Complement Deficiency

Basics

DESCRIPTION

  • 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.
Clinical Manifestations of Complement Deficiencies
DeficiencyClinical Manifestations
C1q,r,s, C2Systemic lupus erythematosus (SLE)-like, bacterial infections, invasive pneumococcal infections
C4SLE-like, autoimmune disorders, infections
C3Severe infections with encapsulated bacteria (i.e., Haemophilus influenzae), glomerulonephritis, immune complex diseases (i.e., atypical hemolytic uremic syndrome [aHUS])
Factor H, ISecondary C3 deficiency, aHUS, age-related macular degeneration (AMD), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome
ProperdinMales with neisserial and sinopulmonary infections
Factor BNeisserial infections, aHUS, AMD
Factor DNeisserial infections
MBL, MASPInfections with encapsulated bacteria, respiratory infections
Ficolin-3Respiratory infections, necrotizing enterocolitis
C5, 6, 7, 8, 9Disseminated neisserial infections, SLE
DAF, CD59Paroxysmal nocturnal hemoglobinuria
C1 inhibitorHereditary angioedema (HAE)

EPIDEMIOLOGY

  • 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.

RISK-FACTORS

GENETICS

  • Properdin deficiency is X-linked.
  • Most other complement deficiencies are autosomal recessive.
  • C1 inhibitor deficiency is autosomal dominant.
  • Heterozygotes are usually phenotypically normal.

PATHOPHYSIOLOGY

  • 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.

ETIOLOGY

  • 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)

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