The role of somatic mutation and auto-immune mediated bone marrow failure in the pathophysiology of PNH.

The top panel is a cartoon of normal hematopoietic stem cells (HSC): the arrow indicates a somatic mutation in the PIG-A gene in one of the HSC. As a result, the cell and its progeny lose surface GPI-anchored proteins. As time goes on, micro clones arising from such mutant cells may become exhausted, and new ones may arise: however, there is no clonal expansion. The middle panel illustrates the presence in the bone marrow of auto reactive immune cells, which may be cytotoxic T cells: these attack the HSC, which gradually decrease in numbers, eventually resulting in the picture of aplastic anemia (AA). The bottom panel illustrates the consequences of the co-existence of a PIG-A somatic mutation and autoreactive immune cells in the bone marrow. If we make the specific hypothesis that the target of the autoimmune attack is a GPI-anchored protein, the mutant clone will expand as a result of negative selection against the normal HSC. As a result, the majority of hematopoiesis will consist of GPI-anchored protein deficient cells. The large numbers of c-susceptible red cells will cause hemolytic anemia; the large numbers of abnormal platelets will cause a high risk of thrombotic complications.