The complement system is an intricate network of serum proteins that mediates humoral innate immunity through an amplification cascade that ultimately leads to recruitment of inflammatory cells or opsonisation or killing of pathogens. One effector arm of this network is the terminal pathway of complement, which leads to the formation of the membrane attack complex (MAC) composed of complement components C5b, C6, C7, C8 and C9. Upon formation of C5 convertases via the classical or alternative pathways of complement activation, C5b is generated from C5 by proteolytic cleavage, nucleating a series of association and polymerisation reactions of the MAC-constituting complement components that culminate in pore formation of pathogenic membranes.
Complement component 5 is the fifth component of complement, which plays an important role in inflammatory and cell killing processes. The Complement C5 protein is comprised of the C5 alpha and beta chains, which are linked by a disulfide bridge. Cleavage of the alpha chain by C5 convertase results in the formation of the C5a fragment, a potent anaphylatoxin and chemoattractant, and the C5b macromolecular cleavage product, a subunit of the membrane attack complex (MAC).
Inherited deficiency states of the membrane attack complex (MAC) component C5 are rare and often associated with increased risk of recurrent Neisseria infections. More than 50 cases with primary C5 deficiency have been reported. In spite of this, the molecular basis has only been documented in a few cases. Schejbel et al. investigated two unrelated Caucasian probands with C5 deficiency originating from Norway and Denmark, respectively, and found three previously undescribed mutations. With these data, thirteen mutations associated with complement component C5 deficiency have been described. By genetic screening of the family of the Norwegian patient, previously diagnosed as homozygous C5 deficient and suffering four Neisseria infections, an additional case of complement component C5 deficiency was discovered, who had experienced one episode of Neisseria infections. Detailed review of the clinical history of the patients and their healthy relatives did not reveal any differences between C5 deficient and sufficient individuals with regard to clinical presentation, apart from the susceptibility to Neisseria infections. Of note, one of the patients described here, and several C5 deficient patients from the literature had Neisseria meningitidis serotype B infections, which is not covered by the current vaccines. These data support the clinical guidelines for patients treated with C5 inhibitors, who are functional C5 deficient by the treatment.
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3. Schejbel L, et al. (2013). Primary complement C5 deficiencies–Molecular characterization and clinical review of two families. Immunobiology, 218(10), 1304-1310.