Complement proteins

What is being measured?
The complement system is a group of proteins that circulate in the blood and act as mediators of the inflammatory response (especially in destroying foreign agents such as bacteria and viruses), and it is part of the body’s innate immune system. It does not require previous exposure to microorganisms or foreign substances (as antibodies do) and keeps no memory of previous contacts. The complement system has evolved to recognise antigen–antibody complexes (immune complexes) and certain structures and polysaccharides (complex sugars) found on the membranes of microorganisms and other foreign cells. Once complement activation begins, the complement proteins are activated in sequence along two different pathways, the classical or the alternative pathway, which end in the formation of the membrane attack complex (MAC). Complement activation triggers a series of events:

microorganisms are killed by the action of the membrane attack complex (MAC). This is formed from the activated complement proteins C5 to C9 and works by creating a lesion in the microbial membrane, causing lysis (rupture) of the cell.
The permeability of blood vessels increases, allowing white blood cells to pass from the blood into the tissues.
White blood cells are attracted to the affected area.
Phagocytosis is stimulated (the process by which microorganisms are engulfed and killed by macrophages and neutrophils).
The solubility of immune complexes increases and their clearance is made easier.
An important component of the complement system, however, is the membrane attack complex (MAC). A MAC is assembled on the surface of microorganisms and abnormal cells targeted for destruction (lysis). Each activated complement protein is added to the structure which, once complete, creates a lesion (a hole) in the cell membrane and lyses the cell (destroys it by letting its contents leak out, as happens when you puncture a water-filled balloon).

Complement and the regulation of its activity are an important part of the immune system. While antibodies take some time to be produced, complement is immediately available and helps alert other parts of the immune system. Inherited or acquired deficiencies of one or more complement components can adversely affect the integrity and function of the immune system.

The complement components measured most often are C3 and C4. If the doctor suspects a deficiency that C3 and C4 testing cannot detect, total complement activity (CH50 or CH100) is requested. CH50 measures the function of the classical complement pathway, C1–C9. If this measurement is outside the normal reference range, each of the 9 complement components must be measured individually to identify the inherited or acquired deficiency.

How is the sample collected?
The blood sample is taken from a vein in the arm.

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

How is this test used?
C3 and C4 measurements are used to determine whether deficiencies or abnormalities of the complement system may be causing, or contributing to, a person’s illness. Total complement activity (CH50 or CH100) may be requested to assess the integrity of the classical complement pathway. Other complement components may be measured to detect inherited deficiencies.

Complement testing may be requested to find the cause of recurrent bacterial infections, angioedema (which causes oedema, swelling and hives) or inflammation. It can also be used to diagnose and monitor the activity of acute or chronic autoimmune diseases such as systemic lupus erythematosus (SLE). Because complement helps clear immune complexes from the blood, it may be tested and monitored in immune complex diseases such as glomerulonephritis, serum sickness, rheumatoid arthritis and vasculitis.

When is this test requested?
Complement testing may be requested when there is otherwise unexplained inflammation or oedema, or symptoms of an autoimmune disease such as lupus erythematosus. It may also be requested when the doctor suspects an immune complex disease and wants to assess the state of the complement system.
C3 and C4 levels are requested most often, but others, such as C1, may be requested if other deficiencies are suspected. Individual complement component levels may be requested when total complement activity is abnormal, to determine which component is deficient or abnormal.

When an acute or chronic disease has been diagnosed, complement testing can give a rough idea of its severity (assuming that severity is linked to the fall in complement levels). Complement testing may sometimes also be requested to assess the person’s current condition.

What does the test result mean?
Complement levels may be lower because of an inherited deficiency (relatively rare) or increased consumption. An inherited deficiency of one of the complement proteins leads to frequent bacterial infections or autoimmune diseases. If the deficiency is due to an acute or chronic disease, complement levels return to normal once the disease resolves.
Decreased complement levels are seen with:

• recurrent infections (usually bacterial)
• autoimmune diseases, including lupus and vasculitis
• hereditary angioedema
• acquired angioedema
• various types of kidney disease, including glomerulonephritis, lupus nephritis, membranous nephropathy and IgA nephropathy
• malnutrition
• septicaemia
• serum sickness (immune complex disease)

Complement protein levels are increased, together with those of other unrelated proteins known as acute-phase proteins, during acute or chronic inflammation. These levels generally return to normal when the inflammation resolves. In these conditions, however, complement proteins are rarely measured compared with C-reactive protein.

Is there anything else I should know?
Abnormal complement protein levels do not tell you what is wrong; they only indicate that the disease involves the immune system. Complement levels may increase in the presence of disease, and this increase comes before that of other markers such as the erythrocyte sedimentation rate (ESR) and C-reactive protein.

1. What are the other components of the innate immune system?
The innate immune system also includes:

The phagocytic system (macrophages, neutrophils and monocytes), which ingests and digests foreign microorganisms
Inflammatory mediators produced by various cells, including basophils, mast cells and eosinophils
Natural killer cells (which kill some tumour cells, microorganisms and virus-infected cells)
Acute-phase substances and cytokines (a group of soluble proteins that can cause changes in the growth of many cells, including the white blood cells that produce them).