Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant clonal hematopoietic disorder. There are two components to the pathogenesis of PNH: (i) a mutant stem cell, (ii) expansion of the mutant clone. Component (i) is straightforward: there is almost always an inactivating somatic mutation of the X-linked gene PIGA. As for (ii), different mechanisms may be involved. In rare cases expansion may be driven by independently arisen mutations (e.g. in JAK2): however, in the large majority of PNH patients such mutations are not found. Instead, clonal expansion may result from the escape of GPI-negative (PIGA mutant) stem cells from a T cell-mediated autoimmune attack on non-mutant stem cells. Several lines of evidence support this mechanism. (1) PNH is closely related to aplastic anemia (AA). (2) PIGA mutant microclones exist in normal people but they do not expand. (3) In PNH patients receiving syngeneic 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 expanding. (5) There is evidence that cytotoxic T cells may spare GPI(-) 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 from a specific selective environment. The findings in PNH are also highly relevant to the pathogenesis of AA.
Copyright © 2025 American Society of Hematology.