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Complement proteins are components of the innate immune system. There are 3 pathways to complement activation: 1) the classic pathway, 2) the alternative (or properdin) pathway, and 3) the lectin activation (mannan-binding protein [MBP]) pathway. The classic pathway of the complement system is composed of a series of proteins that are activated in response to the presence of immune complexes. The activation process results in the generation of peptides that are chemotactic for neutrophils and that bind to immune complexes and complement receptors. The end result of the complement activation cascade is the formation of the lytic membrane attack complex (MAC).
The absence of early components (C1-C4) of the complement cascade results in the inability of immune complexes to activate the cascade. Patients with deficiencies of the early complement proteins are unable to generate the peptides that are necessary clear immune complexes and to attract neutrophils or to generate to lytic activity. These patients have increased susceptibility to infections with encapsulated microorganisms. They may also have symptoms that suggest autoimmune disease and complement deficiency may be an etiologic factor in the development of autoimmune disease.
Approximately 20 cases of C4 deficiency have been reported. Most of these patients have systemic lupus erythematosus (SLE) or glomerulonephritis. Patients with C4 deficiency may also have frequent bacterial infections.
Complement levels can be detected by antigen assays that quantitate the amount of the protein (C4 / Complement C4, Serum). For most of the complement proteins, a small number of cases have been described in which the protein is present but is non-functional. These rare cases require a functional assay to detect the deficiency.
Diagnosis of C4 deficiency
Investigation of a patient with an undetectable total complement (CH50) level
Low levels of complement may be due to inherited deficiencies, acquired deficiencies, or due to complement consumption (eg, as a consequence of infectious or autoimmune processes).
Absent C4 levels in the presence of normal C3 and C2 values are consistent with a C4 deficiency.
Normal results indicate both normal C4 protein levels and normal functional activity.
In hereditary angioedema, a disorder caused by C1 esterase inhibitor deficiency, absent or low C4 and C2 values are seen in the presence of normal C3 (due to activation and consumption of C4 and C2).
The total complement assay (COM / Complement, Total, Serum) should be used as a screen for suspected complement deficiencies before ordering individual complement component assays. A deficiency of an individual component of the complement cascade will result in an undetectable total complement level.
Absent (or low) C4 functional levels in the presence of normal C4 antigen levels should be replicated with a new serum specimen to confirm that C4 inactivation did not occur during shipping.
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