C3 Deficiency

Complement component 3 (C3) deficiency is the absence, reduction, or dysfunction of complement factor C3 and its fragments, C3a and C3b. Complement factors are key components of the innate immune system. Reduced levels of C3b increase the probability of developing infections with encapsulated organisms (e.g., Pneumococcus, Haemophilus influenza, Neisseria meningitidis), especially respiratory infections, due to reduced opsonization. Individuals with C3 deficiencies are also more susceptible to type III hypersensitivity reactions because a reduced clearance of antigen-antibody C3b complexes from the circulation causes an increased risk of hypersensitivity reactions.

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Overview

Epidemiology

Complement component 3 (C3) deficiency is part of the larger category of complement deficiencies:

  • Complement deficiencies are rare: They make up 5% of all immune deficiencies.
  • Prevalence varies by geographic location.
  • No gender or ethnic propensity reported.

Etiology

  • Hereditary C3 deficiency:
    • Encoded on chromosome 19 by the C3 gene
    • 17 mutations in C3 gene prevent C3 protein from forming: commonly affects fragment C3b
    • Autosomal recessive inheritance
  • Acquired C3 deficiency:
    • Increased consumption of C3 during infection:
      • C3 overactivation by immune complexes
      • Seen in lepromatous leprosy, bacterial endocarditis, malaria, infectious mononucleosis, dengue hemorrhagic fever, and acute hepatitis B
    • Consumption of C3 due to medical conditions:
      • Lupus
      • Membranoproliferative glomerulonephritis

Pathophysiology

  • Complement cascade (3 pathways converging in common pathway):
    1. Classical pathway (C1qrs, C2, C4)
    2. Alternative pathway (C3, factor B, properdin)
    3. Lectin pathway (mannan-binding lectin (MBL))
  • C3 deficiency results in malfunction of complement cascade: 
    • Decreased levels of opsonin C3b → impaired opsonization of pathogens (especially bacteria) 
    • Leads to reduced clearance of immune complexes
    • Increased risk of pyogenic bacterial infections
C3 deficiency

Complement cascade

Image: “Complement pathway” by Perhelion. License: Public Domain

Diagnosis

Clinical presentation

  • Recurrent bacterial infections during childhood, especially encapsulated organisms:
    • Upper respiratory tract infections
    • Pneumonia
    • Meningitis
  • Generalized infections and sepsis can occur similar to Bruton agammaglobulinemia: infections with Staphylococcus, Pneumococcus, or Haemophilus influenzae
  • Also associated with autoimmune diseases:
    • Systemic lupus erythematosus
    • Type III hypersensitivity reactions
    • 25% of patients develop glomerulonephritis.

Laboratory testing

Clinical testing directed by pattern of infection:

  • Bacterial types
  • Location of infection

Management

Management of patients with C3 deficiency centers on prevention of illness.

Prevention of infection

  • Promotion of hygiene and frequent hand washing
  • Monitor closely for early signs of illness.
  • Vaccination: meningococcal, pneumococcal, and H. influenzae vaccines are critical.
  • Prophylactic antibiotic:
    • Chronic prophylaxis is controversial.
    • May be indicated in select individuals based on severity, frequency, and kind of infection

Treatment of infection

  • Antibiotic therapy directed by bacteria isolated
  • Complement infusion: indicated with acute illness

References

  1. Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014 Oct. 61(2):110-117
  2. Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev. 1991 Jul;4(3):359-95. doi: 10.1128/cmr.4.3.359. PMID: 1889047; PMCID: PMC358203.
  3. Botto M, Kirschfink M, Macor P, Pickering MC, Würzner R, Tedesco F. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol. 2009 Sep;46(14):2774-83. doi: 10.1016/j.molimm.2009.04.029. Epub 2009 May 28. PMID: 19481265.

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