Paroxysmal Nocturnal Hemoglobinuria from Bench to Bedside

Jeffrey J. Pu, Robert A Brodsky

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)219-224
Number of pages6
JournalClinical and Translational Science
Volume4
Issue number3
DOIs
StatePublished - Jun 2011

Fingerprint

Paroxysmal Hemoglobinuria
Glycosylphosphatidylinositols
Biosynthesis
Proteins
Diffuse Esophageal Spasm
Genes
Multipotent Stem Cells
Drug therapy
Antibodies, Monoclonal, Humanized
Hematologic Diseases
Scavenging
Cell membranes
Rare Diseases
Hematopoietic Stem Cells
Hemolysis
Stem cells
Anchors
Fatigue
Complement System Proteins
Nitric Oxide

Keywords

  • Hematopoiesis
  • Hematopoiesis-stem and primitive progenitor cells
  • Paroxysmal nocturnal hemoglobinuria
  • Translational research

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Paroxysmal Nocturnal Hemoglobinuria from Bench to Bedside. / Pu, Jeffrey J.; Brodsky, Robert A.

In: Clinical and Translational Science, Vol. 4, No. 3, 06.2011, p. 219-224.

Research output: Contribution to journalArticle

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