Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

C5b-C9 Deficiency

  • Anete Sevciovic GrumachEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_3-1



C5b-C9 represents the terminal pathway of complement system. Complete genetic deficiency of any of those components can lead to increased risk of meningococcal disease, often recurrent infections caused by unusual serogroups.


Three major activation pathways, the classical, the alternative, and the lectin pathway, lead to a common pathway, the terminal complement system that consists of components five to nine. All pathways lead to cleavage of C3, and when additional C3b molecules are bound to the C3 convertases, this results in formation of C5 convertases (C4b2a3b) and subsequently cleavage of C5. This splits C5 into the small C5a molecule, and the larger C5b molecule, which is the initial component of the membrane attack complex (MAC). C5a is a strong chemotactic factor and an anaphylatoxin; it has an immunostimulatory role which also participates in the pathological process including the response to sepsis (Grimnes et al. 2011). The C5b fragment can then form a complex with C6, C7, C8, and a number of C9 molecules creating the MAC (C5b-C9). On cell membranes, MAC is capable of forming transmembrane channels through which ions migrate, leading to cell lysis and cell death.

Components six to nine are related plasma proteins, which differ in size and complexity. Components C6, C7, and C9 are single-chain serum proteins which interact with each other to become a functional unit and are also biochemically and structurally very similar (Würzner et al. 1998). Furthermore, they are coded by closely linked genes in proximity on chromosome 5p13. All genes are also strongly structurally related and likely derived from one common ancestor (Würzner et al. 1998). Both the C6 and C7 genes are polymorphic and are close homologues of the C8α, C8β, and C9 genes (Hobart et al. 1995). C8A, C8B, and C8G genes encode the α-, β-, and γ-subunits of C8, respectively. Genetic linkage and chromosomal localization studies have established that C8A and C8B are linked closely on chromosome 1p32. Significant protein sequence similarity exists between C8α and C8β and also the other terminal components, C6, C7, and C9, whereas C8γ is a member of the lipocalin family and is not related to any other complement component. The C8G gene is located on 9q22.3–q32 close to a cluster of other lipocalin genes (Lovelace et al. 2011).

C5b-9 Deficiency/Late Component Complement Deficiency (LCCD)

Genetically determined human deficiencies of any of the terminal complement components are associated with increased susceptibility to Neisseria meningitidis and N. gonorrhoeae infections indicating that the serum bactericidal function of MAC is important for the defense against neisserial infections (Ross and Densen 1984; Figueroa and Densen 1991; Sjoholm et al. 2006; Würzner et al. 1992). These organisms either possess a capsular polysaccharide, which precludes successful phagocytosis, or can invade cells and propagate intracellularly. Neisseriae are capable of intracellular survival. The association between the inabilities to form the lytic plug of the complement system with infection by these organisms implies that extracellular lysis is of major physiological importance as a mechanism of killing these organisms (Walport 1993). In either case, phagocytosis is ineffective. Fortunately, these organisms are susceptible to the serum bactericidal effect of MAC.

Meningococci colonize the nasopharynx of 5–15% of individuals in areas of non-endemicity, and a larger proportion of individuals may be colonized during epidemics of invasive disease (Ross and Densen 1984). At the time of birth, individuals have bactericidal antibodies (transplacental transfer of maternal antibodies) against meningococci. These maternal antibodies however disappear after a few months. After maturation of their own immune system and after contact with pathogenic as well as nonpathogenic Neisseria and cross-reacting gram-negative bacteria, individuals develop meningococcal antibodies (Bols et al. 1993).

Terminal complement pathway and properdin deficiencies expose the patients to a higher risk of invasive meningococcal infections, reaching up to 5000–7000 times in comparison with general population (Figueroa and Densen 1991; Mayilyan 2012; Platonov et al. 1992). In European countries, 61% of Neisseria meningitidis infections occurred in patients with terminal pathway defects (Turley et al. 2015). Unusual meningococcal serogroups (particularly Y, W-135, and X) usually infect patients with complement deficiencies (Figueroa and Densen 1991; Ross and Densen 1984), and the frequency of these among patients with meningococcal disease caused by these serogroups is also increased (Fijen et al. 1989).

While the average age at the onset of the first meningococcal infection is 3 years in the general population, and 56% occurs before 5 years, the average age for complement deficiency patients is 17 years, and only 10% of the cases occur before 5 years of age. Previous infection with meningococcus in this group of immunodeficient patients does not reduce the risk of new episodes; relapses occur in 7.6% of those with deficiency of C5-C9, and recurrent disease (new infection more than 1 month after a previous episode) occurs in 45% (Ross and Densen 1984; Andreoni et al. 1993; Rosa et al. 2004). This could be explained in part by the fact that antibodies against subcapsular antigens, although bactericidal and protective, are poor opsonins; they offer little protection in patients with complement deficiency, as these patients do not have the proteins needed for the expression of bactericidal activity (Andreoni et al. 1993; Rosa et al. 2004). On the other side, in individuals with terminal complement deficiency, opsonization involving C3 and immunoglobulin prevents many other invasive infections by other bacterial species (Figueroa and Densen 1991; Pallares et al. 1996).

Multiple reports of autoimmune findings have been recorded (C5 deficiency with SLE-like symptoms, C6 deficiency with SLE-like symptoms and MPGN, C7 deficiency with scleroderma, rheumatoid arthritis, and with SLE-like syndrome, C9 deficiency, and IgA nephropathy), but no firm associations have been established (Frank 2000; Pickering et al. 2000; Barilla-La Barca and Atkinson 2003; O’Neil 2000; Yoshioka et al. 1992).


In a study of 7732 patients from Netherlands with meningococcal disease, the prevalence of complement deficiency was 3% (Fijen et al. 1999). When patients with unusual serotypes were examined, the prevalence of any complement deficiency was 33%, and the prevalence of C8 deficiency was 23% (Le Bastard et al. 1989). Platonov et al. (1993) evaluated 262 patients with meningococcal infection admitted to a hospital in Moscow for LCCD and four of them had their first episode of meningococcal infection (1.5%). Among patients with recurrent meningitis or meningococcemia in previous Soviet Union (USSR), 30% had LCCD. The median age of the individuals with LCCD at the time of this study was 27 years (range, 9–62), and the median age at the time of the first episode of meningococcal disease was 15 years (range, 1–46) (Platonov et al. 1993). According to the epidemic occurrence of meningococcal disease in previous USSR, prevalence of functional LCCD in the general population could be estimated as approximately 12 persons per 100,000. In Japan, a frequency of 11 per 100,000 was observed after evaluating 145,640 blood donors, similar to USSR observation (Inai et al. 1989). In countries where meningococcal disease is less common, the proportion of individuals with LCCD is higher.


Generally most inherited disorders of the complement system leading to deficiency are autosomal recessive except for deficiency of C1-INH (autosomal dominant), deficiency of properdin (X-linked) and MBL, and Factor I deficiencies (autosomal codominant) (Pettigrew et al. 2009). Complement deficiencies are usually caused by null alleles. These are alleles that do not produce functional protein. In most cases, heterozygotes produce one half of the normal plasma level of a specific complement protein, and homozygotes of null alleles usually produce undetectable levels. Interestingly, individuals who are heterozygotes for a null allele usually have normal total complement activity in a total hemolytic assay (CH50) (Pettigrew et al. 2009).


Both the frequency of different types of complement deficiency and the frequency of diseases associated with these deficiencies depend on the ethnic composition of the population and the incidence of the diseases in the population (Figueroa and Densen 1991). Complete C6 deficiencies have been reported in Japan and Afro-Americans living in the USA. The same defects had also been reported in the Western Cape, South Africa, as well as occurring in a patient from Afro-Caribbean origin. It has been reported in Netherlands too. Family studies have revealed some C6D (C6-deficient) siblings of index cases who have suffered no infections at all (Orren and Potter 2004; Zhu et al. 2000). C7 deficiency can occur with a relatively high frequency in certain populations as Jews of Moroccan Sephardic descent living in Israel or Irish individuals (Würzner et al. 1998; Halle et al. 2001). C8 is composed of three different subcomponents termed α, β, and γ. C8 α–γ deficiency has been predominantly reported amongst Afro-Caribbeans, Hispanics, and Japanese, whereas C8β deficiency is by far the most frequent in Caucasians (Ross and Densen 1984; Tedesco 1986; Inai et al. 1989; Ram et al. 2010; Mayilyan 2012). In contrast to the situation in Japan, where C9 deficiency has a very high incidence (0.045–0.104%) (Fukumori and Horiuchi 1998), it is a rare finding in Europe (Table 1).
Table 1

Components of terminal pathway of complement system, alleles, and chromosomal localization








Black Africans




Japanese, Africans, Afro-Americans, Afro-Caribbeans, Hispanics




Moroccan Sephardic Jews, Irish

C8 α-chain



Afro-Caribbeans, Hispanics, Japanese

C8 β-chain




C8 γ-chain



Afro-Caribbeans, Hispanics, Japanese





C5 Deficiency

C5 deficiency (C5D) has been diagnosed worldwide (Schejbel et al. 2013). It has been found in approximately 7% of Black African meningococcal disease cases in the Western Cape (Owen et al. 2015). The system in patients with C5 deficiency is normal up to factor C3. It contains normal opsonic activity which is mainly due to normal C3 levels but fails to generate adequate chemotactic activity and, even more important, lacks serum bactericidal activity of “serum-sensitive” bacteria such as Neisseria (Bols et al. 1993). C5 deficiency differs from deficiency of other terminal components in that C5a is not formed during activation. Since C5a is both a strong chemotactic factor and an anaphylatoxin, it could be expected that this deficiency would have other consequences regarding infection susceptibility. In the case of a meningococcal infection, opsonophagocytosis and intracellular killing could achieve elimination of meningococci by phagocytes, but this mechanism is hampered by defective chemotaxis (Figueroa and Densen 1991; Bols et al. 1993). However, the bacterial etiology in systemic infections does not differ (Figueroa and Densen 1991).

Nowadays, patients treated with a monoclonal antibody against C5 behave as genetically C5-deficient patients. That drug links specifically to C5 fraction of complement with high affinity, preventing the formation of C5-9 and leading to meningococcal susceptibility. According to French health system, meningococcal vaccination is recommended and prophylactic antibiotics with penicillin (Haut conseil de la santé publique 2012)

C6 Deficiency

Some individuals with inherited C6 deficiency who appeared to lack C6 by conventional hemolytic complement assays were unequivocally shown by a sensitive ELISA to have C6 at a concentration of 1–2% of normal mean (Würzner et al. 1991). Their C6 was able to integrate itself into the terminal complement complex (TCC) upon complement activation (Würzner et al. 1991). It was, furthermore, hemolytically active but structurally abnormal, as it was 14% smaller than normal C6. This condition has been designated subtotal C6 deficiency (C6SD). In contrast, the majority of C6-deficient individuals investigated by sensitive hemolytic assays and ELISA were found to completely lack C6 functional and antigenic activity and have been designated “quantitatively zero C6 deficient” (C6Q0) (Orren et al. 1992; Würzner et al. 1995). C6SD subjects do not appear to be more susceptible to neisserial infection than the population at large (Würzner et al. 1995). Some individuals come from families in which family members who are totally C6 deficient were ascertained by their history of meningococcal infection. Thus, we may assume that the C6SD subjects in these families were exposed to meningococci but did not become ill, perhaps because their very small amount of C6 protected them. If this assumption is true, C6SD subjects will be less likely to be identified than C6Q0 patients, who were ascertained because of meningococcal disease either in themselves or in a sibling (Ross and Densen 1984). C6 deficiency can be associated with subtotal C7 deficiency (Würzner et al. 1998).

C7 Deficiency

It is not always possible to distinguish genotypic total C7 deficiency from subtotal deficiency. A study of a patient with virtually no C7 in his circulation showed that he carried the same C6/C7D defects as the other C6/C7SD subjects, as well as another C7 defect. The presence of C5b6 in the circulation led to a consumption of the low amounts of secreted C7. In contrast, patients with the combined deficiency apparently do not have sufficient C6 to allow the production of C5b6, and these subjects have detectable levels of C7 in the circulation (Würzner et al. 1998; Fernie et al. 1996).

C8 Deficiency

C8 is an oligomeric protein composed of three nonidentical subunits (α, 64 kDa; β, 64 kDa; γ, 22 kDa). These subunits are arranged asymmetrically as a covalently linked α–γ heterodimer with a non-covalently associated β-chain. The α-subunit has a domain that interacts with the β-subunit, and it provides the binding site for C9 on C5b-8. The β-subunit has a domain that specifically allows recognition and binding of C8 to C5b-7. The γ-subunit, the function of which remains uncertain, is linked to the α-subunit by a disulfide bond. C8 deficiency may result from lack of the α–γ-chain or the β-chain (Arnold et al. 2009; Ross and Densen 1984).

C9 Deficiency

C9 deficiency leads to incomplete membrane attack complex formation and may therefore predispose to recurrent neisserial infections (Figueroa and Densen 1991). C9-deficient individuals have still some bactericidal activity (Nagata et al. 1989). The formation of the C5b-8 complex in absence of C9 has some protective effect, and it has been shown that sera from C9-deficient individuals can support lysis of antibody-coated sheep erythrocytes although the reaction is 100-fold slower than with normal serum (Lint et al. 1980).


Recurrent infections caused by N. meningitidis (or N. gonorrhoeae) should raise suspicion of a complement deficiency (Grumach and Kirschfink 2014). In the case of deficiency of a factor of the classical or terminal pathway, the total hemolytic complement level (CH50) will be undetectable or very low. Hemolytic assay evaluation alternative pathway (AP50) is also undetectable in the case of terminal components of complement system.

After this screening test, the determination of individual complement factors is mandatory. Low levels of multiple factors point to an acquired deficiencies. Many individuals may not be diagnosed because individuals with only one episode of meningococcal infection are seldom investigated (Orren and Potter 2004; de Marcellu et al. 2015) (Fig. 1).
Fig. 1

Laboratorial diagnosis of C5-9 deficiency


Prevention of disease in patients with known terminal component complement deficiency relies on antibiotic prophylaxis, vaccination, and hygienic measures (Skattum et al. 2011).

Antibodies against meningococcal polysaccharide capsule confer protection by the induction of complement-mediated bacteriolysis and by stimulation of Fc-mediated or C3b-mediated opsonophagocytosis (Schlesinger et al. 1994; Platonov et al. 2003). Vaccination can enhance opsonophagocytosis (Gomez-Lus et al. 2003), and vaccination with the tetravalent polysaccharide capsule vaccines A, C, Y, and W135 is recommended for terminal complement-deficient individuals (Centers for Disease Control and Prevention 2013; Platonov et al. 1995). Although in Europe and the USA, infections in complement-deficient individuals are frequently with the rare serogroup W135 or Y strains (Orren et al. 1994), serogroup B strains were nevertheless found responsible for about 20% of all infections in deficient patients (Ross and Densen 1984); moreover, in South Africa, serogroup B infections represented almost 50% of infections in complement-deficient individuals (Orren and Potter 2004). In the last years, vaccination against invasive meningococcal capsular group B disease is available and effective (Ladhani et al. 2014).

Antibiotic prophylaxis was used to protect the more vulnerable patients. And previous studies showed that antibiotics did lessen the risk of recurrent infections but frequently have poor patient acceptance and carry the risk of generating antibiotic-resistant strains (Potter et al. 1990; Schwartz 1991; Morgan and Orren 1998; Kuruvilla and de la Morena 2013).

The use of antibiotics as well as booster vaccination is in keeping with previous studies, which have shown that meningococcal vaccination reduces but does not eliminate the risk of meningococcal disease (Platonov et al. 2003).


Lower mortality from meningococcal disease had been reported in the deficient individual as compared with complement-sufficient persons (Platonov et al. 1993). However, there is no convincing evidence that primary meningococcal infection is milder in complement-deficient individuals (Orren and Potter 2004). It has been suggested that the generation of membrane attack complexes during excessive complement activation in meningococcal disease in complement-sufficient individuals may contribute to the activation and injury of circulating blood leukocytes and endothelial cells during meningococcal disease and that the absence of this effect may contribute to the lower mortality in individuals with LCCD (Brandtzaeg et al. 1989; Ross and Densen 1984; Platonov et al. 1993) (Table 2).
Table 2

Clinical characteristics of meningococcal meningitis in patients with C5b-C9 deficiency



General population

Neisseria infection






Age of first episode

17 years

3 years




Therapeutic failure




Y = 44%

Y = 11%




Modified from Ross and Densen (1984)



  1. Andreoni J, Käyhty H, Densen P. Vaccination and the role of capsular polysaccharide antibody in prevention of recurrent meningococcal disease in late complement component-deficient individuals. J Infect Dis. 1993;168:227–31.CrossRefPubMedGoogle Scholar
  2. Arnold DF, Roberts AG, Thomas A, Ferry B, Morgan BP, Chapel HA. Novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent meningococcal meningitis. J Clin Immunol. 2009;29:691–5.CrossRefPubMedGoogle Scholar
  3. Barilla-LaBarca ML, Atkinson JP. Rheumatic syndromes associated with complement deficiency. Curr Opin Rheumatol. 2003;15:55–60.CrossRefPubMedGoogle Scholar
  4. Bols A, Janssens J, Petermans W, Stevens E, Bobbaers H. Recurrent meningococcal infections in a patient with congenital C5 deficiency. Acta Clin Belg. 1993;48(10):42–7.CrossRefPubMedGoogle Scholar
  5. Brandtzaeg P, Mollnes TE, Kierulf P. Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis. 1989;160:58–65.CrossRefPubMedGoogle Scholar
  6. Centers for Disease Control and Prevention. Prevention and control of meningococcal disease. Recommendations of the advisory committee on immunization practices. Morbidity and mortality weekly report. 2013;62:2.Google Scholar
  7. de Marcellus C, Taha MK, Gaudelus J, Fremeaux-Bacchi V, de Pontual L, Guiddir T. Complement terminal fraction deficiency revealed at first invasive meningococcal infection. Arch Pediatr. 2015;22(3):296–9.CrossRefPubMedGoogle Scholar
  8. Fernie BA, Würzner R, Orren A, Morgan BP, Potter PC, Platonov AE, Vershinina IV, Shipulin GA, Lachmann PJ, Hobart MJ. Molecular bases of combined subtotal deficiencies of C6 and C7; and theis effects in combination with other C6 and C7 deficiencies. J Immunol. 1996;157:3648–57.PubMedGoogle Scholar
  9. Figueroa JE, Densen P. Infectious diseases associated with complemente deficiencies. Clin Microbiol Rev. 1991;4:359–95.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Fijen CA, Kuijper EJ, Hannema AJ, Sjöholm AG, van Putten JP. Complement deficiencies in patients over ten years old with meningococcal disease due to uncommon serogroups. Lancet. 1989;2:585–8.CrossRefPubMedGoogle Scholar
  11. Fijen CA, Kuijper MT, Bulte MT, Daha MR, Dankert J. Assessment of complement deficiency in patients with meningococcal disease in the Netherlands. Clin Infect Dis. 1999;28:98–105.CrossRefPubMedGoogle Scholar
  12. Frank MM. Complement deficiencies. Pediatr Clin N Am. 2000;47:1339–54.CrossRefGoogle Scholar
  13. Fukumori Y, Horiuch T. Terminal complemente componente deficiencies in Japan. Exp Clin Immunogenet. 1998;15:244–8.CrossRefPubMedGoogle Scholar
  14. Gomez-Lus ML, Giménez MJ, Vázquez JA, Aguilar L, Anta L, Berrón S, Laguna B, Prieto J. Opsonophagocytosis versus complemente bactericidal killing as effectors following Neisseria meningitidis group C vaccination. Infection. 2003;31:51–4.CrossRefPubMedGoogle Scholar
  15. Grimnes G, Beckman H, Lappegård KT, Mollnes TE, Skogen V. Recurrent meningococcal sepsis in a presumptive immunocompetent host shown to be complement C5 deficient-a case report. APMIS. 2011;119(7):479–84.CrossRefPubMedGoogle Scholar
  16. Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61(2):110–7.CrossRefPubMedGoogle Scholar
  17. Halle D, Elsten D, Geudalia D, Sasson A, Shinar E, Schlesinger M, Zimran A. High prevalence of complement C7 deficiency among healthy blood donors of Moroccan Jewish ancestry. Am J Med Genet. 2001;99:325–7.CrossRefPubMedGoogle Scholar
  18. Haut conseil de la santé publique. Avis relatif à l’antibioprophylaxie et la caccination méningococcique des personnes traitées par eculizumab (Soliris 300 mg solution à diluer pour perfusion), séance du 8 novembre 2012.Google Scholar
  19. Hobart MJ, Fernie BA, DiScipio RG. Structure of the human C7 gene and comparison with the C6, C8A, C8B and C9 genes. J Immunol. 1995;154:5188–94.PubMedGoogle Scholar
  20. Inai S, Akagaki Y, Moriyama T, Fukumori Y, Yoshimura K, Ohnoki S, Yamaguchi H. Inherited deficiencies of the late-acting complement components other than C9 found among healthy blood donors. Int Arch Allergy Appl Immunol. 1989;90:274–9.CrossRefPubMedGoogle Scholar
  21. Kuruvilla M, de la Morena MT. Antibiotic prophylaxis in primary immune deficiency disorders. J Allergy Clin Immunol Pract. 2013;1:573–82.CrossRefPubMedGoogle Scholar
  22. Ladhani SN, Cordery R, Mandal S, Christensen H, Campbell H, Boirrow R, Ramsay ME, PHE VaPIBI Forum Members. Preventing secondary cases of invasive meningococcal capsular group B (Men B) disease using a recently-licensed, multi-component, protein-based vaccine (Bexsero ®). J Infect. 2014;69:470–80.CrossRefPubMedGoogle Scholar
  23. Le Bastard D, Riou JY, Konczaty H, Bourrillon A, Guibourdenche M. Neisseria meningitidis: Sérogroupe Y A propos de trente-huit observations. Pathol Biol. 1989;37(78):901–7.PubMedGoogle Scholar
  24. Lint TF, Zeitz HJ, Gewurz H. Inherited deficiency of the ninth component of complement in man. J Immunol. 1980;125:2252–7.Google Scholar
  25. Lovelace LL, Cooper CL, Sodetz JM, Lebioda L. Structure of human C8 protein provides mechanistic insight into membrane pore formation by complement. J Biol Chem. 2011;286(20):17585–92.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Mayilyan KR. Complement genetics, deficiencies, and disease associations. Protein Cell. 2012;3:487–96.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Morgan BP, Orren A. Vaccination against meningococcus in complement-deficient individuals. Clin Exp Immunol. 1998;114:327–9.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Nagata M, Hara T, Aoki T, Mizuno Y, Akeda H, Inaba S, Tsumoto K, Ueda K. Inherited deficiency of ninth component of complement: an increased risk of meningococcal meningitis. J Pediatr. 1989;11:260–4.CrossRefGoogle Scholar
  29. O’Neil KM. Complement deficiency. Clin Rev Allergy Immunol. 2000;19:83–108.CrossRefPubMedGoogle Scholar
  30. Orren A, Potter PC. Complement component C6 deficiency and susceptibility to Neisseria meningitidis infections. SAMJ. 2004;94(5):345–6.PubMedGoogle Scholar
  31. Orren A, Würzner R, Potter PC, Fernie BA, Coetzee S, Morgan BP, Lachmann PJ. Properties of a low molecular weight complement component C6 found in human subjects with subtotal C6 deficiency. Immunology. 1992;75:10–6.PubMedPubMedCentralGoogle Scholar
  32. Orren A, Caugant DA, Fijen CAP, Dankert J, van Schalkwyk EJ, Poolman JT, Coetzee GJ. Characterization of strains of Neisseria meningitides recovered from complement -normal and complement-deficient patients in the Cape, South Africa. J Clin Microbiol. 1994;32:2185–91.PubMedPubMedCentralGoogle Scholar
  33. Owen EP, Würzner R, Leisegang F, Rizkallah P, Whitelaw A, Simpson J, Thomas AD, Harris CL, Giles JL, Hellerud BC, Mollnes TE, Morgan BP, Potter PC, Orren A. A complement C5 gene mutation, c.754G>A:p.A252T, is common in the Western Cape, South Africa and found to be homozygous in seven percent of Black African meningococcal disease cases. Mol Immunol. 2015;64(1):170–6.CrossRefPubMedGoogle Scholar
  34. Pallares DE, Figueroa JE, Densen P, Giclas PC, Marschall GS. Invasive Haemophilus influenza type b infection in a child with familial deficiency of the beta subunit of the eigth component of complement. J Pediatr. 1996;128:102–3.CrossRefPubMedGoogle Scholar
  35. Pettigrew HD, Teuber SS, Gershwin E. Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009;1173:108–23.CrossRefPubMedGoogle Scholar
  36. Pickering MC, Botto M, Taylor P. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol. 2000;76:227–324.CrossRefPubMedGoogle Scholar
  37. Platonov AE, Beloborodor VB, Gabrilovitch DI, Khabarova VV, Serebrovskaya LV. Immunological evaluation of late complement component-deficient individuals. Clin Immunol Immunopathol. 1992;64(2):98–105.CrossRefPubMedGoogle Scholar
  38. Platonov AE, Beloborodov VB, Pavlova LI, Vershinina IV, Kayhty H. Vaccination of patients deficient in a late complement component with tetravalent meningococcal capsular polysaccharide vaccine. Clin Exp Immunol. 1995;100:32–9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Platonov AE, Beloborodov VB, Vershinina IV. Meningococcal disease in patients with late complement component deficiency: studies in the U.S.S.R. Medicine. 1993;72(6):374–92.CrossRefPubMedGoogle Scholar
  40. Platonov AE, Vershinina IV, Kuijper EJ, Borrow R, Käyhty H. Long term effects of vaccination of patients deficienct in a late complemente componente with a tetravalente meningococcal polysaccharide vaccine. Vaccine. 2003;11:4437–47.CrossRefGoogle Scholar
  41. Potter PC, Frasch CE, van der Sande WJM, Cooper RC, Patel Y, Orren A. Prophylaxis against Neisseria meningitidis infections and antibody responses in patients with deficiency of the sixth component of complement. J Infect Dis. 1990;161:932–7.CrossRefPubMedGoogle Scholar
  42. Ram S, Lewis LA, Rice PA. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev. 2010;23:740–80.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Rosa DD, Pasqualotto AC, de Quadros M, Prezzi SH. Deficiency of the eighth component of complement associated with recurrent meningococcal meningitis – case report and literature review. Braz J Infect Dis. 2004;8(4):328–30.CrossRefPubMedGoogle Scholar
  44. Ross SC, Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore). 1984;63(5):243–73.CrossRefGoogle Scholar
  45. Schejbel L, Fadnes D, Permin H, Lappegård KT, Garred P, Mollnes TE. Primary complement C5 deficiencies – molecular characterization and clinical review of two families. Immunobiology. 2013;218(10):1304–10.CrossRefPubMedGoogle Scholar
  46. Schlesinger M, Grienberg R, Levy J, Kayhty H, Levy R. Killing of meningococci by neutrophils: effect of vaccination on patients with complement deficiency. J Infect Dis. 1994;170:449–53.CrossRefPubMedGoogle Scholar
  47. Schwartz B. Chemoprophylaxis for bacterial infections: principles and application to meningococcal infections. Rev Infect Dis. 1991;13(Suppl. 2):S170–3.CrossRefPubMedGoogle Scholar
  48. Sjöholm AG, Jönsson G, Braconier JH, Sturfelt G, Truedsson L. Complement deficiency and disease: an update. Mol Immunol. 2006;43(1–2):78–85.CrossRefPubMedGoogle Scholar
  49. Skattum L, van Deuren M, van der Poll T, Truedsson L. Complement deficiency states and associated infections. Mol Immunol. 2011;48:1643–55.CrossRefPubMedGoogle Scholar
  50. Tedesco F. Component deficiencies. The eighth component. Prog Allergy. 1986;39:295–306.Google Scholar
  51. Turley AJ, Gathmann B, Bangs C, Bradbury M, Seneviratne S, Gonzalez-Granado LI, et al. Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe. J Clin Immunol. 2015; doi:10.1007/s10875-015-0137-5.PubMedGoogle Scholar
  52. Walport MJ. Inherited complemente deficiency – clues to the physiological activity of complemente in vivo. Q J Med. 1993;86:355–8.PubMedGoogle Scholar
  53. Würzner R, Orren A, Potter P, Morgan BP, Ponard D, Späth P, Brai M, Schulze M, Happe L, Götze O. Functionally active complement proteins C6 and C7 detected in C6- or C7-deficient individuals. Clin Exp Immunol. 1991;83:430–7.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Würzner R, Orren A, Lachmann PJ. Inherited deficiencies of the terminal components of human complement. Immunodefic Rev. 1992;3:123–47.PubMedGoogle Scholar
  55. Würzner R, Hobart MJ, Fernie BA, Mewar D, Potter PC, Orren A, Lachmann PJ. Molecular basis of subtotal complement C6 deficiency a carboxy-terminally truncated but functionally active C6. J Clin Invest. 1995;95:1877–83.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Würzner R, Witzel-Schlömp K, Tokunaga K, Fernie BA, Hobart MJ, Orren A. Reference typing report for complement componentes C6, C7 and C9 including mutations leading to deficiencies. Exp Clin Immunogenet. 1998;15:268–85.CrossRefPubMedGoogle Scholar
  57. Yoshioka K, Takemura T, Akano N, Okada M, Yagi K, Maki S, Inai S, Akita H, Koitabashi Y, Takekoshi Y. IgA nephropathy in patients with congenital C9 deficiency. Kidney Int. 1992;42(5):1253–8.CrossRefPubMedGoogle Scholar
  58. Zhu Z, Atkinson TP, Hovanky KJ, Boppana SB, Dai YL, Densen P, Go RC, Jablecki JS, Volanakis JE. High prevalence of complement component C6 deficiency among African-Americans in the South-Eastern USA. Clin Exp Immunol. 2000;119:305–10.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2016

Authors and Affiliations

  1. 1.Faculdade de Medicina ABCSanto AndreBrazil

Section editors and affiliations

  • Kathleen Sullivan
    • 1
  1. 1.University of PennsylvaniaPhiladelphiaUSA