Which clinical history findings are characteristic of immune complex diseases in complement deficiencies?

Updated: Apr 28, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Michael A Kaliner, MD  more...
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Answer

Patients with complement deficiencies of the classic pathway are predisposed to develop immune complex diseases.

Patients with deficiencies of the classic pathway components C1qrs, C2, or C4 have been shown to have an increased likelihood of developing SLE. C1q deficiency is less commonly linked with neuropsychiatric SLE, which may be first evident with seizures. [15]  Homozygous deficiency of C1q has the highest association with SLE, with a recently quoted prevalence rate of 93%. Subsequent components of the classic pathway have respective prevalence rates of 57% for C1rs deficiency, 75% association with homozygous C4 deficiencies, and 10% prevalence in patients with C2 deficiencies.

The reason complement deficiency increases the risk of developing SLE is that complement helps in the prevention of immune complex disease by decreasing the number of circulating immune complexes; the greater the concentration of these precipitating immune complexes, the higher the likelihood that they will deposit in nearby tissues and cause an inflammatory response.

Complement aids in neutralization and clearance of antigen-antibody complexes in several ways. The classic pathway acts to inhibit immune complex precipitation by physically interfering with immune complex aggregation. Secondly, complement enhances the clearance of circulating immune complexes by binding to complement receptors (CR1) on cells such as erythrocytes, B lymphocytes, T lymphocytes, and macrophages. When complement (specifically C3b) binds to CR1 on erythrocytes, the immune complex can be transported through the circulation to be presented to the macrophage systems in the spleen and liver.

Components of the classical pathway also play an important role in the recognition and clearance of apoptotic cells. Normally, intracellular proteins are displayed on the surface of cells undergoing apoptosis. If these apoptotic cells are not cleared efficiently by the complement system, these cell surface proteins have the potential to act as autoantigens, acting as potential triggers for autoimmune diseases such as systemic lupus.

In addition to its role in the development of diseases such as SLE, complement activation also likely plays a role in the pathogenesis of the antiphospholipid antibody syndrome (APS), a thrombophilic inflammatory disorder that can be associated with SLE or can occur independently. In a mouse model of antiphospholipid-antibody associated fetal death, mice who were deficient in C3 and mice who were treated with a regulatory protein that inhibits C3 cleavage were protected from fetal loss. Recent studies in human subjects have also found a positive association between the presence of C4d deposition on activated platelets and the presence of arterial thrombosis. Further studies in human subjects are ongoing. [16]

Complement component C8, when entirely absent, results in increased susceptibility to gram-negative bacteria such as Neisseria species. [10] Two functionally distinct C8 deficiency states have been described: C8 alpha-gamma deficiency and C8beta deficiency. A duplication mutation in C8-beta deficiency was recently documented, extending the molecular heterogeneity of this disorder. Complement screening would detect this rare primary immunodeficiency and allow prophylaxis to prevent recurrent Neisseria infections with this potentially severe outcome. [17]

A relatively small sampling of Finnish non-tuberculous mycobacteria patients had significantly more often C4 deficiencies than the healthy control subjects, suggesting that both a deficiency of complement C4 and bronchiectasis in healthy females as risk factors for pulmonary NTM infections. [18]


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