title: Paroxysmal nocturnal hemoglobinuria from bench to bedside.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease that presents with protean manifestations. Clinical and laboratory investigation over the past 25 years has uncovered most of the basic science underpinnings of PNH and has led to the development of a highly effective targeted therapy. PNH originates from a multipotent hematopoietic stem cell (HSC) that acquires a somatic mutation in a gene called phosphatidylinositol glycan anchor biosynthesis, class A (PIG-A). The PIG-A gene is required for the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Failure to synthesize GPI anchors leads to an absence of all proteins that utilize GPI to attach to the plasma membrane. Two GPI-anchor proteins, CD55 and CD59, are complement regulatory proteins; their absence on the surface of PNH cells leads to complement-mediated hemolysis. The release of free hemoglobin leads to scavenging of nitric oxide and contributes to many clinical manifestations, including esophageal spasm, fatigue, and possibly thrombosis. Aerolysin is a pore-forming toxin that binds GPI-anchored proteins and kills normal cells, but not PNH cells. A fluorescinated aerolysin variant (FLAER) binds GPI-anchor and serves as a novel reagent diagnosing PNH. Eculizumab, a humanized monoclonal antibody against C5, is the first effective drug therapy for PNH.
authors.affiliation: Division of Hematology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Pu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001427:Bacterial Toxins / Q000378:metabolism; D018958:CD55 Antigens / Q000235:genetics; D018957:CD59 Antigens / Q000235:genetics; D003165:Complement System Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000175:diagnosis* / Q000628:therapy*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D019851:Thrombophilia / Q000378:metabolism; D057170:Translational Research, Biomedical / Q000379:methods / Q000639:trends
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001427:Bacterial Toxins; D018958:CD55 Antigens; D018957:CD59 Antigens; D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; C080086:phosphatidylinositol glycan-class A protein; C032676:aerolysin; D003165:Complement System Proteins; C481642:eculizumab