Complement Deficiency Clinical Presentation

The following may be associated with complement deficiency:

• Patient or family history of recurrent systemic infection caused by encapsulated bacteria, especially meningococci
• Family history of fulminant meningococcal disease occurring in males, suggestive of X-linked properdin deficiency
• Meningococcal disease occurring in persons older than 10 years, especially when caused by non–group B meningococci (especially serogroups Y and W-135)
• Family history of systemic lupus erythematosus (SLE) or occurrence of atypical features of SLE, especially negative lupus serology findings (negative antinuclear antibody [ANA] and negative dsDNA findings)
• Specific syndromes such as partial lipodystrophy, angioedema, and paroxysmal nocturnal hemoglobinuria (PNH): Consider evaluation of the complement system in patients with these syndromes.
• Recurrent pyogenic infection, including severe pneumococcal diseases in infants and young children with normal humoral immune workup findings

• Classical pathway deficiencies - C1, C4, and C2

  • Deficiencies of the classical complement pathway have been strongly linked to the development of autoimmune disorders, especially those in which excessive immune complexes are formed. Patients may develop collagen vascular disorders, mainly SLE. Ninety-five percent of patients with C1q deficiency, 75% of those with C4 deficiency, 30% of those who are deficient in C2, and 50-55% of those who are deficient in C1r and C1s (deficiency usually involves both C1r and C1s) develop collagen vascular diseases (mainly SLE). Evidence suggests that this may result from the combination of impaired complement-dependent B-cell tolerance and impaired clearance of immune complex and apoptotic cells.
  • C1 deficiency generally leads to severe immune complex disease with features of SLE and glomerulonephritis. Serum levels of anti-C1q antibodies were increased significantly in patients with SLE and proliferative nephritis. Among different serological parameters for assessing the renal activity of SLE, only anti-C1q antibodies titers showed significant differences between quiescent and active lupus nephritis. Patients with C2 deficiency are reported to reveal anti-C1q antibody in the absence of anti-dsDNA.
  • Complete C4 deficiency is rare. Two genes, C4A and C4B, encode the C4 complement. Both genes are highly polymorphic, and, to date, at least 35 different alleles have been described. Almost all patients with complete C4 deficiency have discoid or SLE, with or without associated glomerulonephritis.
  • C2 deficiency has been the most commonly reported classical pathway defect. Skin and joint manifestations are common, and renal disease is relatively rare. Patients with C2 deficiency are also reported to have recurrent or invasive infections.
• C3 deficiency

  • C3 deficiency is rare. Because of its importance as a convergence point of the 3 complement pathways, all patients with C3 deficiency develop recurrent, severe, pyrogenic infections early in life. Some patients may also develop membranoproliferative glomerulonephritis.
  • C3 deficiency leads to an inability to formulate membrane attack complex (MAC), thus markedly compromising chemotactic and bactericidal activities of the complement cascade.
  • Patients with C3 deficiency generally have less than 1% of the normal amount of C3 antigen and C3 function in their serum.
  • Because of ineffective opsonization of pathogens, patients with C3 deficiency present with severe recurrent pyogenic infections, mainly caused by meningococci and pneumococci.
  • According to published studies, 78% of patients have repeated infections, and 79% experience autoimmune disorders, such as arthralgia and vasculitic rashes, lupuslike syndrome, and membranoproliferative glomerulonephritis.
• Alternate pathway deficiencies (properdin, factor B, factor D)

  • These deficiencies are rare. Properdin deficiency is associated with increased risk of infections with encapsulated bacterial organisms. Patients often present with a history of invasive meningococcal diseases, as well as severe pneumococcal and H influenzae infection. Recurrent infections may be rare in patients with properdin deficiency because the classical pathway can take over the actions of the alternate pathway once antigen-specific adaptive immune responses are established with immunoglobulin (Ig)G and IgM antibody formation.
  • Only 3 adults with factor D deficiency have been described in the literature. A 6-day-old newborn boy with pneumococcal sepsis and meningitis was diagnosed with complete deficiency of factor D and diminished functional factor B. The addition of purified factor D restored the capacity of the patient's serum to generate the alternate pathway fluid-phase C3 convertase (C3bBbP) in response to zymosan. This also restored activity of factor B in the patient's serum. In contrast, the addition of factor B did not alter factor D activity in the serum, indicating requirement of factor D for function of factor B.
• Late complement component deficiencies - C5, C6, C7, C8, and C9

  • MAC cannot be formed; hence, bactericidal activity is depressed.
  • Patients are susceptible to recurrent pyogenic infections.
  • Patients typically present with meningococcal meningitis or extragenital gonococcal infection.
  • Two thirds of patients experience at least one episode of meningococcal disease, and as many as one half of patients experience recurrent neisserial infections.
  • Patients with C9 deficiency have the ability to kill Neisseria, but at a slower rate.
• Deficiency of C1INH (HAE): This leads to recurrent episodes of angioedema. See Angioedema (Hereditary).
• Mannose-binding lectin (MBL) pathway deficiency

  • Newborns with MBL deficiency are at increased risk for infection. Individuals with MBL deficiency have a higher propensity for severe infection in early life.
  • In young children and newborns with repeated infections, MBL defects should be considered.
  • Worsening clinical features are also reported in patients with rheumatoid arthritis and MBL deficiency.
  • In a study of patients with cystic fibrosis (CF) with or without MBL variant alleles, Garred et al found the following:^[1]
    • Lung function in carriers of MBL variant alleles was significantly reduced compared with patients with normal homozygotes.
    • The negative impact of variant alleles on lung function was especially confined to patients with CF and chronic Pseudomonas aeruginosa infection.
    • Burkholderia cepacia (previously named Pseudomonas cepacia) infection was significantly more frequent in patients with CF and MBL variant alleles.
    • Using a modified life table analysis, the authors estimated that the predicted age of survival was reduced by 8 years in patients with CF who carried variant alleles compared with normal homozygotes with CF.
• C3 nephritic factor (C3NeF) and mesangiocapillary glomerulonephritis (MCGN)

  • C3Nef is an autoantibody that binds to and stabilizes the C3 convertase (C3bBb).
  • The association of C3NeF and MCGN, especially MCGN type II, has been well defined. Different isotypes of C3NeF are recognized, the main one being an IgG autoantibody against factor H. Factor H is an important regulator of the C3 conversion step in the alternate pathway. C3NeF inhibits functions of factor H, which leads to overwhelming complement activation at the stage of C3 conversion. Continuous C3 activation in vivo results in the well-known consequences of very low serum levels of C3 in MCGN.
  • C3NeF may act directly within glomeruli to cause local complement activation and ensuing renal damage.
  • C3Nef is also associated with partial lipodystrophy.
• Factor H deficiency

  • Factor H deficiency is associated with hemolytic-uremic syndrome (HUS), especially in familial cases that involve homozygous factor H deficiency.
  • Factor H deficiency also occurs with membranoproliferative glomerulonephritis.
  • Parents have one half the normal levels of factor H.
  • HUS associated with factor H deficiency is characterized by verotoxin-negative (diarrhea-negative) HUS. Atypical and recurrent HUS is also seen in CD46 deficiency.

• Classical pathway deficiencies (C1, C4, C2) are inherited in an autosomal recessive pattern.
• C3 deficiency is inherited in an autosomal recessive pattern.
• No known homozygous deficiency of factor B has been reported, although one heterozygous case has been described. Properdin deficiency is the only X-linked complement deficiency. All reported cases of properdin deficiency involve males.
• Late complement component deficiencies (ie, C5, C6, C7, C8, C9) are inherited in an autosomal recessive fashion.