C3, C4 – complement

What is being tested?
The complement system consists of a series of circulating proteins that work together to promote the immune and inflammatory responses. Their main role is to destroy foreign substances such as bacteria and viruses. The nine main complement proteins are named C1 to C9. They are supported and regulated by numerous subcomponents and inhibitors.

The complement system is part of the innate immune system. Unlike the acquired immune system, which produces antibodies that recognise and protect the body against specific threats, the innate immune system is non-specific and can respond rapidly to foreign substances. It does not need previous exposure to the invading microorganism, nor does it keep a memory of those it has previously encountered. As a component of the innate immune system, the complement system has evolved to recognise antigen-antibody complexes (immune complexes), as well as certain structures and polysaccharides (complex carbohydrates) found on the outer membrane of microorganisms and foreign cells.

Complement activation can be started through different routes, called the classical, alternative and lectin pathways. However, the end product of all the different pathways is always the same: the formation of the membrane attack complex (MAC). Complement activation causes several events:

• The MAC binds to the surface of any microorganisms or abnormal cells marked for destruction. In doing so it makes a lesion (hole) in the membrane wall, causing lysis, i.e. the destruction of the cell as its contents leak out, just as happens when a water-filled balloon is punctured.
• It increases the permeability of blood vessels, allowing white blood cells (WBCs) to leave the bloodstream and enter the tissues.
• It attracts WBCs to the site of infection
• It stimulates phagocytosis, a process in which microorganisms are “swallowed” and killed by macrophages and neutrophils.
• It increases the solubility of immune complexes, helping to remove them from the blood.

These activities are both promoted and regulated by complement proteins. Inherited or acquired abnormalities or deficiencies of one or more complement components can impair the integrity and function of the immune system. Low levels of these proteins can result either from reduced production or from increased consumption of one or more complement proteins.

These tests can measure the amount or the function (activity) of complement proteins in the blood. To assess whether the system is working normally, complement components can be measured individually or together. The complement proteins most often measured are C3 and C4. Total complement activity (CH50 or CH100) can be measured if the doctor suspects a defect that is not shown by measuring C3 and C4. CH50 measures the complete function of the classical complement pathway, C1-C9. If this measurement is outside the reference range, each of the nine different proteins can be measured individually to identify inherited or acquired deficiencies

How is it used?
When is it requested?
What does the test result mean?
Is there anything else I should know?

How is it used?
C3 and C4 are used to establish whether a disease or a particular condition in a patient is caused wholly or partly by deficiencies or abnormalities of the complement system. Total complement activity (CH50 or CH100) may be requested to investigate the overall integrity of the classical complement pathway. Further complement components may also be requested as needed to check for deficiencies.

Complement testing may be requested to help diagnose the cause of recurrent microbial infections, angioedema or inflammation. It can also be used to help diagnose and monitor the activity of acute and chronic autoimmune diseases, such as systemic lupus erythematosus (SLE). It can be measured and monitored in immune complex-related diseases such as glomerulonephritis (a kidney disorder), serum sickness, rheumatoid arthritis and vasculitis (inflammation of the blood vessels). When immune complexes form, complement helps remove them from the blood, and as a result its blood levels fall.

When is it requested?
Complement testing may be requested when you have inflammation or swelling with no recognisable cause, or symptoms of an autoimmune disorder such as SLE. It may also be requested if your doctor suspects you have a condition linked to immune complexes and wants to check the state of your complement system.

C3 and C4 levels are the tests most often requested, but when other types of deficiency are suspected, other tests may be requested, such as C1 inhibitor. Individual complement components may be measured when total complement activity (CH50 or CH100) is abnormal, to help identify which components are reduced or abnormal.

After an acute or chronic condition has been diagnosed, complement testing can be used to get a rough idea of the severity of the condition (assuming that severity is linked to a fall in complement levels). Complement testing may also be requested occasionally when your doctor wants to monitor the activity of your condition.

Complement levels may be reduced because of an inherited deficiency (a relatively rare condition) or because of increased consumption. An inherited deficiency of one of the complement proteins usually causes more frequent microbial infections or autoimmune diseases. If the deficiency is caused by an underlying acute or chronic condition, complement levels usually return to normal once the condition resolves.

Reduced complement levels are seen with:

• Recurrent microbial infections (mostly bacterial)
• Autoimmune diseases, including SLE and vasculitis
• Hereditary angioedema
• Acquired angioedema
• Various types of kidney disease, including glomerulonephritis, lupus nephritis, membranous nephritis and IgA nephropathy
• Malnutrition
• Septicaemia
• Serum sickness (immune complex disease)

Complement protein levels are usually raised, together with those of unrelated proteins called acute phase proteins, during chronic or acute inflammation. They all usually return to normal when the condition resolves. However, compared with the widely requested C-reactive protein, complement proteins are rarely measured in this situation, and the relevance of measuring them in these situations is not discussed here.

Is there anything else I should know?
Raised or reduced complement levels will not tell your doctor what is wrong, but they will indicate that the immune system is involved in your condition. Complement levels can be raised when there is inflammation, and their rise comes before that of other markers such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

What are the other components of the innate immune system?
They include:

• The phagocytic system (white blood cells, including macrophages, neutrophils and monocytes), whose role is to swallow and digest invading microorganisms.
• Inflammatory mediators produced by various types of cells, including basophils, mast cells and eosinophils
• Natural killer (NK) cells, specialised lymphocytes that can kill some cancer cells, microorganisms and virus-infected cells
• Cytokines and acute phase reactants, a group of soluble proteins that can cause changes in the growth of many cells, including the white blood cells that produce them.