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What is complement?
The complement system is a group of over 20 serum glycoproteins that are mainly secreted by hepatocytes. It forms part of the innate immune system and its functions include:
- Promotion of the inflammatory response.
- Helping to eliminate pathogens.
- Enhancing the immune response.
Components of the complement system are represented by the letter 'C' followed by a number. There are also two proteins involved in the alternative complement pathway that are known as factors: factor B and factor D.
The complement system is activated in a cascade sequence, similar to that of the blood clotting cascade.
The complement cascade
- The complement cascade has three main pathways which are activated in different ways. They all converge in one final common pathway at C3.
- This common pathway results in C5 to C9 being assembled into the membrane attack complex (MAC). The MAC disrupts cell membranes and leads to cell lysis.
- The classical pathway (C1, C4, C2) is activated by the presence of antigen-antibody immune complexes and some viral envelopes.
- The alternative pathway (factor B, factor D and properdin) is activated by these components. Its activation is therefore antigen-independent.
- The mannose-binding lectin (MBL) pathway is activated by MBL, an acute phase protein secreted by the liver. MBL recognises microbes and rapidly activates the complement cascade, providing initial antigen-independent immune defense.
- There is complex regulation and control of the complement cascade involving cell membrane-associated proteins and other plasma proteins.
- Complement deficiency is a form of primary immunodeficiency disorder.
- Deficiency in any component of the complement system can lead to immunocompromise and overwhelming infection and sepsis.
- Deficiency can be inherited or acquired and complete or partial.
- Acquired deficiency can be caused by infection.
- MBL deficiency is thought to be the most common.
- Uncontrolled or deranged complement activity can also cause disease by promoting inflammation. The complement system can be involved in the pathogenesis of autoimmune diseases.
Complement deficiencies are rare. However, they are poorly characterised clinically and have been difficult to detect, so there is likely to be significant underdiagnosis in current practice:
- Complement deficiencies form about 2% of all primary immunodeficiency disorders.
- One review estimates the prevalence of C2 deficiency as roughly 1/20,000 in Western countries.
- Various racial preponderances are hypothesised but there is little firm evidence to back these up. There appears to be an equal gender prevalence.
- Most complement deficiencies follow autosomal recessive inheritance.
- Properdin deficiency may be inherited as an X-linked trait.
- MBL deficiency can be both autosomal dominant and recessive.
- Complement deficiencies can also be acquired - for example, post-infection.
Classical pathway component deficiencies (C1, C4, C2)
- Individuals are prone to immune complex disease, commonly systemic lupus erythematosus (SLE). The reason for this is thought to be that the complement deficiency leads to an inability to clear circulating immune complexes. This in turn leads to their deposition in tissues and an associated inflammatory response.Reduced clearance of apoptotic cells by the complement system may also lead to the development of autoantigens.
- C2 deficiency is also associated with recurrent bacterial infection and an increased risk of cardiovascular disease. It is thought to influence the development of atherosclerosis.[5, 6]
- Classically presents with recurrent pyogenic infection in childhood.
- Deficiency of MBL increases susceptibility to Saccharomyces cerevisiae infection as well as pneumococcal and neisserial infection.[1, 7]Pneumococcal infection is particularly common.
- There is also an association with SLE and possibly atherosclerosis.
Alternative pathway component deficiencies (properdin, factor B and factor D)
- Affected individuals are prone to pneumococcal and meningococcal infections.
- With properdin deficiency, there is a particular risk of overwhelming neisserial infection.
- C3 is required for opsonisation (the coating of pathogenic cells with opsonin to facilitate phagocytosis).
- A defect in the pathway that results in deficiency of C3 can lead to problems with opsonisation. There may be a deficiency of C3 itself or a deficiency of other complement components in the classic, alternative or MBL pathways (ie above C3 in the cascade).
- Primary C3 deficiency tends to present in early life with overwhelming infection with encapsulated organisms.
- There is also a tendency to connective tissue diseases.
MAC deficiencies (C5-C9)
- Recurrent infections are again a feature.
- Infection with Neisseria meningitidis is particularly common. More rare serotypes of this organism such as Y and W135 tend to cause the infection.[1, 8]
- This is a paediatric condition associated with a deficiency of C5. It has also been reported with C3 and C4 deficiency.
- It causes wasting, chronic diarrhoea and widespread seborrhoeic dermatitis.
Complement regulatory protein deficiency
- If the proteins that regulate the complement cascade are deficient, the complement system can become over-activated.
- C1-inhibitor (C1-INH) is an inhibitory protein that regulates the classical pathway. Deficiency results in angio-oedema. C1-INH deficiency can be hereditary, resulting in hereditary angio-oedema, or acquired.
- Paroxysmal nocturnal haemoglobinuria can also occur as a result of over-activation of the complement system.
- Immunoglobulin deficiencies.
- Other causes of immunosuppression - eg, steroids, chemotherapy, leukaemia.
- Incidental infection with relevant organisms.
- Incidental autoimmune disease.
- Any presenting infection should be adequately investigated with causative organism identification.
- Ask about family history of SLE.
- The total serum classic haemolytic complement (CH50) test screens for complement deficiencies in the classic pathway. This involves looking at the ability of the patient's serum to lyse antibody-coated sheep erythrocytes.
- The alternative haemolytic complement (AP50) test screens for complement deficiencies in the alternative pathway (AP). It is also called the AH50.
- Specific tests using enzyme-linked immunosorbent assay (ELISA) or other techniques can be used to measure the levels of individual complement proteins, inhibitor proteins and associated factors.
- If a complement deficiency in the classic pathway is detected, the presence of, and any effects of, immune-complex disease should be investigated (eg, assessment of end-organ damage using urinalysis or creatinine clearance). This may alert the clinician to the need for current or future therapy to treat immune-complex disease.
- Infections should be treated aggressively with appropriate agents according to local protocols.
- Autoimmune disease should be treated with immunosuppressive therapy according to protocols for the particular disease in question. This may lead to an increased susceptibility to infection and a balance must often be struck between controlling immune complex disease and increasing propensity to infection.
- C1-INH plasma-derived concentrate has been used successfully in people with hereditary angio-oedema with C1-INH deficiency. Androgen therapy can also be used to prevent attacks in hereditary angio-oedema.
- In other complement deficiencies, treatment is just supportive at present.
- Patients with complement deficiencies should be immunised against pneumococcus, meningococcus and haemophilus infections.
- There should be education of patient and family/carers on the need to seek treatment early if infection is suspected.
- Death due to overwhelming infection.
- CNS damage due to recurrent meningitis.
- Respiratory tract damage due to recurrent infection.
- Unusual or occult infections.
- End-organ damage due to circulating immune complexes - eg, chronic kidney disease.
- C3 deficiency can lead to recurrent infections with severe sequelae and high morbidity and mortality. There may be overwhelming sepsis in early life.
- Deficiencies of the components of the MAC (C5-C9) tend to lead to less severe infections and have a better prognosis with careful management.
- People with a classical pathway deficiency are at high risk of developing autoimmune disease but have a lower risk of overwhelming sepsis.
- Family members should be screened.
- Screening should be considered in someone with recurrent infection.
- Also consider after meningococcal infection if an unusual serotype has caused the infection, if the infection is recurrent, if the infection has followed an abnormal cause, or it there have been previous suspicious infections.
Further reading and references
Sarma JV, Ward PA; The complement system. Cell Tissue Res. 2011 Jan343(1):227-35. doi: 10.1007/s00441-010-1034-0. Epub 2010 Sep 14.
Sjoholm AG, Jonsson G, Braconier JH, et al; Complement deficiency and disease: an update. Mol Immunol. 2006 Jan43(1-2):78-85.
Cooper MA, Pommering TL, Koranyi K; Primary immunodeficiencies. Am Fam Physician. 2003 Nov 1568(10):2001-8.
Pettigrew HD, Teuber SS, Gershwin ME; Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009 Sep1173:108-23. doi: 10.1111/j.1749-6632.2009.04633.x.
Jonsson G, Sjoholm AG, Truedsson L, et al; Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency. Rheumatology (Oxford). 2007 Jul46(7):1133-9. Epub 2007 May 3.
Jonsson G, Truedsson L, Sturfelt G, et al; Hereditary C2 deficiency in Sweden: frequent occurrence of invasive infection, atherosclerosis, and rheumatic disease. Medicine (Baltimore). 2005 Jan84(1):23-34.
Roos A, Garred P, Wildenberg ME, et al; Antibody-mediated activation of the classical pathway of complement may compensate for mannose-binding lectin deficiency. Eur J Immunol. 2004 Sep34(9):2589-98.
Drogari-Apiranthitou M, Kuijper EJ, Dekker N, et al; Complement activation and formation of the membrane attack complex on serogroup B Neisseria meningitidis in the presence or absence of serum bactericidal activity. Infect Immun. 2002 Jul70(7):3752-8.
Leiner disease; DermNet NZ
Blanch A, Roche O, Urrutia I, et al; First case of homozygous C1 inhibitor deficiency. J Allergy Clin Immunol. 2006 Dec118(6):1330-5. Epub 2006 Sep 18.
Costabile M; Measuring the 50% haemolytic complement (CH50) activity of serum. J Vis Exp. 2010 Mar 29(37). pii: 1923. doi: 10.3791/1923.
Levi M, Choi G, Picavet C, et al; Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol. 2006 Apr117(4):904-8. Epub 2006 Feb 14.
Banerji A, Sloane DE, Sheffer AL; Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol. 2008 Jan100(1 Suppl 2):S19-22.
Hoare S, El-Shazali O, Clark JE, et al; Investigation for complement deficiency following meningococcal disease. Arch Dis Child. 2002 Mar86(3):215-7.
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