Complement Deficiencies

• The complement system is a group of over 20 serum glycoproteins that are mainly secreted by hepatocytes.¹ It forms part of the innate immune system and its functions include:
  • Promotion of the inflammatory response
  • Helping to eliminate pathogens
  • Enhancing the immune response²
• 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 has 3 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 mannose-binding lectin, an acute phase protein secreted by the liver. MBL recognises microbes and rapidly activates the complement cascade, providing initial antigen-independent immune defense.¹
• 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.¹
• Acquired deficiency can be caused by infection.¹
• MBL deficiency is thought to be the most common.¹
• Uncontrolled or deranged complement activity can also cause disease by promoting inflammation. The complement system can be involved in the pathogenesis of auto-immune diseases.

• Complement deficiencies are rare. However, they are poorly characterised clinically and have been difficult to detect, so there is likely to be significant under-diagnosis in current practice.³
• Complement deficiencies form about 2% of all primary immunodeficiency disorders.⁴
• A recent review estimates the prevalence of C2 deficiency as roughly 1/20,000 in Western countries.³
• Various racial preponderances are hypothesized 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.²
• Properdin deficiency may be inherited as an X-linked trait.²
• MBL deficiency can be both autosomal dominant and recessive.²
• 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.² 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

MBL deficiency

• Classically presents with recurrent pyogenic infection in childhood.
• Deficiency of MBL increases susceptibility to Saccharomyces cerevisiae infection as well as pneumococcal and neisserial infection.² Pneumococcal infection is particularly common.
• There is also an association with SLE and possibly atherosclerosis.¹

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 deficiency

• 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 (i.e. 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.²

Leiner's disease²

• This is a paediatric condition associated with a deficiency of C5. It has also be 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 (C1INH) is an inhibitory protein that regulates the classical pathway. Deficiency results in angioedema. C1INH deficiency can be hereditary, resulting in hereditary angioedema, or acquired.⁷
• Paroxysmal nocturnal haemoglobinuria can also occur as a result of over-activation of the complement system.²

• Immunoglobulin deficiencies
• Other causes of immunosuppression, e.g. steroids, chemotherapy, leukaemia
• Incidental infection with relevant organisms
• Incidental auto-immune 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.²
• The alternative haemolytic complement (AP₅₀) test screens for complement deficiencies in the alternative pathway.
• Specific tests using 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 (e.g. 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.
• C1INH plasma-derived concentrate has been used successfully in people with hereditary angioedema with C1INH deficiency.⁸ Androgen therapy can also be used to prevent attacks in hereditary angioedema.¹
• 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
• Damage to respiratory tract due to recurrent infection
• Unusual or occult infections
• End-organ damage due to circulating immune complexes, e.g. renal failure

• 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 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.⁹