Complement deficiencies

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Immunodeficiency Affecting Cellular and Humoral Immunity
Combined Immunodeficiency
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Congenital Defects of Phagocytes
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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: Sabawoon Mirwais, M.B.B.S, M.D.[2], Zahir Ali Shaikh, MD[3], Anmol Pitliya, M.B.B.S. M.D.[4]

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.

Classification

Complement Deficiencies

Susceptibility to infections

HIGH

LOW

Disseminated Neisserial infections

Recurrent pyogenic infections

SLE like syndrome

Atypical hemolytic uremic syndrome (aHUS)

Others

Absent CH50 & AH50 hemolytic activity, defective bacterial activity

Normal CH50, Absent AH50 hemolytic activity

C3 loss-of-function

C1Q deficiency: C1QA, C1QB, C1QC

C3 gain-of-function

C1-Inhibitor (C1NH)

C5 deficiency

Properdin deficiency

Mannan-binding lectin serine protease 2 (MASP2) deficiency

C1R deficiency

Factor B gain-of-function

Membrane attack complex inhibitor (CD59) deficiency

C6 deficiency

Factor D deficiency

Ficolin-3 (FCN3) deficiency

C1S deficiency

Factor H deficiency

Decay accelerating factor (DAF) or CD55 deficiency

C7 deficiency

Factor B loss-of-function

C2 deficiency

Factor H-related protein deficiencies

C8 deficiency

C4 deficiency

Factor I deficiency

C9 deficiency

Thrombomodulin deficiency

Membrane cofactor protein (MCP) deficiency

Disseminated Neisserial Infections

C5 Deficiency

• C5 deficiency is the basis of lack of phagocytosis-enhancing activity of serum.
• C5 deficiency leads to the failure to form the membrane attack complex (MAC) which is responsible for the lytic action of the complement.
• It is associated with recurrent disseminated gonococcal infection.
• Patients present with recurrent meningitis and meningococcemia, as well as recurrent purulent otitis media.

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).
• C6 deficiency is a genetic disorder presenting as an increased susceptibility to invasive Neisseria meningitidis infections.
• 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.

C7 Deficiency

• C7 is part of the membrane attack complex (MAC) and deficiency of this complement protein leads to the loss of complement lytic function.
• Patients with C7 deficiency present with recurrent meningococcal infection.
• It can also rarely present with severe and aggressive pyoderma gangrenosum.
• Patients can also suffer from recurrent otitis media, tonsilitis and chronic mucopurulent rhinitis with subsequent pansinusitis complicated by nasal polyposis.
• 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.
• Patients suffer from recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes.
• It can present with juvenile chronic arthritis.
• Prophylaxis with conjugate polysaccharide vaccines is recommended and antibiotic prophylaxis should be considered in individual cases.

C9 Deficiency

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

Properdin Deficiency

• Properdin, a part of the innate immune system, is a positive regulatory factor of the alternative complement pathway that binds to the microbial surfaces and stabilizes C3b, Bb convertase.

• Properdin deficiency is associated with a heightened susceptibility to Neisseria species.
• Patients can present with severe pneumococcal and Haemophilus influenza infections.
• Recurrent infections are extremely rare, indicating a capacity for properdin-deficient individuals to develop-mediated defences against subsequent infections, hence promoting bactericidal and phagocytic activity via the intact classical complement pathway.

Factor D Deficiency

• Factor D is the initial obligatory and rate-limiting catalytic component in the alternative complement pathway.
• 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.
• A rare case of pneumococcal neonatal sepsis in infants with factor D deficiency has also been documented.

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).
• 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.
• 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.
• The deficiency is classically defined as mannan-binding lectin serine protease 2 (MASP2) protein level of less than 100 ng/ml.
• 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.
• 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 pattern.
• 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.
• The consequences of Ficolin-3 (FCN3) deficiency are not clear-cut and it may act as a disease modifier.
• 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.
• Prematurely born infants with this deficiency have developed necrotizing enterocolitis followed by recurrent skin infections with Staphylococcus aureus.
• It can present with nephrotic syndrome due to membranous nephropathy in adults.

Factor B Loss-of-Function

• Factor B loss-of-function mutation has an autosomal recessive inheritance.
• 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.
• It has 2 different forms, absent C1Q protein or presence of a dysfunctional molecule.
• 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.
• Patients with cutaneous disorders can present with vesicles, hyperpigmentation, and atrophic areas with exacerbation upon light exposure.
• 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.
• 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.

C1R Deficiency

• C1R is the catalytic subunit of complement component C1.
• Clinical features include discoid lupus erythematosus, nondeforming rheumatoid-like arthritis, mild nephritis, and reurrent rhinobronchitis.
• Missense or in-frame insertion/deletion mutations in the C1R gene results in Ehlers-Danlos syndrome periodontal type 1 (EDSPD1).
• C1R deficiency usually accompanies a deficiency of C1S.

C1S Deficiency

• C1S is a catalytic subunit of the complement component C1.
• C1S deficiency is usually reported with a deficiency of C1R.
• Patients can present with systemic lupus erythematosus (SLE)-like syndrome and chronic glomerulonephritis.
• It can result in the absence of classic complement (CH50) pathway activity.
• Missense mutation and an in-frame deletion in the C1S gene results in Ehlers-Danlos syndrome periodontal type 2 (EDSPD2).

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.
• Patients can also present with discoid lupus erythematosus, polyarteritis, membranoproliferative glomerulonephritis, cutaneous vasculitis, sicca syndrome, and seropositive rheumatoid arthritis.

C4 Deficiency

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

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.
• C3 gain-of-function mutation follows an autosomal dominant inheritance leading to the increased activation of complement.
• It can present with glomerulonephritis and predispose individiuals to atypical hemolytic uremic syndrome, microhematuria, hypertension, and chronic renal failure.

Factor B Gain-of-Function

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

Factor H Deficiency

• Factor H is a serum glycoprotein that regulates the function of the alternative complement pathway in fluid phase and on cellular surfaces.
• Factor H deficiency is caused by a mutation in the gene encoding complement factor H on chromosome 1q31 and follows an autosomal dominant or recessive pattern of inheritance.
• It can manifest as multiple phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure.
• Renal pathologies include atypical hemolytic-uremic syndrome (aHUS), membranoproliferative glomerulonephritis type II (MPGN II), IgA nephropathy, and nonspecific hematuria or nephritis.
• Patients can also present with systemic lupus erythematosus (SLE) and neisserial infections.

Factor H-related Protein Deficiencies

• Factor H-related proteins comprise a group of 5 plasma proteins, CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5.
• Mutations, genetic deletions, duplications or rearrangements in the individual CFHR genes are associated with multiple diseases including atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephritis, dense deposit disease (DDD), CFHR5 nephropathy, IgA nephropathy, age related macular degeneration (AMD), and systemic lupus erythematosus (SLE).
• The deficiencies follow an autosomal dominant or recessive mode of inheritance with later onset and may present with autoantibodies to complement factor H.

Factor I Deficiency

• Factor I deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding complement factor I on chromosome 4q25 and has an autosomal recessive inheritance.
• Clinical features include bacterial meningitis due to Streptococcus pneumoniae and Neisseria meningitidis, otitis media, recurrent sinusitis, septic arthritis due to Staphylococcus epidermidis, recurrent pyogenic infections, bronchopneumonia, systemic vasculitis with purpura.
• The deficiency leads to uncontrolled activation of the alternative complement pathway which causes serum depletion of other complement components, especially C3.
• A progressive loss of renal function accompanied by proteinuria and hematuria has also been documented with renal biopsy showing focal segmental glomerulonephritis (FSGN) with glomerular deposits of immunoglobulins and complement C3, C4 fragments.

Thrombomodulin Deficiency

• Thrombomodulin, an anticoagulant glycoprotein, functions to modulate the activity of the hemostatic protease thrombin.
• Thrombomodulin deficiency has an autosomal dominant inheritance.
• It results in enhanced thrombus formation in a murine model of carotid artery thrombosis.
• It may also contribute to microvascular ischemia in the pathogenesis of diabetic neuropathy.
• The deficiency may also influence collagen production by fibroblasts in the wound matrix.

Membrane Cofactor Protein (MCP) Deficiency

• Membrane cofactor protein (MCP), a C3B/C4B-binding molecule of the complement system with cofactor activity for the factor I-dependent cleavage of C3B and C4B.
• Membrane Cofactor Protein (MCP) deficiency follows an autosomal dominant inheritance pattern.
• Partial membrane cofactor protein (MCP) deficiency with or without Clostridium dfficile infection can result in atypical hemolytic uremic syndrome (aHUS).
• The deficiency can also present with glomerulonephritis, infections, and decreased C3b binding.

Others

C1-Inhibitor (C1NH)

• C1-inhibitor (C1NH), a plasma protein involved in the regulation of the complement cascade, is a member of a large serine protease inhibitor (serpin) gene family.
• Mutations in the C1-inhibitor (C1NH) gene has been known to cause hereditary angioedema.
• Patients with hereditary angioedema type I (absent or low levels of an antigenically-normal protein) have a deletion of the C1-inhibitor gene or a truncated transcript because of a stop codon while hereditary angioedema type II (elevated or normal levels of a dysfunctional protein) patients have a single base substitution.
• C1-inhibitor (C1NH) deficiency can result in spontaneous activation of the complement pathway causing consumption of C4/C2 components.
• Patients with low levels of C1-inhibitor (C1NH) have been reported to have presented with vasculitic neuropathy.
• Acquired C1-inhibitor (C1NH) deficiency, causing angioedema, can be associated with benign or malignant B-cell lymphoproliferative disorders.

Membrane Attack Complex Inhibitor (CD59) Deficiency

• Membrane Attack Complex Inhibitor (CD59) deficiency is caused by mutation in the CD59 gene, which maps to chromosome 11p13.
• Pateints present with hemolytic anemia and immune-mediated polyneuropathy.

Decay Accelerating Factor (DAF) or CD55 Deficiency

• Decay accelerating factor (DAF) or CD59 deficiency leads to CHAPLE (complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy) syndrome which is characterized by abdominal pain and diarrhea, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption.
• Some patients also exhibit bowel inflammation, recurrent infections associated with hypogammaglobulinemia, and/or angiopathic thromboembolic disease.
• Affected children with CHAPLE syndrome have presented with growth retardation, edema, clubbing, iron-deficiency anemia, and hypoproteinemia with death occuring in multiple cases and on autopsy, the liver revealed hepatic vein stenosis with Budd-Chiari syndrome.