Clinical Information

Complement proteins are components of the innate immune system. There are 3 pathways to complement activation: 1) the classical pathway, 2) the alternative (or properdin) pathway, and 3) the lectin (mannan-binding lectin) pathway. The classical pathway of the complement system is composed of a series of proteins that are activated in response to the presence of immune complexes. A single IgM molecule or 2 IgG molecules are sufficient to trigger activation of the recognition complex initiated by C1q. The activation process triggers a cascade that includes an amplification loop. The amplification loop is mediated by C3, with cleavage of a series of proteins, and results in 3 main end products: 1) anaphylatoxins that promote inflammation (C3a, C5a), 2) opsonization peptides that are chemotactic for neutrophils (C3b) and facilitate phagocytosis, and 3) the membrane attack complex (MAC), which promotes cell lysis.

Patients with deficiencies of the late complement proteins (C5, C6, C7, C8, and C9) are unable to form the MAC, and may have increased susceptibility to neisserial infections.

C8 deficiency is relatively rare, over 50 cases have been described. The C8 protein is comprised of 3 subunits: alpha, beta, and gamma. However, variants leading to deficiency have not been reported in C8 gamma, and the majority are in the C8 beta subunit. C8 deficiency is characterized by recurrent neisserial infections, particularly meningitis. Autoimmune disease (systemic lupus erythematosus-like) has also been reported. Given the 3 subunits, it is possible to have a low-normal C8 concentration but a nonfunctional protein, therefore the recommendation for testing is the functional assay.

For most of the complement proteins, a small number of cases have been described in which the protein is present but is nonfunctional. These rare cases require a functional assay to detect the deficiency.