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Membrane Attack Complex/MAC Deficiency

Membrane Attack Complex/MAC Deficiency (Proteins | Antibodies | Genes | ELISA Kits)

C5 C6 C7 C8A
C8B C8G    

Membrane Attack Complex/MAC Deficiency Background

The terminal complement components, C5-9, form the cytolytic membrane attack complex / MAC and deficiency of any one of these proteins will block membrane attack complex / MAC formation. The membrane attack complex / MAC plays an important role in neutralizing Neisseria and deficiencies therefore predispose to infection with meningococci and gonococci. Deficient individuals typically present after the age of ten with recurrent episodes of meningococcal meningitis.

The very high prevalence of deficiencies of proteins of the membrane attack complex / MAC found in diverse racial groups from different parts of the world suggests that there may be a selective advantage to the heterozygous deficiency state. It has been suggested that the low mortality associated with meningococcal infection in patients with deficiency of a MAC component may be partly due to the absence of the systemic inflammatory consequences of production of the MAC.

Other features common to all of the terminal component deficiencies include disseminated gonococcal infections and, probably, a slightly increased incidence of immune complex disease. The reasons for this are uncertain, but one hypothesis is that MAC formation contributes to the efficient elimination of viruses and other microorganisms. Deficiency might slow the clearance of these organisms, allowing them to persist for long enough to evoke an abnormal immune response and hence disease.

Membrane Attack Complex/MAC: C5 Deficiency

C5 deficiency is rare, a total of only 27 cases having been reported to date. No C5 protein was detected in these cases. Deficiency of C5 not only blocks membrane attack complex / MAC formation but also removes the source of the anaphylatoxin, C5a. However, the effects of C5 deficiency are very similar to those of C6, C7 and C8 deficiency and it is not certain whether the loss of C5a as an effector of inflammation has any clinical consequences per se.

Membrane Attack Complex/MAC: C6 Deficiency

C6 deficiency is the second most common complement deficiency in Caucasoids. Over 50 individuals with homozygous deficiency have so far been described and its incidence in the Caucasian population is estimated to be about 1 in 60 000. At least 25% of the reported cases are healthy. Although most cases were reported to have no detectable C6 protein, the application of highly sensitive assay methods has recently shown that most deficient individuals have small amounts of dysfunctional protein.

Membrane Attack Complex/MAC: C7 Deficiency

C7 is structurally similar to, and genetically linked with, C6 but deficiency of C7 is less common in Caucasians. In contrast, C7 deficiency is the second most common complement deficiency in the Japanese (incidence about 1:25000). Deficient individuals have residual traces of C7, which is, presumably, dysfunctional. Two apparently unrelated cases of combined deficiency of C6 and C7 have been reported, reflecting the close genetic linkage of these components.

Membrane Attack Complex/MAC: C8 Deficiency

C8 is a complex molecule composed of three nonidentical chains ( α, β and γ ),each the product of a distinct gene. The α and γ chains are covalently linked in the intact protein and the β chain is noncovalently associated with the αγ complex. Deficiency of C8 may thus be the result of a defect in synthesis of either the αγ subunit or of the β chain. Only the C8β defect has been found in Caucasians whereas defects in the synthesis of C8αγ predominate in Negroes and Japanese. In both forms of deficiency the uninvolved subunit is present in serum, albeit at a diminished concentration. It has recently been shown that a dysfunctionalform of the affected subunit is also present in serum in many cases.

Membrane Attack Complex/MAC: C9 Deficiency

Deficiency of C9 is rare in Caucasians: only five cases have been reported. Of these, three presented with meningococcal disease and the others were healthy. However, in the Japanese population, C9 deficiency is by far the most common homozygous complement deficiency with an incidence approaching 1:1000, making this one of the most common genetic abnormalities in the Japanese population. The original population studies indicated that C9 deficiencyin Japan was without clinical consequence, but recently it has been shown that C9 deficiency confers a much increased risk of developing meningococcal meningitis, albeit less of a risk than deficiency of C7.

Membrane Attack Complex/MAC Deficiency References

1. Pettigrew H D, et al. (2009). Clinical significance of complement deficiencies. Annals of the New York Academy of Sciences, 1173(1), 108-123.
2. Skattum L, et al. (2010). Complement: deficiency diseases. eLS.
3. Morgan B P, et al. (1991). Complement deficiency and disease. Immunology today, 12(9), 301-306.
4. Botto M. (1999). C1q knock-out mice for the study of complement deficiency in autoimmune disease. Experimental and clinical immunogenetics, 15(4), 231-234.
5. Sjöholm A G, et al. (2006). Complement deficiency and disease: an update. Molecular immunology, 43(1), 78-85.