Complement deficiencies

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Immunodeficiency Affecting Cellular and Humoral Immunity

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Predominantly Antibody Deficiency

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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

  • Mannan-binding Lectin Serine Protease 2 (MASP2 deficiency has an autosomal recessive inheritance.[32]
  • The deficiency is classically defined as Mannan-binding Lectin Serine Protease 2 (MASP2) protein level of less than 100 ng/ml.[33][34]
  • 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.[35]
  • It is also associated with severe pneumococcal pneumonia and progressive lung fibrosis.

Ficolin-3 (FCN3) Deficiency

  • Ficolin-3 (FCN3) deficiency follows an autosomal recessive inheritance.[36][37]
  • Ficolin-3 (FCN3), also known as H-ficolin, activates the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system.[38][39]
  • The consequences of Ficolin-3 (FCN3) deficiency are not clear-cut and it may act as a disease modifier.[40]
  • Patients may show increased susceptibility to infection in the perinatal or neonatal period and autoimmune diseases as adults.
  • Clinical features include brain abscesses, recurrent warts on the fingers, pneumonia, and selective deficient antibody response to pneumococcal polysaccharide vaccine.[41][42]
  • Prematurely born infants with this deficiency have developed necrotizng enterocolitis followed by recurrent skin infections with Staphylococcus aureus.[43]
  • It can present with nephrotic syndrome due to membranous nephropathy in adults.[44]

Factor B Loss-of-Fucntion (CFB LOF)

  • Factor B loss-of-function mutation has an autosomal recessive inheritance.[45]
  • It leads to the failure of activation of alternative complement pathway.
  • Patients are susceptible to infections with encapsulated organisms.

SLE-like Syndrome

C1q Deficiency

  • C1q Deficiency can be caused by homozygous mutation in the C1QA, C1QB or C1QC gene.[46][47][48][49]
  • It has 2 different forms, absent C1q protein or presence of a dysfunctional molecule.[50][51]
  • It is characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE), or SLE-like illnesses, such as discoid lupus erythematosus, fever, joint pain, and oral ulceration.[52]
  • Patients with cutaneous disorders can present with vesicles, hyperpigmentation, and atrophic areas with exacerbation upon light exposure.[53]
  • It can present with the loss of eyelashes, eyebrows, and scalp hair.
  • Patients with episodes of pneumonia, septicemia, bacterial meningitis, and bacterial keratitis have also been reported.[54][55]
  • Patients can present with a wide range of renal pathologies, such as chronic glomerulonephritis, renal failure, and with biopsy results showing mesangioproliferative glomerulonephritis, IgA nephropathy, membranous glomerulopathy, deposition of immune complexes, and tubulointerstitial abnormalities.[56][57][58]

C1r Deficiency

  • C1r is the catalytic subunit of complement component C1.[59]
  • Clinical features include discoid lupus erythematosus, nondeforming rheumatoid-like arthritis, mild nephritis, and reurrent rhinobronchitis.[60]
  • Missense or in-frame insertion/deletion mutations in the C1r gene results in Ehlers-Danlos syndrome, periodontal type 1 (EDSPD1).[61]
  • C1r deficiency usually accompanies a deficiency of C1s.[62]

C1s Deficiency

  • C1s is a catalytic subunit of the complement component C1.[59]
  • C1s deficiency is usually reported with a deficiency of C1r.[59]
  • Patients can present with systemic lupus erythematosus (SLE)-like syndrome and chronic glomerulonephritis.[63]
  • It can result in the absence of classic complement (CH50) pathway activity.[64]
  • Missense mutation and an in-frame deletion in the C1s gene results in Ehlers-Danlos syndrome, periodontal type 2 (EDSPD2).[61]

C2 Deficiency

  • C2 deficiency is caused by homozygous or compound heterozygous mutation in the C2 gene on chromosome 6p21.
  • Majority of the patients with this deficiency have autoimmune diseases, most commonly systemic lupus erythematosus (SLE), Henoch-Schonlein purpura, or polymyositis.[65][66]
  • Patients can also present with discoid lupus erythematosus, polyarteritis, membranoproliferative glomerulonephritis, cutaneous vasculitis, sicca syndrome, and seropositive rheumatoid arthritis.[67][68][69]

C4 Deficiency

  • C4 complement component is encoded by 2 distinct but closely linked genes, C4A and C4B.[70]
  • It has an autosomal recessive inheritance.[71]
  • C4 partial deficiency (either C4A or C4B) is common and has a modest effect on the host defense.[71]
  • Complete C4 deficiency is associated with renal disease presenting as severe Henoch-Schonlein purpura and patients can develop hypertension, nephrotic syndrome requriring hempdialysis.[72]
  • Homozygous deficiency of C4A is associated with systemic lupus erythematosus (SLE) and type I diabetes mellitus.[73]
  • Homozygous deficiency of C4B is associated with susceptibility to bacterial meningitis.[74]
  • C4 deficiency is a predisposing factor for Streptococcus pneumoniae-induced autoantibody production.[75]

Atypical Hemolytic Uremic Syndrome (aHUS)

C3 Gain-of-Function

  • Complement component C3 plays a central role in the activation of all 3 complement pathways, classical, alternative, and lectin.[76]
  • C3 gain-of-function mutation follows an autosomal dominant inheritance leading to the increased activation of complement.[71]
  • It can present with glomerulonephritis and predispose individiuals to atypical hemolytic uremic syndrome, microhematuria, hypertension, and chronic Renal Failure.[77][71]

Factor B Gain-of-Function

  • Factor B gain-of-function is a mutation in the CFB gene that has autosomal dominant inheritance.[71]
  • It leads to the increased alternate pathway hemolytic activity (AH50) by enhancing the generation of C3b.[71][78]
  • It increases the susceptibility of individuals to atypical hemolytic uremic syndrome-4 (aHUS4).

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. ↑ 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)
  33. ↑ 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)
  34. ↑ 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)
  35. ↑ 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)
  36. ↑ 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)
  37. ↑ Luregn J. Schlapbach, Steffen Thiel, Ulf Kessler, Roland A. Ammann, Christoph Aebi & Jens C. Jensenius (2011). "Congenital H-ficolin deficiency in premature infants with severe necrotising enterocolitis". Gut. 60 (10): 1438–1439. doi:10.1136/gut.2010.226027. PMID 20971976. Unknown parameter |month= ignored (help)
  38. ↑ Lea Munthe-Fog, Tina Hummelshoj, Christian Honore, Hans O. Madsen, Henrik Permin & Peter Garred (2009). "Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency". The New England journal of medicine. 360 (25): 2637–2644. doi:10.1056/NEJMoa0900381. PMID 19535802. Unknown parameter |month= ignored (help)
  39. ↑ Mateusz Michalski, Anna St Swierzko, Izabela Pagowska-Klimek, Zofia I. Niemir, Karolina Mazerant, Iwona Domzalska-Popadiuk, Maciej Moll & Maciej Cedzynski (2015). "Primary Ficolin-3 deficiency--Is it associated with increased susceptibility to infections?". Immunobiology. 220 (6): 711–713. doi:10.1016/j.imbio.2015.01.003. PMID 25662573. Unknown parameter |month= ignored (help)
  40. ↑ Mateusz Michalski, Anna St Swierzko, Izabela Pagowska-Klimek, Zofia I. Niemir, Karolina Mazerant, Iwona Domzalska-Popadiuk, Maciej Moll & Maciej Cedzynski (2015). "Primary Ficolin-3 deficiency--Is it associated with increased susceptibility to infections?". Immunobiology. 220 (6): 711–713. doi:10.1016/j.imbio.2015.01.003. PMID 25662573. Unknown parameter |month= ignored (help)
  41. ↑ Lea Munthe-Fog, Tina Hummelshoj, Christian Honore, Hans O. Madsen, Henrik Permin & Peter Garred (2009). "Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency". The New England journal of medicine. 360 (25): 2637–2644. doi:10.1056/NEJMoa0900381. PMID 19535802. Unknown parameter |month= ignored (help)
  42. ↑ Mateusz Michalski, Anna St Swierzko, Izabela Pagowska-Klimek, Zofia I. Niemir, Karolina Mazerant, Iwona Domzalska-Popadiuk, Maciej Moll & Maciej Cedzynski (2015). "Primary Ficolin-3 deficiency--Is it associated with increased susceptibility to infections?". Immunobiology. 220 (6): 711–713. doi:10.1016/j.imbio.2015.01.003. PMID 25662573. Unknown parameter |month= ignored (help)
  43. ↑ Luregn J. Schlapbach, Steffen Thiel, Ulf Kessler, Roland A. Ammann, Christoph Aebi & Jens C. Jensenius (2011). "Congenital H-ficolin deficiency in premature infants with severe necrotising enterocolitis". Gut. 60 (10): 1438–1439. doi:10.1136/gut.2010.226027. PMID 20971976. Unknown parameter |month= ignored (help)
  44. ↑ Mateusz Michalski, Anna St Swierzko, Izabela Pagowska-Klimek, Zofia I. Niemir, Karolina Mazerant, Iwona Domzalska-Popadiuk, Maciej Moll & Maciej Cedzynski (2015). "Primary Ficolin-3 deficiency--Is it associated with increased susceptibility to infections?". Immunobiology. 220 (6): 711–713. doi:10.1016/j.imbio.2015.01.003. PMID 25662573. Unknown parameter |month= ignored (help)
  45. ↑ 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)
  46. ↑ R. Topaloglu, A. Bakkaloglu, J. H. Slingsby, M. J. Mihatsch, M. Pascual, P. Norsworthy, B. J. Morley, U. Saatci, J. A. Schifferli & M. J. Walport (1996). "Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family". Kidney international. 50 (2): 635–642. PMID 8840296. Unknown parameter |month= ignored (help)
  47. ↑ F. Petry, A. I. Berkel & M. Loos (1997). "Multiple identification of a particular type of hereditary C1q deficiency in the Turkish population: review of the cases and additional genetic and functional analysis". Human genetics. 100 (1): 51–56. PMID 9225968. Unknown parameter |month= ignored (help)
  48. ↑ J. H. Slingsby, P. Norsworthy, G. Pearce, A. K. Vaishnaw, H. Issler, B. J. Morley & M. J. Walport (1996). "Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families". Arthritis and rheumatism. 39 (4): 663–670. PMID 8630118. Unknown parameter |month= ignored (help)
  49. ↑ Yousuke Higuchi, Junya Shimizu, Michiyo Hatanaka, Etsuko Kitano, Hajime Kitamura, Hidetoshi Takada, Masataka Ishimura, Toshiro Hara, Osamu Ohara, Kenji Asagoe & Toshihide Kubo (2013). "The identification of a novel splicing mutation in C1qB in a Japanese family with C1q deficiency: a case report". Pediatric rheumatology online journal. 11 (1): 41. doi:10.1186/1546-0096-11-41. PMID 24160257. Unknown parameter |month= ignored (help)
  50. ↑ R. Topaloglu, A. Bakkaloglu, J. H. Slingsby, M. J. Mihatsch, M. Pascual, P. Norsworthy, B. J. Morley, U. Saatci, J. A. Schifferli & M. J. Walport (1996). "Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family". Kidney international. 50 (2): 635–642. PMID 8840296. Unknown parameter |month= ignored (help)
  51. ↑ G. Vassallo, R. W. Newton, S. E. Chieng, M. R. Haeney, A. Shabani & P. D. Arkwright (2007). "Clinical variability and characteristic autoantibody profile in primary C1q complement deficiency". Rheumatology (Oxford, England). 46 (10): 1612–1614. doi:10.1093/rheumatology/kem207. PMID 17890276. Unknown parameter |month= ignored (help)
  52. ↑ Yousuke Higuchi, Junya Shimizu, Michiyo Hatanaka, Etsuko Kitano, Hajime Kitamura, Hidetoshi Takada, Masataka Ishimura, Toshiro Hara, Osamu Ohara, Kenji Asagoe & Toshihide Kubo (2013). "The identification of a novel splicing mutation in C1qB in a Japanese family with C1q deficiency: a case report". Pediatric rheumatology online journal. 11 (1): 41. doi:10.1186/1546-0096-11-41. PMID 24160257. Unknown parameter |month= ignored (help)
  53. ↑ F. Mampaso, J. Ecija, L. Fogue, I. Moneo, N. Gallego & F. Leyva-Cobian (1981). "Familial C1q deficiency in 3 siblings with glomerulonephritis and Rothmund-Thomson syndrome". Nephron. 28 (4): 179–185. doi:10.1159/000182170. PMID 7029321.
  54. ↑ Hanne Vibeke Marquart, Lone Schejbel, Anders Sjoholm, Ulla Martensson, Susan Nielsen, Anders Koch, Arne Svejgaard & Peter Garred (2007). "C1q deficiency in an Inuit family: identification of a new class of C1q disease-causing mutations". Clinical immunology (Orlando, Fla.). 124 (1): 33–40. doi:10.1016/j.clim.2007.03.547. PMID 17513176. Unknown parameter |month= ignored (help)
  55. ↑ L. Schejbel, L. Skattum, S. Hagelberg, A. Ahlin, B. Schiller, S. Berg, F. Genel, L. Truedsson & P. Garred (2011m). "Molecular basis of hereditary C1q deficiency--revisited: identification of several novel disease-causing mutations". Genes and immunity. 12 (8): 626–634. doi:10.1038/gene.2011.39. PMID 21654842. Unknown parameter |month= ignored (help)
  56. ↑ F. Mampaso, J. Ecija, L. Fogue, I. Moneo, N. Gallego & F. Leyva-Cobian (1981). "Familial C1q deficiency in 3 siblings with glomerulonephritis and Rothmund-Thomson syndrome". Nephron. 28 (4): 179–185. doi:10.1159/000182170. PMID 7029321.
  57. ↑ A. J. Hannema, J. C. Kluin-Nelemans, C. E. Hack, A. J. Eerenberg-Belmer, C. Mallee & H. P. van Helden (1984). "SLE like syndrome and functional deficiency of C1q in members of a large family". Clinical and experimental immunology. 55 (1): 106–114. PMID 6319055. Unknown parameter |month= ignored (help)
  58. ↑ R. Topaloglu, A. Bakkaloglu, J. H. Slingsby, M. J. Mihatsch, M. Pascual, P. Norsworthy, B. J. Morley, U. Saatci, J. A. Schifferli & M. J. Walport (1996). "Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family". Kidney international. 50 (2): 635–642. PMID 8840296. Unknown parameter |month= ignored (help)
  59. ↑ 59.0 59.1 59.2 Journet A, Tosi M (December 1986). "Cloning and sequencing of full-length cDNA encoding the precursor of human complement component C1r". Biochem. J. 240 (3): 783–7. PMC 1147487. PMID 3030286.
  60. ↑ Lee SL, Wallace SL, Barone R, Blum L, Chase PH (1978). "Familial deficiency of two subunits of the first component of complement. C1r and C1s associated with a lupus erythematosus-like disease". Arthritis Rheum. 21 (8): 958–67. PMID 737019.
  61. ↑ 61.0 61.1 Kapferer-Seebacher I, Pepin M, Werner R, Aitman TJ, Nordgren A, Stoiber H, Thielens N, Gaboriaud C, Amberger A, Schossig A, Gruber R, Giunta C, Bamshad M, Björck E, Chen C, Chitayat D, Dorschner M, Schmitt-Egenolf M, Hale CJ, Hanna D, Hennies HC, Heiss-Kisielewsky I, Lindstrand A, Lundberg P, Mitchell AL, Nickerson DA, Reinstein E, Rohrbach M, Romani N, Schmuth M, Silver R, Taylan F, Vandersteen A, Vandrovcova J, Weerakkody R, Yang M, Pope FM, Byers PH, Zschocke J (November 2016). "Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement". Am. J. Hum. Genet. 99 (5): 1005–1014. doi:10.1016/j.ajhg.2016.08.019. PMC 5097948. PMID 27745832.
  62. ↑ Loos M, Heinz HP (1986). "Component deficiencies. 1. The first component: C1q, C1r, C1s". Prog Allergy. 39: 212–31. PMID 3031693.
  63. ↑ Inoue N, Saito T, Masuda R, Suzuki Y, Ohtomi M, Sakiyama H (October 1998). "Selective complement C1s deficiency caused by homozygous four-base deletion in the C1s gene". Hum. Genet. 103 (4): 415–8. PMID 9856483.
  64. ↑ Dragon-Durey MA, Quartier P, Frémeaux-Bacchi V, Blouin J, de Barace C, Prieur AM, Weiss L, Fridman WH (June 2001). "Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases". J. Immunol. 166 (12): 7612–6. PMID 11390518.
  65. ↑ Cole FS, Whitehead AS, Auerbach HS, Lint T, Zeitz HJ, Kilbridge P, Colten HR (July 1985). "The molecular basis for genetic deficiency of the second component of human complement". N. Engl. J. Med. 313 (1): 11–6. doi:10.1056/NEJM198507043130103. PMID 2582254.
  66. ↑ Einstein LP, Alper CA, Bloch KJ, Herrin JT, Rosen FS, David JR, Colten HR (May 1975). "Biosynthetic defect in monocytes from human beings with genetic deficiency of the second component of complement". N. Engl. J. Med. 292 (22): 1169–71. doi:10.1056/NEJM197505292922207. PMID 1124106.
  67. ↑ Provost TT, Arnett FC, Reichlin M (October 1983). "Homozygous C2 deficiency, lupus erythematosus, and anti-Ro (SSA) antibodies". Arthritis Rheum. 26 (10): 1279–82. PMID 6605148.
  68. ↑ Friend, Peter S.; Handwerger, Barry S.; Kim, Youngki; Michael, Alfred F.; Yunis, Edmond J. (1975). "C2 deficiency in man. genetic relationship to a mixed lymphocyte reaction determinant (7a*)". Immunogenetics. 2 (1): 569–576. doi:10.1007/BF01572325. ISSN 0093-7711.
  69. ↑ D'Cruz D, Taylor J, Ahmed T, Asherson R, Khamashta M, Hughes GR (November 1992). "Complement factor 2 deficiency: a clinical and serological family study". Ann. Rheum. Dis. 51 (11): 1254–6. PMC 1012468. PMID 1361318.
  70. ↑ Awdeh ZL, Alper CA (June 1980). "Inherited structural polymorphism of the fourth component of human complement". Proc. Natl. Acad. Sci. U.S.A. 77 (6): 3576–80. PMC 349660. PMID 6932037.
  71. ↑ 71.0 71.1 71.2 71.3 71.4 71.5 Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, Chatila T, Crow YJ, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Puck J, Tang M, Tangye SG, Torgerson TR, Casanova JL, Sullivan KE (January 2018). "The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies". J. Clin. Immunol. 38 (1): 129–143. doi:10.1007/s10875-017-0465-8. PMC 5742599. PMID 29226301. Vancouver style error: initials (help)
  72. ↑ Lhotta K, König P, Hintner H, Spielberger M, Dittrich P (1990). "Renal disease in a patient with hereditary complete deficiency of the fourth component of complement". Nephron. 56 (2): 206–11. doi:10.1159/000186134. PMID 2243578.
  73. ↑ Huang DF, Siminovitch KA, Liu XY, Olee T, Olsen NJ, Berry C, Carson DA, Chen PP (April 1995). "Population and family studies of three disease-related polymorphic genes in systemic lupus erythematosus". J. Clin. Invest. 95 (4): 1766–72. doi:10.1172/JCI117854. PMC 295700. PMID 7706484.
  74. ↑ McKusick, Victor (1998). Mendelian inheritance in man : a catalog of human genes and genetic disorders. Baltimore: Johns Hopkins University Press. ISBN 9780801857423.
  75. ↑ Yammani RD, Leyva MA, Jennings RN, Haas KM (December 2014). "C4 Deficiency is a predisposing factor for Streptococcus pneumoniae-induced autoantibody production". J. Immunol. 193 (11): 5434–43. doi:10.4049/jimmunol.1401462. PMC 4373073. PMID 25339671.
  76. ↑ S Reis E, Falcão DA, Isaac L (March 2006). "Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H". Scand. J. Immunol. 63 (3): 155–68. doi:10.1111/j.1365-3083.2006.01729.x. PMID 16499568.
  77. ↑ Lhotta K, Janecke AR, Scheiring J, Petzlberger B, Giner T, Fally V, Würzner R, Zimmerhackl LB, Mayer G, Fremeaux-Bacchi V (August 2009). "A large family with a gain-of-function mutation of complement C3 predisposing to atypical hemolytic uremic syndrome, microhematuria, hypertension and chronic renal failure". Clin J Am Soc Nephrol. 4 (8): 1356–62. doi:10.2215/CJN.06281208. PMC 2723975. PMID 19590060.
  78. ↑ Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, López-Trascasa M, Sánchez-Corral P, Morgan BP, Rodríguez de Córdoba S (January 2007). "Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome". Proc. Natl. Acad. Sci. U.S.A. 104 (1): 240–5. doi:10.1073/pnas.0603420103. PMC 1765442. PMID 17182750.
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