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Diagnosis of first component of complement (C1) deficiency
Investigation of a patient with an absent total complement (CH50) level
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 (or 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.
The first component of complement (C1) is composed of 3 subunits designated as C1q, C1r, and C1s. C1q recognizes and binds to immunoglobulin complexed to antigen and initiates the complement cascade. Congenital deficiencies of any of the early complement components (C1-C4) result in an inability to generate the peptides that are necessary to clear immune complexes and to attract neutrophils or generate 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.
Inherited deficiency of C1 is rare. C1 deficiency is associated with increased incidence of immune complex disease (systemic lupus erythematosus [SLE], polymyositis, glomerulonephritis, and Henoch-Schonlein purpura), and SLE is the most common manifestation of C1 deficiency. The SLE associated with C1 deficiency is similar to SLE without complement deficiency, but the age of onset is often prior to puberty.
Low C1 levels have also been reported in patients with abnormal immunoglobulin levels (Bruton's and common variable hypogammaglobulinemia and severe combined immunodeficiency), and this is most likely due to increased catabolism.
Complement levels can be detected by antigen assays that quantitate the amount of the protein. 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.
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).
The measurement of C1q activity is an indicator of the amount of first component of complement (C1) present. Absent C1q levels in the presence of normal C3 and C4 values are consistent with a C1 deficiency. Low C1q levels in the presence of low C4 but normal C3 may indicate the presence of an acquired inhibitor (autoantibody) to C1 esterase inhibitor.
The total complement (CH50) 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 CH50.
Absent (or low) C1q functional levels in the presence of normal C1q antigen levels should be replicated with a new serum specimen to confirm that C1q inactivation did not occur during shipping.
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