The Complement System and C3G

[DavidF_NKF]

THE COMPLEMENT SYSTEM AND C3G

Understanding the Cause of C3G: What is the complement system?

The complement system is part of the immune system. Normally, the immune system keeps you healthy by fighting germs like bacteria and viruses. In C3G, the complement system becomes over-active (too “revved up”). In normal health, the complement system fights germs when they enter the body, and it does this without hurting the body itself. In C3G, the complement system fights the body itself, especially in your kidneys.

The complement system is a family of proteins in the blood that interact with each other. Some of these complement proteins have strong germ-fighting abilities. They travel in the blood in an inactive form- like they’re asleep. To fight germs, these proteins must be “woken up” (activated). When one of these complement proteins in the blood becomes activated, it activates its neighbor, and begins a chain reaction of activation.

The 3rd complement protein is called C3 (complement 3). It has special germ-fighting abilities. Complement proteins that are already activated keep activating “sleeping” neighboring complement proteins down the line. This chain reaction allows the system to respond very quickly against germs. Then, after the last complement molecule (C5) is activated, it gathers its neighbor complement proteins and together, they kill bacteria.

This activation process happens by thousands of complement proteins- all at the same time.

All of this is a very important way for the body to fight off germs that may make us sick.

What does this have to do with C3G?

The problem is that complement can attack organs in your body as well as germs that invade. This can happen when complement is too activated. In C3G, the complement proteins are not controlled well and can attack the filters in your kidneys, called glomeruli. These tiny filters are special blood vessels that clean the blood by letting wastes pass across their walls. The wastes go into the urine. In C3G, complement from the blood goes to the glomeruli and builds up. Here, it activates other complement proteins and damages the glomeruli. When this happens, the glomeruli can’t filter (clean) the blood, the kidney becomes damaged, waste builds up, and you feel sick.

How does this process start?

There are three ways that the complement system gets activated, but in C3G, most researchers think that one of these ways is most important. This is called the alternative pathway. Normally, the alternative pathway is turned on, but its “volume” is set to low. In C3G, the “volume” is set to high.

Why is the complement system over-active in C3G?

Normally, the complement system is controlled and cannot get over-active. This prevents it from damaging organs. This control happens because certain proteins in the blood and organs called regulatory proteins slow the activation of complement. Regulatory proteins can 1) block the activation of complement or 2) speed the destruction of activated complement proteins. In some types of C3G, these regulatory proteins don’t work well, and they don’t slow down the complement system. This leads to activation of the complement system. Sometimes in C3G, proteins called auto-antibodies “rev up” the complement system and attack the body, including the kidneys. It is not fully understood why this is harmful particularly to the kidneys.

Problems with the complement system can be genetic (from your genes) or acquired (things that happen during your life).

Trying to prevent the damage caused by an over active complement system has been an active area of research. Now that researchers know how complement proteins become activated, and which proteins seem to do the damage, compounds that block the action of these proteins have been developed. These compounds may become drugs to treat C3G and other diseases that are caused by an over-active complement system. Studies with humans, called clinical trials, are testing the benefits of these compounds.