Complement deficiency

Definitions & Key takeaways

A complement deficiency is a condition in which the body doesn't have enough of the proteins called complements, which work together to fight infection. Complement deficiencies can be inherited or acquired. Inherited complement deficiencies are caused by a change (mutation) in the gene that codes for one of the proteins in the complement system. Acquired complement deficiencies can be caused by infections, cancer, and autoimmune diseases such as lupus. People with an inherited or acquired complement deficiency are at risk of severe infections, including meningitis, sepsis, and pneumonia.

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Introduction0:00–0:18

With complement deficiency, there’s a deficiency in one or more of the complement proteins, which are part of the immune system.
Complement deficiencies can either be acquired or inherited, and often result in a weaker immune response to infections.

Physiology0:18–3:28

So let’s start with the proteins that make up the classical pathway - C1, C2, C3, C4, C5, C6, C7, C8, and C9. And parts of these proteins are designated with lower case letters like “a” or “b”.
Pretty easy right? Now these were numbered, in the order they were discovered, but not the order in which they function.
Generally speaking, each complement protein is normally inactive, and it becomes activated when it’s cleaved - in other words when some part of it breaks free.
A bit like how a fire extinguisher isn’t “active” until a pin is pulled out. The complement system helps with three important immune processes: inflammation, phagocytosis, and the creation of membrane attack complexes or MACs.
Inflammation is when chemicals and cells collect to protect a damaged or infected area; phagocytosis is when certain white blood cells called phagocytes engulf and digest antigens; and membrane attack complexes are structures which dig into antigen surfaces and lyse them, or rupture and kill them.
There are actually three complement pathways: The classical pathway - called that because it was discovered first, the alternative pathway which was found second and is always at work, and the Lectin binding pathway - which was found third and when folks got more descriptive with their naming.
So all three pathways start out a bit differently, but end the same way - with a membrane attack complex which is a protein complex that creates a hole in a bacterial cell membrane - effectively destroying mainly gram negative bacteria.
The various complement fragments contribute to these three pathways, but also play other additional roles as well. For example, C3b serves as an opsonin - which means that it helps immune cells phagocytose debris.
C5a and C3a also act as chemotaxins which recruit neutrophils, eosinophils, monocytes, and macrophages to the site of inflammation.
C5a and C3a are also anaphylatoxins which means that they helps basophils and mast cells degranulate, releasing proinflammatory molecules like histamine and heparin into an area.
This can cause contraction of the smooth muscles, bronchial constriction, and increased vascular permeability. Finally, because C1, C2, C3, and C4 are all involved in removing antigen-antibody complexes, individuals that lack any of these proteins can experience a lupus-like illness, chronic renal disease, and repeated infections.
Individuals who are deficient in C5, C6, C7, or C8 suffer from repeated Neisseria infections and are at higher risk for developing gonorrhea or meningitis.
Interestingly, individuals who are deficient in C9 seem to have no problems because C5,C6, C7, C8 can lyse a bacterium all on their own, with C9 being icing on the cake!

Pathology3:28–5:23

In complement deficiency, there’s either too little of one or more of these complement system proteins, or they just don’t function properly.
This can cause an underactive immune response, like in C3 deficiency, since C3 would normally activate the complement system.
In fact, a C3 deficiency causes severe clinical manifestations, because C3 is needed in large quantities. It plays a central role in phagocytosis and the formation of membrane attack complexes.
By comparison, a C4 deficiency causes less significant problems, because C4 is only needed in small quantities. Even if a small amount of it is available, it will be able to continue playing its role in activating other complement proteins.
In addition to more frequent infections, complement deficiencies can also lead to worsening of autoimmune diseases, like rheumatoid arthritis and lupus.
That’s because small immune complexes don't get opsonized or picked up by circulating immune cells and deposit in various tissues around the body.
Complement deficiencies can also cause an overactive immune responses, if the affected protein, is something like a C1-inhibitor, which is a complement protein that normally inhibits the complement system.
That’s particularly helpful when it’s time for the complement system to wind down. Many cases of complement deficiency are inherited, and most complement deficiencies are autosomal recessive, although some have other modes of inheritance.
It's also possible to acquire a complement deficiency, for example, when a severe infection or autoimmune condition causes complement proteins to get consumed or used up.
For example, in lupus both C3 and C4 get used up, creating a deficiency of those two proteins. Symptoms of complement deficiency are usually based upon the specific infection that may be occuring.

Symptoms and diagnosis5:23–5:46

Diagnosis of complement deficiencies can be done through blood analysis, by testing overall complement activity, denoted by "CH50" or "CH100".
If there is a deficiency, it's also possible to test for specific protein levels like C3 or C4. Treatment of complement deficiencies depends on the cases, those that lead to an overactive immune response, can be given immunosuppressors.

Treatment5:46–6:10

In cases with an underactive immune response, it's important to treat harmful infections, and to take precautions like prophylactic antibiotics.
In some cases, it’s possible to supplement a deficient protein, like with C1- inhibitor. All right, as a quick recap… Complement deficiencies are a group of disorders, all of which have a deficiency in one or more complement proteins.

Review6:10–6:56

Overall, the complement system helps with three important processes: inflammation, phagocytosis, and the creation of membrane attack complexes.
Complement deficiencies can either cause underactive immune response, like if a deficient protein would normally activate the complement system, say with C3, or an overactive immune response, like if a deficient protein would normally inhibit the complement system, say with the C1-inhibitor.
Typically, complement deficiencies lead to recurrent bouts of infection or autoimmune reactions.