Pathogenesis of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria: (par-uk-SIZ-muhl nok-TURN-uhl hee-muh-gloe-buh-NYOOR-ee-uh) A rare and serious blood disease that causes red blood cells to break apart. Paroxysmal means sudden and irregular. Nocturnal means at night. Hemoglobinuria means hemoglobin in the urine. Hemoglobin is the red part of red blood cells. A… (PNH) is a nonmalignant clonal hematopoietic disorder. There are 2 components to the pathogenesis of PNH: (1) a mutant stem cell and (2) expansion of the mutant clone clone: To make copies. Bone marrow stem cells clone themselves all the time. The cloned stem cells eventually become mature blood cells that leave the bone marrow and enter the bloodstream. . Component 1 is straightforward: there is almost always an inactivating somatic mutation mutation: Any change or alteration in a gene. A mutation may cause disease or may be a normal variation. Paroxysmal nocturnal hemoglobinuria (PNH) occurs because of a mutation in the PIG-A gene of a single stem cell in the bone marrow. of the X-linked gene PIGA. As for component 2, different mechanisms may be involved. In rare cases, expansion may be driven by independently arisen mutations (eg, in JAK2); however, in most patients with PNH, such mutations are not found. Instead, clonal expansion may result from the escape of glycosylphosphatidylinositol (GPI)-negative (PIGA-mutant) stem cells stem cells: Cells in the body that develop into other cells. There are two main sources of stem cells. Embryonic stem cells come from human embryos and are used in medical research. Adult stem cells in the body repair and maintain the organ or tissue in which they are found. Blood-forming (hemapoietic) stem… from a T-cell-mediated autoimmune attack on nonmutant stem cells. Several lines of evidence support this mechanism. (1) PNH is closely related to aplastic anemia aplastic anemia: (ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells - red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most… (AA). (2) PIGA-mutant microclones exist in normal people but they do not expand. (3) In patients with PNH receiving syngeneic bone marrow bone marrow: The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow. transplantation, PNH remission has occurred only when immunosuppressive conditioning was applied. (4) After targeted inactivation of piga in mice, large populations of GPI-negative blood cells are produced, but they gradually disappear rather than expand. (5) There is evidence that cytotoxic T cells may spare GPI-negative stem cells, and CD1d-restricted GPI-specific T cells have been demonstrated in patients with PNH and with AA. Thus, the pathogenesis of PNH conforms to a Darwinian model within somatic cell populations: it results from a somatic mutation and a specific selective environment. The findings in PNH are also highly relevant to the pathogenesis of AA.