Complement deficiencies

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Classification

Immunodeficiency Affecting Cellular and Humoral Immunity

Combined Immunodeficiency

Predominantly Antibody Deficiency

Diseases of Immune Dysregulation

Congenital Defects of Phagocytes

Defects in Intrinsic and Innate Immunity

Auto-inflammatory Disorders

Complement Deficiencies

Phenocopies of Primary Immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2], Anmol Pitliya, M.B.B.S. M.D.[3]

Overview

The complement system is a biochemical cascade which helps clear pathogens from an organism. It belongs to the innate immune system. Complement deficiencies can be inherited or acquired (as a result of complement-consuming disease state). Complement deficiency states may predispose affected individuals to angioedema, collagen vascular disease, or infection due to encapsulated organisms, especially Neisseria meningitidis.[1]

Classification

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complement Deficiencies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Susceptibility to Infections
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIGH
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOW
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disseminated Nisserial Infections
 
 
 
 
 
Recurrent Pyogenic Infections
 
 
 
 
 
 
SLE like syndrome
 
 
 
Atypical hemolytic uremic syndrome
 
 
Others
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Absent CH50 & AH50 hemolytic activity, defective bacterial activity
 
 
 
Normal CH50, Absent AH50 hemolytic activity
 
 
 
 
 
C3LOF,C3,AR
 
 
 
 
 
 
 
C1q def: C1QA, C1QB, C1QC
 
 
 
 
C3GOF, C3, AD
 
 
 
C1 inhibitor SERPING1, AD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C5 def:,C5
 
 
 
 
Properdin def:, PFC, XL
 
 
 
MASP2 def:, MASP2, AR
 
 
 
 
 
 
 
C1r def:
 
 
 
 
FactorB, GOF, CFB, AD
 
 
 
Membrane attack complex inhibitor def:, CD59
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C6 def:, C6
 
 
 
 
Factor D def:, CFD, AR
 
 
 
Fincolin3 def:, FCN3, AR
 
 
 
 
 
 
 
C1s def:
 
 
 
 
Factor H def:, CFH, AD or AR
 
 
 
CD55 def:, (CHAPLE disease), AR
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C7 def:, C7+vasculitis
 
 
 
 
 
 
 
 
 
Factor B, CFB, LOF, AR
 
 
 
 
 
 
 
C2 def:
 
 
 
 
Factor H related protein def:, CFHR1-5, AR, AD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C8 def:, C8A, C8B, C8G
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C4 def:, C4A, C4B, AR
 
 
 
 
Factor I def:, AR
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C9 def:, C9 mild susceptibility
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombomodulin def:, THBD, AD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Membrane cofactor protein def:, CD46, AD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Disseminated Nisserial Infections

C5 Deficiency

C6 Deficiency

  • C6 is structurally similar to other terminal complement components, C5b, C7, C8, and C9, all of which participate in the formation of the membrane attack complex (MAC).[6]
  • C6 deficiency is a genetic disorder presenting as an increased susceptibility to invasive Neisseria meningitidis infections.[7]
  • Complete C6 deficiency presents with recurrent Neisseria meningitidis infection and it should be distinguished from subtotal C6 deficiency in which the complement protein is functionally active and there is no association with Neisserial infections.[8]

C7 Deficiency

  • C7 is part of the membrane attack complex (MAC) and the deficiency of this complement protein leads to the loss of complement lytic function.[9]
  • Patients with C7 deficiency present with recurrent meningococcal infection.[10]
  • It can also rarely present with severe and aggressive pyoderma gangrenum.[11]
  • Patients can also suffer from recurrent otitis media, tonsilitis and chronic mucopurulent rhinitis with subsequent pansinusitis complicated by nasal polyposis.[12]
  • Antibiotics prophylaxis can be used to decrease the number of ear nose and throat (ENT) infections.

C8 Deficiency

  • C8 deficiency results in the failure of membrane attack complex (MAC) assembly.[13]
  • Patients suffer from recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes.[14]
  • It can present with juvenile chronic arthritis.[15]
  • Prophylaxis with conjugate polysaccharide vaccines is recommended and antibiotic prophylaxis should be considered in individual cases.[16]

C9 Deficiency

  • C9 deficiency impairs the assembly of membrane attack complex (MAC) and results in the loss of complement lytic activity.
  • Patients have a significantly increased risk of developing meningococcal meningitis.[17]
  • Patients with this deficiency have also presented with SLE-like and sicca symptoms.[18]
  • An Arg95Stop mutation resulting in C9 deficiency is associated with membranoproliferative pattern of glomerular injury.[19]
  • Patients with paroxysmal nocturnal hemoglobinuria benefit by having high quality of life conferred by coexisting C9 deficiency.[20]

Properdin Deficiency

  • Properdin, a part of the innate immune system, is a positive regulatory factor of the altetnative complement pathway that binds to the microbial surfaces and stabilizes C3b, Bb convertase.[21]
  • Properdin deficiency is associated with a heightened susceptibility to Neisseria species.[22]
  • Patients can present with severe pneumococcal and Haemophilus influenza infections.[23][24]
  • Recurrent infections are extremely rare, indicating a capacity for properdin-deficient individuals to develop antibody-mediated defences against subsequent infections, hence promoting bactericidal and phagocytic activity via the intact classical pathway.[25][26]

Factor D Deficiency

  • Factor D is the initial obligatory and rate-limiting catalytic component in the alternative complement pathway.[27]
  • Factor D deficiency, an autosomal recessive immunologic disorder reflecting a defect in the alternative complement pathway, is characterized by the increased susceptibility to bacterial infections, particularly Neisseria infections.[28]
  • A rare case of pneumococcal neonatal sepsis in an infant with factor D deficiency has also been documented.[29]

Recurrent Pyogenic Infections

C3 Loss-of-Function

  • C3 loss-of-function leads to absent alternate pathway hemolytic activity (AH50) and complement pathway hemolytic activity (CH50).[30]
  • It results in defective opsonization and humoral response.
  • The loss-of-function mutation in C3 complement does not lead to familial disease in contrast to the gain-of-function mutation.[31]
  • It results in potential exacerbation of immune complex disorders.

Mannan-binding Lectin Serine Protease 2 (MASP2) Deficiency

  • MASP2 deficiency is classically defined as MASP2 protein level of less than 100 ng/ml.[32][33]
  • It leads to the defects in the complement system as it plays a role in the activation of the lectin pathway of the complement system.
  • Patients present with ulcerative colitis, erythema multiforme bullosum and SLE with favorable response to treatment with prednisolone, and other immunosuppressive drugs.[34]
  • It is also associated with severe pneumococcal pneumonia and progressive lung fibrosis.

References

  1. ↑ Michael Corvini, Christopher Randolph & Steven I. Aronin (2004). "Complement C7 deficiency presenting as recurrent aseptic meningitis". Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 93 (2): 200–205. doi:10.1016/S1081-1206(10)61476-7. PMID 15328683. Unknown parameter |month= ignored (help)
  2. ↑ Miller, Michael E.; Nilsson, Ulf R. (1970). "A Familial Deficiency of the Phagocytosis-Enhancing Activity of Serum Related to a Dysfunction of the Fifth Component of Complement (C5)". New England Journal of Medicine. 282 (7): 354–358. doi:10.1056/NEJM197002122820702. ISSN 0028-4793.
  3. ↑ A. Orren (2000). "Molecular mechanisms of complement component C6 deficiency; a hypervariable exon 6 region responsible for three of six reported defects". Clinical and experimental immunology. 119 (2): 255–258. PMID 10632659. Unknown parameter |month= ignored (help)
  4. ↑ R. Snyderman, D. T. Durack, G. A. McCarty, F. E. Ward & L. Meadows (1979). "Deficiency of the fifth component of complement in human subjects. Clinical, genetic and immunologic studies in a large kindred". The American journal of medicine. 67 (4): 638–645. PMID 495634. Unknown parameter |month= ignored (help)
  5. ↑ O. Sanal, M. Loos, F. Ersoy, G. Kanra, G. Secmeer & I. Tezcan (1992). "Complement component deficiencies and infection: C5, C8 and C3 deficiencies in three families". European journal of pediatrics. 151 (9): 676–679. PMID 1396929. Unknown parameter |month= ignored (help)
  6. ↑ Z. Zhu, T. P. Atkinson, K. T. Hovanky, S. B. Boppana, Y. L. Dai, P. Densen, R. C. Go, J. S. Jablecki & J. E. Volanakis (2000). "High prevalence of complement component C6 deficiency among African-Americans in the south-eastern USA". Clinical and experimental immunology. 119 (2): 305–310. PMID 10632667. Unknown parameter |month= ignored (help)
  7. ↑ M. R. Moya-Quiles, M. V. Bernardo-Pisa, P. Martinez, L. Gimeno, A. Bosch, G. Salgado, H. Martinez-Banaclocha, J. Eguia, J. A. Campillo, M. Muro, J. B. Vidal-Bugallo, M. R. Alvarez-Lopez & A. M. Garcia-Alonso (2013). "Complement component C6 deficiency in a Spanish family: implications for clinical and molecular diagnosis". Gene. 521 (1): 204–206. doi:10.1016/j.gene.2013.03.027. PMID 23537992. Unknown parameter |month= ignored (help)
  8. ↑ A. Orren (2000). "Molecular mechanisms of complement component C6 deficiency; a hypervariable exon 6 region responsible for three of six reported defects". Clinical and experimental immunology. 119 (2): 255–258. PMID 10632659. Unknown parameter |month= ignored (help)
  9. ↑ Sung Hoon Sim, Jung Yeon Heo, Eui-Chong Kim & Kang-Won Choe (2013). "A case of meningococcal sepsis and meningitis with complement 7 deficiency in a military trainee". Infection & chemotherapy. 45 (1): 94–98. doi:10.3947/ic.2013.45.1.94. PMID 24265955. Unknown parameter |month= ignored (help)
  10. ↑ L. J. Egan, A. Orren, J. Doherty, R. Wurzner & C. F. McCarthy (1994). "Hereditary deficiency of the seventh component of complement and recurrent meningococcal infection: investigations of an Irish family using a novel haemolytic screening assay for complement activity and C7 M/N allotyping". Epidemiology and infection. 113 (2): 275–281. PMID 7523157. Unknown parameter |month= ignored (help)
  11. ↑ L. J. Egan, A. Orren, J. Doherty, R. Wurzner & C. F. McCarthy (1994). "Hereditary deficiency of the seventh component of complement and recurrent meningococcal infection: investigations of an Irish family using a novel haemolytic screening assay for complement activity and C7 M/N allotyping". Epidemiology and infection. 113 (2): 275–281. PMID 7523157. Unknown parameter |month= ignored (help)
  12. ↑ A. Srotova, J. Litzman, S. Rumlarova, M. Drahosova, D. Bartonkova, I. Krcmova, A. Roberts, S. Jolles & P. Kralickova. "[Recurrent meningitis and inherited complement deficiency]". Epidemiologie, mikrobiologie, imunologie : casopis Spolecnosti pro epidemiologii a mikrobiologii Ceske lekarske spolecnosti J.E. Purkyne. 65 (4): 238–242. PMID 28078901.
  13. ↑ L. Saucedo, L. Ackermann, A. E. Platonov, A. Gewurz, R. M. Rakita & P. Densen (1995). "Delineation of additional genetic bases for C8 beta deficiency. Prevalence of null alleles and predominance of C-->T transition in their genesis". Journal of immunology (Baltimore, Md. : 1950). 155 (10): 5022–5028. PMID 7594510. Unknown parameter |month= ignored (help)
  14. ↑ S. C. Ross & P. Densen (1984). "Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency". Medicine. 63 (5): 243–273. PMID 6433145. Unknown parameter |month= ignored (help)
  15. ↑ N. M. Wulffraat, E. A. Sanders, C. A. Fijen, A. Hannema, W. Kuis & B. J. Zegers (1994). "Deficiency of the beta subunit of the eighth component of complement presenting as arthritis and exanthem". Arthritis and rheumatism. 37 (11): 1704–1706. PMID 7980680. Unknown parameter |month= ignored (help)
  16. ↑ A. Srotova, J. Litzman, S. Rumlarova, M. Drahosova, D. Bartonkova, I. Krcmova, A. Roberts, S. Jolles & P. Kralickova. "[Recurrent meningitis and inherited complement deficiency]". Epidemiologie, mikrobiologie, imunologie : casopis Spolecnosti pro epidemiologii a mikrobiologii Ceske lekarske spolecnosti J.E. Purkyne. 65 (4): 238–242. PMID 28078901.
  17. ↑ M. Nagata, T. Hara, T. Aoki, Y. Mizuno, H. Akeda, S. Inaba, K. Tsumoto & K. Ueda (1989). "Inherited deficiency of ninth component of complement: an increased risk of meningococcal meningitis". The Journal of pediatrics. 114 (2): 260–264. PMID 2915285. Unknown parameter |month= ignored (help)
  18. ↑ M. Sugimoto, M. Nishikai, A. Sato, Y. Suzuki, M. Nihei, J. Uchida & N. Mimura (1987). "SLE-like and sicca symptoms in late component (C9) complement deficiency". Annals of the rheumatic diseases. 46 (2): 153–155. PMID 3827337. Unknown parameter |month= ignored (help)
  19. ↑ Takayoshi Miura, Shin Goto, Seitaro Iguchi, Hisaki Shimada, Mitsuhiro Ueno, Shin-ichi Nishi & Ichiei Narita (2011). "Membranoproliferative pattern of glomerular injury associated with complement component 9 deficiency due to Arg95Stop mutation". Clinical and experimental nephrology. 15 (1): 86–91. doi:10.1007/s10157-010-0358-0. PMID 21057849. Unknown parameter |month= ignored (help)
  20. ↑ Nobuyoshi Hanaoka, Yoshiko Murakami, Masahide Nagata, Shoichi Nagakura, Yuji Yonemura, Takashi Sonoki, Taroh Kinoshita & Hideki Nakakuma (2012). "Persistently high quality of life conferred by coexisting congenital deficiency of terminal complement C9 in a paroxysmal nocturnal hemoglobinuria patient". Blood. 119 (16): 3866–3868. doi:10.1182/blood-2012-02-408161. PMID 22517879. Unknown parameter |month= ignored (help)
  21. ↑ S. M. Linton & B. P. Morgan (1999). "Properdin deficiency and meningococcal disease--identifying those most at risk". Clinical and experimental immunology. 118 (2): 189–191. PMID 10540177. Unknown parameter |month= ignored (help)
  22. ↑ Janeway, Charles (2001). Immunobiology 5 : the immune system in health and disease. New York: Garland Pub. ISBN 081533642X.
  23. ↑ E. W. Gelfand, C. P. Rao, J. O. Minta, T. Ham, D. B. Purkall & S. Ruddy (1987). "Inherited deficiency of properdin and C2 in a patient with recurrent bacteremia". The American journal of medicine. 82 (3 Spec No): 671–675. PMID 3826129. Unknown parameter |month= ignored (help)
  24. ↑ M. Schlesinger, U. Mashal, J. Levy & Z. Fishelson (1993). "Hereditary properdin deficiency in three families of Tunisian Jews". Acta paediatrica (Oslo, Norway : 1992). 82 (9): 744–747. PMID 8241670. Unknown parameter |month= ignored (help)
  25. ↑ S. M. Linton & B. P. Morgan (1999). "Properdin deficiency and meningococcal disease--identifying those most at risk". Clinical and experimental immunology. 118 (2): 189–191. PMID 10540177. Unknown parameter |month= ignored (help)
  26. ↑ A. G. Sjoholm (1990). "Inherited complement deficiency states: implications for immunity and immunological disease". APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 98 (10): 861–874. PMID 2147105. Unknown parameter |month= ignored (help)
  27. ↑ R. T. White, D. Damm, N. Hancock, B. S. Rosen, B. B. Lowell, P. Usher, J. S. Flier & B. M. Spiegelman (1992). "Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue". The Journal of biological chemistry. 267 (13): 9210–9213. PMID 1374388. Unknown parameter |month= ignored (help)
  28. ↑ D. H. Biesma, A. J. Hannema, H. van Velzen-Blad, L. Mulder, R. van Zwieten, I. Kluijt & D. Roos (2001). "A family with complement factor D deficiency". The Journal of clinical investigation. 108 (2): 233–240. doi:10.1172/JCI12023. PMID 11457876. Unknown parameter |month= ignored (help)
  29. ↑ S. J. Weiss, A. E. Ahmed & V. R. Bonagura (1998). "Complement factor D deficiency in an infant first seen with pneumococcal neonatal sepsis". The Journal of allergy and clinical immunology. 102 (6 Pt 1): 1043–1044. PMID 9847449. Unknown parameter |month= ignored (help)
  30. ↑ Aziz Bousfiha, Leila Jeddane, Capucine Picard, Fatima Ailal, H. Bobby Gaspar, Waleed Al-Herz, Talal Chatila, Yanick J. Crow, Charlotte Cunningham-Rundles, Amos Etzioni, Jose Luis Franco, Steven M. Holland, Christoph Klein, Tomohiro Morio, Hans D. Ochs, Eric Oksenhendler, Jennifer Puck, Mimi L. K. Tang, Stuart G. Tangye, Troy R. Torgerson, Jean-Laurent Casanova & Kathleen E. Sullivan (2018). "The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies". Journal of clinical immunology. 38 (1): 129–143. doi:10.1007/s10875-017-0465-8. PMID 29226301. Unknown parameter |month= ignored (help)
  31. ↑ Georgia Sfyroera, Daniel Ricklin, Edimara S. Reis, Hui Chen, Emilia L. Wu, Yiannis N. Kaznessis, Kristina N. Ekdahl, Bo Nilsson & John D. Lambris (2015). "Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity". Journal of immunology (Baltimore, Md. : 1950). 194 (7): 3305–3316. doi:10.4049/jimmunol.1402781. PMID 25712219. Unknown parameter |month= ignored (help)
  32. ↑ S. Thiel, R. Steffensen, I. J. Christensen, W. K. Ip, Y. L. Lau, I. J. M. Reason, H. Eiberg, M. Gadjeva, M. Ruseva & J. C. Jensenius (2007). "Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms". Genes and immunity. 8 (2): 154–163. doi:10.1038/sj.gene.6364373. PMID 17252003. Unknown parameter |month= ignored (help)
  33. ↑ Anna Sokolowska, Agnieszka Szala, Anna St Swierzko, Monika Kozinska, Tomasz Niemiec, Maria Blachnio, Ewa Augustynowicz-Kopec, Jaroslaw Dziadek & Maciej Cedzynski (2015). "Mannan-binding lectin-associated serine protease-2 (MASP-2) deficiency in two patients with pulmonary tuberculosis and one healthy control". Cellular & molecular immunology. 12 (1): 119–121. doi:10.1038/cmi.2014.19. PMID 24658431. Unknown parameter |month= ignored (help)
  34. ↑ Kristian Stengaard-Pedersen, Steffen Thiel, Mihaela Gadjeva, Mette Moller-Kristensen, Rikke Sorensen, Lise T. Jensen, Anders G. Sjoholm, Lars Fugger & Jens C. Jensenius (2003). "Inherited deficiency of mannan-binding lectin-associated serine protease 2". The New England journal of medicine. 349 (6): 554–560. doi:10.1056/NEJMoa022836. PMID 12904520. Unknown parameter |month= ignored (help)
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