In a review article in Frontiers in Immunology, researchers outlined how T lymphocytes fit into the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH). The review was written by Chenyuan Li from the Tianjin Medical University General Hospital in Tianjin, China, and colleagues.

“Some researchers believe that it is the immunity of abnormal T lymphocytes that may be involved in the pathogenesis of PNH,” the authors wrote in their report.

As the authors explained, PNH is an acquired condition involving complement-mediated hemolysis due to a mutation of the PIG-A gene. The product of expression of this gene is involved in synthesis of glycosylphosphatidylinositol (GPI) molecules that act as cell-surface anchors. A defect in the PIG-A gene leads to a deficiency of GPI anchors, which in turn leads to a deficit of GPI-anchored proteins (GPI-APs) that act as complement inhibitors. In PNH, this shortage of complement inhibitors is implicated in the destruction of erythrocytes.

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However, as the authors noted, PIG-A mutations have been found in hematopoietic stem cells in the bone marrow of people without PNH, but without the same pattern of growth and expansion as seen in patients with PNH. A mouse model involving a PIG-A knockout also suggests that PIG-A mutation alone may not account for all the clonal advantages of HSCs deficient in PIG-A. These factors have led to some speculation about other processes that may be involved in PNH pathogenesis. One hypothesis relates to immune escape, with T lymphocytes having a possible role in pathogenesis.

The authors described unusual T lymphocyte behavior that has been found in patients with PNH, such as abnormal T-lymphocyte clonal expansion patterns. The authors also described links between PNH and aplastic anemia, which is a condition in which some evidence suggests T lymphocytes may cause damage to HSCs. Additionally, antithymocyte  globulin therapy, which is an immunosuppressive approach primarily affecting activated T lymphocytes, has shown activity in some patients with PNH. However, they noted, results with immunosuppression have also been mixed, with PNH developing after immunosuppressive therapy for aplastic anemia in some patients.

The authors explained that T lymphocytes may be more likely to kill cells expressing GPI, with cells lacking GPI evading attack. They presented lines of evidence suggesting that in PNH T lymphocytes may target HSC cells containing GPI via the GPI molecules themselves, leaving GPI-deficient HSC cells to survive. However, they noted that other evidence suggests a possibility that GPI-APs may be implicated in the targeting of HSCs by cytotoxic T lymphocytes.

“Fully understanding the role of autoimmunity in that T lymphocytes are involved in the pathogenesis of PNH may provide more new and accurate strategies in treatment, which may slow down the attack from T lymphocytes on HSCs without PIG-A gene mutation and improve the quality of life of patients,” the authors concluded in their report.


Li C, Dong X, Wang H, Shao Z. The role of T lymphocytes in the pathogenesis of paroxysmal nocturnal hemoglobinuria. Front Immunol. 2021;12:777649. doi:10.3389/fimmu.2021.777649