Summary
Complement is a group of more than 30 different proteins that are involved in a biochemical pathway, called the complement pathway. This pathway plays a critical role in inflammation, which serves as a defence against some bacterial and viral infections. The term complement deficiency is used when proteins are missing or do not function properly.
Complement deficiencies are rare and will cause people to have different symptoms depending on which complement protein is affected. Most complement deficiencies have a genetic cause and family members of those affected may need to be tested.
Treatments for complement deficiency depend on the complement protein affected. People who are more susceptible to bacterial infections might need to take daily antibiotics and be vaccinated to improve their protection against specific infections.
Complement is the term used to describe a group of over 30 proteins that kill micro-organisms and assist other cells of the immune system to fight infection. Complement proteins also play an important role in inflammation.
Complement proteins are made mainly in the liver and then secreted into the blood. They are numbered C1 to C9, and there are other supporting proteins that are also considered to be complement proteins (e.g. C1 inhibitor, properdin, factor B, factor D, factor H and factor I).
The proteins form part of a tightly regulated pathway that is designed to kill invading microbes whilst limiting damage to other body tissues. When the complement proteins encounter bacteria, a virus, an immune complex, damaged tissue or other substance not usually present in the body, the complement proteins become ‘activated’ and act in a coordinated way. This activation is often referred to as a cascade reaction and is likened to the falling of a row of dominoes because the process must occur in a specific order.
Complement deficiency results when any of the proteins that make up the complement pathway are missing or do not work properly. Because each protein has a different role in the pathway, each complement deficiency has different symptoms and treatments.
Most complement deficiencies have a genetic cause. They are often inherited (passed down between generations) but can arise for the first time in an affected individual. People with genetic causes of complement deficiencies have DNA that does not enable a working form of the affected protein to be made. The way in which complement deficiencies are inherited is complex, so speak to your doctor if you have any questions. In some medical conditions, such as infection, blood cancers and autoimmune conditions, and some types of kidney problems, complement proteins can be ‘used up’ and their levels become low. These conditions are referred to as acquired complement deficiencies.
The signs and symptoms depend on the type of complement deficiency, as changes in different complement proteins can have very different symptoms. Low levels of mannose-binding lectin (MBL) are common, and patients often do not have any symptoms.
By itself, a low level of MBL does not cause a major immunodeficiency. See our separate booklet on MBL deficiency.
C1 inhibitor deficiency includes the conditions of hereditary angioedema (HAE) and acquired angioedema. C1 inhibitor is a protein that helps to regulate the complement pathway and regulates production of a chemical called bradykinin. People with reduced C1 inhibitor may have high levels of bradykinin, which can cause tissue swellings called angioedema. They may also get episodes of severe abdominal pain caused by swelling of the gut. The organisation HAE UK offers support and advice on the symptoms, management and treatment of C1 inhibitor deficiencies.
People with defects in proteins in the early parts of the complement pathway (proteins C1–C4) may be more likely to develop autoimmune diseases, such as systemic lupus erythematosus (also called lupus, or SLE). They may also be susceptible to infections with encapsulated bacteria, such as pneumococcal and neisseria species, that can cause severe infections, including pneumonia and meningitis. Low but not absent C4 is very common and is not usually associated with any major health problems. Antibodies against C3 or C4 can occur and are called nephritic factors because they are associated with kidney disease.
People with defects in proteins in the later parts of the complement pathway (proteins C5–C9) are also susceptible to infection with encapsulated bacteria (bacteria that are surrounded by a coating that helps protect them and evade immune responses).
When complement factors B or D are reduced, this may predispose those affected to recurrent infection. Rarely, changes that lead to over-activity of factor B and factor D may cause a disorder called atypical haemolytic uraemic syndrome (aHUS), characterised by excessive destruction of red blood cells. Factor H and factor I genetic mutations can also cause this disorder.
Sometimes people may have complement abnormalities detected on blood tests before they have any symptoms.
Diagnosis
Complement deficiencies are usually diagnosed by performing special blood tests in people who have symptoms of disease. Sometimes these blood tests have to be repeated to make sure the result is accurate. Complement proteins are often reduced due to infection or because the blood sample didn’t get to the lab quickly enough. The results may also be confirmed by genetic testing. Sometimes relatives of people affected are also tested for the condition.
Treatment depends on the type of complement deficiency. C1 inhibitor deficiencies may be treated by a range of different medications, including C1 inhibitor replacement, Lanadelumab; tranexamic acid; hormones; and drugs such as icatibant that block the action of bradykinin. People with these conditions need to avoid particular drugs for blood pressure (ACE inhibitors). Medications that contain oestrogen, such as some contraceptives, can make the condition worse. The support group HAE UK has information on all the treatments available to patients affected by C1 deficiency.
If patients have autoimmune conditions, such as SLE, they may need to be treated with steroids and other immunosuppressants.
If patients are more susceptible to bacterial infections, they might need to take daily antibiotics and be vaccinated to improve their protection against specific infections. They should seek medical advice early if they are unwell. This is because, if they get an infection, it can progress rapidly, with fewer signs than in people with normal complement function.
Immunisation
Patients with complement deficiencies can usually have all vaccines without any problems. Vaccination is an important part of protecting patients with certain complement deficiencies. If you have a complement deficiency, you should check with your doctor before taking live vaccines, such as the MMR vaccine or the yellow fever vaccine, especially if you are on immunesuppressive drugs. If you are travelling abroad, you should seek advice about any vaccinations needed a few months before you travel.
Associated health complications People with reduced C1 inhibitor may have tissue swellings.
People with defects in the early complement pathways are more likely to get autoimmune conditions, such as Systemic lupus erythematosus (SLE). People with certain complement deficiencies are susceptible to infections caused by encapsulated bacteria.
People with blood cancers, such as lymphoma, may get acquired complement deficiencies, although this is very rare.
The table below summarises the health problems associated with complement deficiency.
‘The time leading up to and just after diagnosis was awful. However, with the right medicine, it gets easier to deal with. If someone had told me six years ago that we would be able to travel around Asia, I wouldn’t have believed them. But that’s what we did last year, and Isaac continues to be a very happy child who just gets on with enjoying life.’ Mum to Isaac, who was diagnosed with C2 complement deficiency in 2013.
European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA). Complement Guideline: Deficiencies, Diagnosis, and Management. Nicholas Brodszki, Ashley Frazer-Abel, Anete S. Grumach, Michael Kirschfink, Jiri Litzman, Elena Perez, Mikko R. J. Seppänen, Kathleen E. Sullivan and Stephen Jolles. Journal of Clinical Immunology (2020) May; 40: 576–591. https://doi.org/10.1007/s10875-020-00754-1
You can download our information booklet here.
