Causes and Underlying Mechanisms of Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired disorder characterized by the destruction of red blood cells due to uncontrolled activation of the complement system. The root cause lies in a genetic mutation at the level of hematopoietic stem cells, which leads to a deficiency in certain protective proteins on the surface of blood cells.

The Role of GPI-Anchored Proteins in Blood Cell Protection

Under normal conditions, red blood cells are protected from unintended immune attack by specific membrane proteins that regulate the complement system—a key part of the body's innate immunity. These protective proteins, such as CD55 and CD59, are attached to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor. This molecular structure ensures that these regulators remain embedded in the outer layer of the cell, where they can perform their defensive functions effectively.

How CD55 and CD59 Prevent Complement-Mediated Damage

CD55, also known as decay-accelerating factor (DAF), plays a critical role in inhibiting the formation of C3 and C5 convertases—enzymes that drive the complement cascade forward. By accelerating the breakdown of these enzymes, CD55 helps prevent excessive complement activation on healthy cells.

Meanwhile, CD59 acts later in the pathway by blocking the assembly of the membrane attack complex (MAC). Specifically, it prevents the conformational change of complement protein C9, stopping it from inserting into the cell membrane and forming pores that would otherwise lead to cell lysis.

Genetic Mutation and Loss of GPI-Anchored Proteins in PNH

In patients with PNH, a somatic mutation occurs in the PIG-A gene within a hematopoietic stem cell. This mutation disrupts the synthesis of the GPI anchor, resulting in the partial or complete absence of all GPI-linked proteins—including CD55 and CD59—on the surface of red blood cells, granulocytes, monocytes, and lymphocytes.

Because these protective proteins are missing, the affected blood cells become highly vulnerable to complement-mediated destruction, even under normal physiological conditions. This leads to intravascular hemolysis—the hallmark of PNH—particularly noticeable during periods of increased complement activity, such as during sleep or infections.

Clonal Nature of PNH and Coexistence of Normal Cells

One distinctive feature of PNH is its clonal origin: only the progeny of the mutated stem cell lack GPI-anchored proteins, while other blood cells derived from unaffected stem cells remain normal. As a result, most PNH patients have a mixed population of blood cells—some resistant and some highly sensitive to complement attack.

This mosaicism explains the variable severity of symptoms among individuals and underscores the importance of targeted therapies that address the underlying complement dysregulation. Treatments like eculizumab, a monoclonal antibody that inhibits terminal complement activation, have significantly improved outcomes by protecting the vulnerable PNH cells from destruction.

Understanding the molecular basis of PNH not only sheds light on this rare disease but also provides insights into broader mechanisms of immune regulation and stem cell biology. Ongoing research continues to explore gene therapy and novel inhibitors as potential future treatments for long-term management.