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

  • 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

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