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- Complement is a major component of the innate immune system.
- Consists of plasma and membrane proteins which mediate three pathways of cascading enzyme reactions (classical, alternative, and lectin pathways)
- Pathway activation leads to inflammatory and immune responses.
- Deficiencies can arise in any of the proteins, leading to loss of activity of the deficient protein as well as loss of function of proteins that follow in the cascade.
- Inherited deficiencies of the complement components may predispose individuals to bacterial infections and autoimmunity.
- Secondary/acquired deficiencies are much more common than inherited deficiencies and are most often caused by increased consumption by immune complexes.
|C1q,r,s, C2||Systemic lupus erythematosus (SLE)-like, bacterial infections, invasive pneumococcal infections|
|C4||SLE-like, autoimmune disorders, infections|
|C3||Severe infections with encapsulated bacteria (i.e., Haemophilus influenzae), glomerulonephritis, immune complex diseases (i.e., atypical hemolytic uremic syndrome [aHUS])|
|Factor H, I||Secondary C3 deficiency, aHUS, age-related macular degeneration (AMD), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome|
|Properdin||Males with neisserial and sinopulmonary infections|
|Factor B||Neisserial infections, aHUS, AMD|
|Factor D||Neisserial infections|
|MBL, MASP||Infections with encapsulated bacteria, respiratory infections|
|Ficolin-3||Respiratory infections, necrotizing enterocolitis|
|C5, 6, 7, 8, 9||Disseminated neisserial infections, SLE|
|DAF, CD59||Paroxysmal nocturnal hemoglobinuria|
|C1 inhibitor||Hereditary angioedema (HAE)|
- Complement deficiency accounts for 1–6% of all primary immune deficiencies (PIDs); up to 10% in some registries.
- Homozygous C2 deficiency 1 in 20,000
- Partial C4 deficiency in 1–3% of Caucasian population
- C9 deficiency almost always found in people of Japanese descent
- C6 deficiency more common in African Americans
- Alternative pathway deficiencies (properdin, factor D) are rare.
- Properdin deficiency is X-linked.
- Most other complement deficiencies are autosomal recessive.
- C1 inhibitor deficiency is autosomal dominant.
- Heterozygotes are usually phenotypically normal.
- Classic complement pathway is activated when IgM or IgG antibodies bind to antigen.
- Lectin pathway is activated when a serum lectin such as mannose-binding lectin (MBL) binds to antigen.
- Alternative pathway does not need antibody or lectins to be activated.
- Main goal of all three pathways is to deposit C3b fragments on the target antigen to mark the target for immune response.
- Primary complement deficiencies are hereditary.
- Acquired deficiencies: accelerated consumption by immune complexes (most common), decreased hepatic production (less common), or loss through the urine (rare)