The Role of T Lymphocytes in the Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell genetic mutation disease that causes defective erythrocyte membrane hemolysis. Its pathologic basis is the mutation of the PIG-A gene, whose product is necessary for the synthesis of glycosylphosphatidylinositol (GPI) anchors; the mutation of PIG-A gene results in the reduction or deletion of the GPI anchor, which leads to the deficiency of GPI-anchored proteins (GPI-APs), such as CD55 and CD59, which are complement inhibitors. The deficiency of complement inhibitors causes chronic complement-mediated intravascular hemolysis of GPI-anchor-deficient erythrocyte. PIG-A gene mutation could also be found in bone marrow hematopoietic stem cells (HSCs) of healthy people, but they have no growth advantage; only the HSCs with PIG-A gene mutation in PNH patients have this advantage and expand. Besides, HSCs from PIG-A-knockout mice do not show clonal expansion in bone marrow, so PIG-A mutation cannot explain the clonal advantage of the PNH clone and some additional factors are needed; thus, in recent years, many scholars have put forward the theories of the second hit, and immune escape theory is one of them. In this paper, we focus on how T lymphocytes are involved in immune escape hypothesis in the pathogenesis of PNH.

Keywords: T lymphocytes; aplastic anemia; immune escape; paroxysmal nocturnal hemoglobinuria; pathogenesis.

Figure 1

Biosynthesis of GPI molecules: PIG-A gene is located on chromosome Xp22.1, whose product is necessary for the synthesis of GPI. In endoplasmic reticulum (ER), the assembly of phosphatidylinositol, acetylglucosamine, and glycan consisting of three mannose molecules and a phosphoethanolamine is the first step of GPI synthesis. GPI and protein form a complex, then the GPI–protein complex transfers to the cell surface, and the GPI molecule becomes the anchor of the protein. The mutation of PIG-A gene causes the deficiency of GPIs and GPI-APs, or none at all. Figure was created in BioRender.com.

Figure 2

Two possible ways that T lymphocytes are involved in the pathogenesis of immune escape. (A) CD1d presents GPI molecule as antigen to T lymphocytes and then activates them, these T lymphocytes kill the GPI⁺HSC; however, the GPI^- HSC can escape from this attack. (B) GPI-AP mediates the activation of T lymphocytes and promotes the release of its cytokines (e.g., IL-2), then T lymphocytes kill HSCs expressing GPI-APs; however, HSCs do not express GPI-APs escape from this effect. Figures were created in BioRender.com.