals also harbor a few, very rare, isolated PNH cells, but these do not outgrow normal cells and do not turn into PNH clones, nor cause PNH disease The main risk factor for developing PNH is an autoimmune blood disease called aplastic anemia, in which nearly half of aplastic anemia patients develop PNH clones. The close association of aplastic anemia and PNH led to the current leading theory in the field that PNH cells outgrow normal cells because they escape autoimmune attack in aplastic anemia. However, how this occurs continues to be a matter of active debate in the field. In recent studies, we observed differences in how intracellular proteins in PNH cells compared to healthy cells are presented for immune surveillance. In the proposed studies, we will perform a comprehensive analysis of how intracellular proteins are processed and presented for immune recognition by PNH cells. We will also test for PNH cell immune evasion from T lymphocytes from aplastic anemia patients. The results of these studies will bring us closer to understanding why PNH disease develops. If successful, these studies will open the door to the future development of more effective, targeted therapies to prevent the onset of PNH and to eradicate PNH clones.