June 28, 2019
The alternative pathway is a specific part of the immune system. In C3 glomerulopathy (C3G), experts believe that people with C3G have an alternative pathway that is very overactive and can lead to the kidneys being damaged.
There is a misconception that C3G, including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), is a type of kidney disease. While C3G does affect the kidneys, the underlying cause originates in the immune system—more specifically in the complement system.
The complement system is an important part of the body’s defenses against outside invaders. It can be activated or "turned on" to help protect the body when one of its 3 pathways—classical, lectin, or alternative—senses a threat. Each of these pathways have their own roles and responsibilities in the complement system, but all of them use a protein called C3 to perform their duties. When a pathway senses a problem it can address, it activates and breaks down the C3 protein into fragments that trigger responses in other parts of the body. These C3 fragments create a chain reaction or domino effect that unleash a powerful ability to fight infection, clear debris, and promote inflammation against an identified threat. Due to their powerful abilities, each complement system pathway is tightly controlled by the body to ensure its proper use.
In a healthy person, the alternative pathway is always running in the background, even when there is no threat present. Think of it like a car engine that's idling—running at a low level, but ready to move in an instant.
When a threat is detected, the pathway revs up to respond, but then returns to its idling state when the threat is neutralized because it is well controlled. However, in a person with C3G, the body loses control of the alternative pathway due to acquired and genetic factors. Instead of idling at a low level in the background, it becomes revved up and hyperactive. Imagine the body not being able to take its foot off the gas pedal of the alternative pathway.
In a person with C3G, when the alternative pathway is poorly controlled and overactive, it is continually breaking down C3 into fragments. Instead of helping the body protect itself from invaders, the overactivity of alternative pathway turns its fighting powers against the kidneys. C3 fragments are continuously deposited into the filters of kidneys known as glomeruli (glo-MER-u-lie). Experts believe this process leads to the serious kidney damage in C3G, including the symptoms of increased protein in the urine and decreased kidney function.
Research is ongoing to learn more about the causes of alternative pathway overactivity in people with C3G. Ongoing clinical studies are assessing potential therapies as more is learned about this disease.
If you haven't already joined the WeC3G Community, register to download the WeC3G Toolkit and learn about the complement system and the different factors that experts believe lead to C3G.
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