Complement Deficiency

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • The complement system is a major component of the innate immune system.
  • Activation of the complement cascade (i) promotes production of proinflammatory mediators, (ii) aids in opsonization of infectious microbes, and (iii) leads to formation of the membrane attack complex.
  • The complement cascade can be activated through three separate pathways that ultimately converge to form the membrane attack complex:
    • Classical: by IgG/IgM binding to C1q
    • Lectin: when lectins, such as mannose binding lectin (MBL) or ficolin, bind to microbial polysaccharides
    • Alternative: spontaneously but inhibited on host cells by complement regulatory proteins
  • Deficiencies can arise in any of the proteins, leading to either halting or overactivation of the complement cascade, the latter of which occurs with deficiencies of complement regulatory proteins
  • Complement deficiencies may result in immunodeficiency, autoimmunity, and/or angioedema.
  • Secondary/acquired complement deficiencies are more common than inherited deficiencies and are most often result from consumption of complement.
Complement Deficiencies (Loss-of-Function)
Protein (Expected CH50/AH50) Clinical Manifestations
C1q/r/s, C2, C4 (CH50 near zero, AH50 normal) Systemic lupus erythematosus (SLE), bacterial infections (including invasive pneumococcal disease)
C3 (CH50 and AH50 near zero) Membranoproliferative glomerulonephritis (MPGN); severe and recurrent infections with encapsulated bacteria
Factor H, I (CH50 and AH50 low) Secondary C3 deficiency (with associated infections), atypical hemolytic uremic syndrome (aHUS), MPGN, age-related macular degeneration (AMD), hemolysis/elevated liver enzymes/low platelets (HELLP) syndrome
Properdin a , factor B, D (CH50 normal, AH50 near zero) Neisserial infections
C5, C6, C7, C8, C9 (CH50 and AH50 near zero but less pronounced for C9) Neisserial infections
DAF/CD55 b , CD59 b (CH/AH50 not pertinent) Paroxysmal nocturnal hemoglobinuria (PNH)
C1 esterase inhibitor (SERPING1) Hereditary angioedema (HAE); acquired angioedema (AAE) c
MBL Limited association with recurrent infections; MBL is variable and may be low-to-absent in healthy controls.

aAH50 may be diminished but not zero.

bPrimarily somatic (acquired) mutations.

cAcquired process (most often adults with malignancy).

Abbreviations: CH50, total hemolytic complement assay; AH50, alternative pathway hemolytic assay.

EPIDEMIOLOGY

  • Complement deficiency is rare and accounts for 0.5–4% of all primary immune deficiencies (PIDs)
  • Homozygous C2 deficiency occurs in 1 in 20,000
  • Partial C4 deficiency seen in 1–3% of White population
  • C9 deficiency is primarily found in people of Japanese descent and does not always result in disease.
  • C6 deficiency is more common in individuals with African ancestry.

ETIOLOGY

  • Primary complement deficiencies are hereditary.
  • Acquired complement deficiencies include accelerated consumption by immune complexes (most common), decreased hepatic production (less common), and loss through the urine (rare).
  • PNH is most frequently an acquired condition caused by somatic mutations.
  • AAE can be caused by
    • Lymphoma or lymphoproliferative cells that directly deplete C1 esterase inhibitor or activate C1, thereby consuming C1 esterase inhibitor
    • Autoantibodies to C1 esterase inhibitor

RISK FACTORS

Genetics

  • Most complement proteins have codominant expression, and therefore, biallelic germline mutations (autosomal recessive) are required for clinical manifestation of most complement deficiencies.
  • Monoallelic germline mutations that do not result in gain-of-function are frequently phenotypically normal but may result in mild complement deficiencies. Gain-of-function mutations have been reported in C1r/s, C3, and factor B and result in different manifestations.
  • Properdin deficiency is X-linked.
  • Hereditary C1 esterase inhibitor deficiency is autosomal dominant, but an acquired form also exists.
  • Most PNH patients with DAF/CD55 or CD59 deficiency harbor somatic (acquired) mutations.

PATHOPHYSIOLOGY

  • Classic complement pathway is activated when IgM or IgG antibodies bind to an antigen.
  • Lectin pathway is activated when a serum lectin, such as MBL, binds to an antigen.
  • The alternative pathway does not need antibody or lectins to be activated but is negatively regulated by the presence of regulatory proteins on host cells.
  • Activation of all three pathways converge on production of C3 convertase and then the (i) release of proinflammatory anaphylatoxins (C3a and C4a), (ii) deposition of opsonizing antigens (C3b, C4b), and (iii) formation of the membrane attack complex (resulting in lysis of the target cell)
  • Deficiencies can arise in any of the proteins, leading to either halting or overactivation of the complement cascade, the latter of which occurs with deficiencies of complement regulatory proteins

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