Apart from the association it has with PNH, what is the function of the complement system?
The complement system initially got that name because it complemented the body’s ability to defend itself against pathogens, in addition to antibody formation. Today, we think of it as an integral part of the innate immune system. We regard the innate immune system as part of the entire human immune system, which is of course intended to defend the body from invading organisms. The innate immune system can’t be altered—we are born with it and it provides an instantaneous response in an almost reflexive manner against infections and non-self particles. It can be triggered in a variety of ways, but the outcome is that it triggers a cascade of proteins that form the system with the purpose of eliminating bacteria and invading pathogens. It also serves to draw in the immune system cells to clear all the dead tissues and byproducts of inflammation, and also educate the adaptive immune system as to how prevent similar events that may occur in the future.
What is the sequence of events leading to PNH and why is a genetic mutation responsible?
When the complement system is activated, it triggers a variety of events leading to cleavage of one component known as C5. Once C5 is cleaved, a variety of events occur that propagate the formation of the membrane attack complex. This member attack complex generates pores, or holes, in cells ultimately leading to the cell’s demise.
So when you have such a powerful system, regulators of the system are needed. These regulators sit on the outer membrane of cells, so the complement system recognizes that these cells are of the self. When those regulators are missing, as is the case in PNH, this leads to the destructions of the cells that are missing these protein shields.
Some of those shields, (2 proteins known as CD 55 and CD 59) are anchored the cell surface by a ‘tail’. We call this tail a GPI anchor – but in PNH this GPI anchor is missing because of a mutation in a gene called PIG-A. This defective gene leads to cause the cell’s inability to form this GPI anchor. So the complement regulator proteins are lost because they aren’t anchored to the cell surface. When the complement system becomes highly active from infections, surgery, or similar events, it creates increased cell death of those cells missing this protein shield.
What happens when the complement system identifies red blood cells with the defective PIG-A gene?
So because of the missing CD 59 protein [note: CD 55 is not mentioned here] on the surface of the red blood cell, the membrane attack complex takes place, which makes the holes and pores on the cell surface, releasing the hemoglobin inside the cell through the holes – the hemoglobin escapes the cell walls. This is the point where hemolysis occurs. Eventually the cell completely ruptures, releasing all the free hemoglobin intravascularly. That has a variety of consequences, including hemolytic anemia, thrombosis because of inflammation, and kidney problems because of free hemoglobin filtering through the kidney tubes—leading to hemoglobinuria (red urine). Continued hemoglobinuria can lead to kidney damage.
What is subclinical PNH?
In its normal form, patients present with overt hemolysis and hemoglobinuria. Subclinical PNH implies that you have a PNH clone [state that PNH is defective red blood cell??] that isn’t manifesting with hemolysis.
The ability of high-sensitivity flow cytometry to identify a small amount of PNH clones has resulted in the classification called ‘subclinical PNH’. So these patient may not present with hemolysis but once a PNH cline is identified, it is important to monitor the sized of the clone and understand the potential consequences of clone growth and the potential for hemolytic events to begin.