eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Complement Deficiency

Author: Ruchir Agrawal, MD,, Chief, Allergy and Immunology, Aurora Sheboygan Clinic
Coauthor(s): Vishweswar Chilumkurti, MBBS, MPH, Rehabilitation Consultant, Career Employment Australia; Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: May 6, 2009

Introduction

Background

The complement system is a part of the immune system that is concerned with the innate immunity. It consists of numerous proteins that are activated by several triggering factors and start a chain of events in the human body. Because the pathway finally culminates in the creation of a cytolytic "membrane attack complex", it is a vital mechanism to fight infection.

In 1896, Jules Bordet, working at the Pasteur Institute in Paris, demonstrated that the factor in the blood serum capable of killing bacteria could be analyzed into two components: heat stable and heat labile. The heat labile component is what is now known as the "complement." The term complement was introduced by Ehrlich in the late 1890s.

In the 1900s, the complement system was understood to be a cytolytic system that primarily lysed bacteria and erythrocytes, which were sensitized with antibody. The complement system is currently known to contain at least 30 different proteins that are primarily formed in the liver and circulate in their inactive form. When activated, these proteins produce various complexes that play a major role in the innate and adaptive immune defense.

The 3 major pathways of complement activation are as follows:

1. The classical pathway (termed classical because it has been studied for >100 y and was the first pathway to be discovered)
2. The alternate pathway
3. The mannose-binding lectin (MBL) pathway

Deficiency of each component of the classical and alternate pathways is rare and comprises less than 1% of patients with primary immunodeficiency. Deficiency of components of the MBL pathway appears to be fairly common. Deficiency of early components of classical pathways has been associated with autoimmune disease, whereas deficiency of late components of complements lead to increased susceptibility to certain infections.

Pathophysiology

The binding of C1 to antigen-antibody complexes that contain immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies (subclasses IgG1, IgG2, and IgG3) activates the classical pathway. Only these Ig isotypes have complement-binding sites in the Fc portion (CH2 domain of IgG and CH3 domain of IgM).

C1 is a large multimeric protein complex composed of 3 subunits: C1q, C1r, and C1s. C1r and C1s are serine esterases. The C1q must bind to the 2 Fc portions of immunoglobulin (Ig) heavy chains to initiate the complement cascade. The binding of C1q to the immune complex leads to enzymatic activation of C1r, which, in turn, cleaves and activates C1s. Activated C1s cleaves C4 into C4a and C4b. A single activated C1s can cleave numerous molecules of C4. This process leads to continuous formation of C4b but is inhibited by C1 esterase inhibitor enzyme (C1INH). Deficiency of C1INH leads to uninhibited formation of C4b and C4a.

C4b has an internal thioester bond that allows C4b to form covalent amide or ester linkages with the immune complex or the cells coated with antibodies. C2 then complexes with immune complex or cell surface–bound C4b and is cleaved into C2a (soluble component) and C2b by C1s. The C2b remains physically associated with C4b on the target cell surface, forming classical pathway C3 convertase (C4bC2b) that proteolytically cleaves C3 into C3a and C3b.

Once C3 is cleaved, all 3 complement activation pathways share the same terminal complement components (C5-C9). The classical pathway is important in antigen-specific adaptive immune defense because it is activated by antigen-antibody complexes. Complement activation via the classical pathway effectively lyses antibody-coated pyogenic bacteria such as Streptococcus pneumoniae and Haemophilus influenzae and cells coated with antibodies (often microbe-infected cells).

Mannose-binding lectin pathway

MBL is an acute-phase protein. It is secreted by hepatocytes as a part of the innate immune defense and activates complement cascade without antigen-antibody complex.

The MBL binds to mannose residues of polysaccharide on the microbial surface. The MBL-associated serine proteinases MASP-1 and MASP-2, analogous to C1r and C1s, cleave C2 and C4, forming C4b/C2b C3 convertase. The terminal components of complement are then activated. The MASP-1 can also directly cleave C3. The MBL has high structural homology with C1q protein and can bind with C1r and C1s, with subsequent activation of C4 and C2. The MBL pathway is generally thought to provide initial antigen-independent immune defense by rapid activation of complement cascade, directly recognizing sugar residues of microbes.

Alternative complement pathway - Properdin, factor B, and factor D

This pathway is activated by the combination of factor B, factor D, and properdin.

C3 in the plasma is continuously cleaved at a low rate (C3 tick over). If active C3 (C3b) attaches to the cell surface that lacks complement regulators, it permits rapid amplification of the complement cascade. Namely, factor B binds to C3b bound to the cell surface by forming amide or ester bonds. Factor B is then cleaved by factor D to generate Bb, which forms alternate pathway C3 convertase (C3bBb). Properdin stabilizes the C3bBb complex.

After the C3 convertase cleaves another C3 bound to the convertase, C3b combines with C3 convertase complex to form the alternate pathway C5 convertase. The C5 convertase further activates C5 to C5b, and sequential binding of terminal components C6, C7, C8, and C9 forms the membrane attack complex (MAC). The alternate pathway, along with the MBL pathway, plays an important role in innate immune defense in an antigen-independent manner. Moreover, even when C3b is generated by the other two pathways, it can form a complex with Bb that can further cleave more C3. Thus, the alternative pathway C3 convertase also amplifies complement activation initiated by other pathways.

C3 component

The central event in complement activation is proteolysis of C3, which produces C3b and C3a. As described above, C3b that is covalently attached to the cell surface or antigen-antibody complex initiates late steps of complement activation common to all 3 pathways, leading to the formation of lipid-soluble pore structures of the MAC. Along with C5a and C4a, C3a functions as an anaphylatoxin, inducing degranulation of mast cells and basophils. They also function as chemotactic factors for leukocytes. C3b is cleaved into C3d, C3dg, and iC3b (inactive C3b) by factor I. C3b and C3b cleavage products bind to complement receptors expressed on various cells and initiate other immune responses. Membrane-bound C3b and iC3b act as opsonins by binding receptors on neutrophils and macrophages. C3d and C3dg augment B-cell responses to antigen.

Late complement components - C5-C9

Converting C5 to C5a and C5b marks the activation of the terminal complement components. These events, in turn, lead to the formation of MAC by C5, C6, C7, C8, and C9. The MAC has a hydrophilic center that increases leakage of water and ions through the cell membrane, causing osmotic lysis and cell death.

Regulatory proteins

• C1INH: This is an inhibitory protein that regulates the classical pathway by covalently attaching to C1r2-C1s2, which dissociates C1r2-C1s2 tetramer from C1q and stops activation of the classical pathway.
• C4BP: This regulates the classical pathway by dissembling the C4bC2b complex. C4BP binds to C4b and blocks binding of C2b. Decay-accelerating factor (DAF) and complement receptor 1 (CR1) also bind to C4b to block C4b/C2b complex formation. DAF also displaces Bb from C3b.
• Factor I: Factor I regulates the complement activation by cleaving C3b. Factor I cleaves cell membrane–associated C3b into iC3b, C3d, and C3dg. It also cleaves C4b. CD46, factor H, C4BP, and CR1 all serve as cofactors for factor I–mediated cleavage of C3b/C4b.
• Factor H: Factor H promotes conversion of C3b to iC3b with factor I and displaces Bb from the alternate pathway C3 convertase (C3bBb). Cell membrane rich in sialic acid has higher binding affinity to factor H than to factor B. Because mammalian cells have higher sialic acid content than microbial cells, factor H prevents excessive complement activation in host cells but not in microbes. Factor H is the major regulator in the alternate pathway activation.
• CD59: CD59 expressed by many cell types inhibits binding of C9 to the membrane-inserted C5b-8 complex and limits MAC formation on host cells. CD59 is not expressed by microbial cells, which allow complement-mediated microbial cell lysis, sparing host cells.
• Membrane cofactor protein: This is a cofactor for factor I–mediated cleavage of C3b and C4b.
• DAF: This accelerates decay of C3/C5 convertase.
• CR1: This is the receptor for C3b/C4b and has an inhibitory profile similar to MCP and DAF.
• Properdin: This stabilizes AP convertases.
• Clusterin: This blocks fluid phase MAC.
• S protein: This blocks fluid phase MAC.
• Anaphylatoxin inactivator: This inactivates C3a, C4a, and C5a.
• Complement system: This is an important regulator of B-cell activation.

Naive B cells receive a stimulus from the B-cell receptor (BCR), leading to activation, elimination, or anergy. The strength of signal transduction of B cells and other antigen-presenting cells (eg, dendritic cells) depends not only on the affinity of antigen binding but also on positive signals via the B-cell coreceptor complex composed of CD21 (complement receptor 2 [CR2])/CD19/CD81(TAPA-1). CD21 binds to antigens via attached C3d while membrane Ig binds to the antigen. This allows an association of CD19 to BCR-associated kinases and rapid phosphorylation of the cytoplasmic tail of CD19, leading to activation of PI-3K, which, in turn, augments BCR-initiated B-cell activation signaling. Thus, the absence of CD21 expression by B cells leads to impaired humoral immune response to T-dependent antigens. This is characterized by a decrease in B-cell follicular retention and germinal center survival.

C3b cleavage products have also been shown to augment immune memory; C3 receptors expressed on dendritic cells bind to both immune complexes and antigen alone. CD21 (CR2) expressed on follicular dendritic cells serves to trap iC3b-coated and C3dg-coated antigen-antibody complex in the germinal center.

Complement deficiency

Deficiencies of the complement components have been reported for most of the constituents. These deficiencies can be inherited or acquired and complete or partial.

Complement deficiency and disease association includes the following:

• Deficiency of early components of classical pathway (C1, C4, C2): Autoimmune disease, especially systemic lupus erythematosus (SLE), is the most common presentation in patients with early component deficiency. The incidence rates of SLE in individuals with C1q and C4 are reported to be around 90% and 75%, respectively. Patients with C2 deficiency develop SLE with lesser frequency (around 15%). The proposed mechanisms of high incidence of autoimmune diseases include impaired clearance of immune complex and apoptotic cells and loss of complement-dependent B-cell tolerance. Recurrent bacterial infection is common in patients with C2 deficiency. Atherosclerosis also appears to occur at a higher frequency in individuals with C2 deficiency.
• MBL pathway
  • MBL deficiency is linked with frequent pyogenic infection, including pneumococcal infection in infants and young children. Severe pneumococcal disease is also reported in patients with MASP-2 deficiency.
  • In addition, MBL deficiency is 2-3 times as common in patients with SLE as in the general population. Others also report an increase in cardiovascular diseases associated with atherosclerosis in patients with MBL deficiency.
  • Schizophrenia is a severe mental disorder, with worldwide prevalence of 1–1.5%. Immunological research in schizophrenia indicates that infectious or autoimmune processes might play a role in the etiopathogenesis.
  • The complement system is a major mediator of innate immune defense against infection and contributes to many functions of the immune system including inflammation, opsonization and cell lysis. 
  • MBL activates the complement system via the lectin pathway.
  • Inherited MBL deficiency, common in most human populations, predisposes to infectious and autoimmune diseases.
  • A modulatory role for MBL in autoimmune disease has been reported. Investigations in Denmark and Hong Kong have suggested that MBL variant alleles are associated with both severity and early onset of disease in patients with rheumatoid arthritis.¹ However, patients with late-onset disease who were also homozygous for wild-type MBL genes were more likely to show evidence of persistent inflammation.
• Alternative pathway (properdin, factor B, factor D): This is associated with severe fulminant neisserial infections with a high mortality rate.
• C3, factor H, and factor I: Deficiency of these factors predisposes individuals to severe pyogenic bacterial infections. Factor H and factor I deficiencies cause secondary C3 deficiency with C3 consumption and impose the same infectious risk as primary C3 deficiency. Factor H deficiency is also associated with atypical (diarrhea-negative) hemolytic-uremic syndrome (HUS) and glomerulonephritis. C3 deficiency is associated with membranoproliferative glomerulonephritis.
• Terminal pathway (C5-C9): The lack of MAC formation results in severe recurrent infection by Neisseria gonorrhoeae or Neisseria meningitidis.
• C1INH: Primary and secondary deficiency of C1INH leads to uninhibited cleavage of C4 by C1s. Hereditary angioedema (HAE) is caused by heterozygous deficiency of C1INH and characterized by recurrent episodes of angioedema, which usually subside within 48-72 hours. C1INH is a regulator for C1r/C1s, as well as for Hageman factor, clotting factor XI, plasma kallikrein, and plasmin. Angioedema is caused by various mediators that involve these pathways.
• DAF and CD59: Defects of these 2 regulatory proteins make erythrocytes highly susceptible to complement-mediated cell lysis. This is typically seen in patients with paroxysmal nocturnal hemoglobinuria (PNH), which has clinical features that are characterized by hemoglobinuria and venous thrombosis of major vessels.

Frequency

United States

Complement deficiency can be acquired or inherited.² Acquired deficiency may be acutely caused by infection or in conjunction with chronic rheumatological or autoimmune disorders. Inherited deficiency is rare in the general population, with an estimated frequency of 0.03%, excluding MBL deficiency. MBL deficiency is thought to be fairly common, with a 3% frequency in general population. Likewise, MASP-2 deficiency may also be very common.

Among C1-C9 components, C2 deficiency is the most common, with an incidence rate of 1 case per 10,000 population.

International

Unlike in Western countries, C9 deficiency is the most common complement deficiency in Japan, excluding MBL pathway defects. High incidence of C9 deficiency is also reported in Korea.

Mortality/Morbidity

Properdin deficiency is associated with a high mortality rate due to fulminant infection with N meningitidis. Primary and secondary C3 deficiency present with severe recurrent pyogenic infections early in life, similar to those observed in patients with hypogammaglobulinemia, leading to high comorbidity. Secondary C3 deficiency occurs in factor H or I deficiency.

Sex

Most complement deficiencies equally affect males and females; however, properdin deficiency is X-linked recessive (ie, only males are affected). The male-to-female ratio of SLE is equal in patients with C1q and C4 deficiency. In general, SLE in individuals with complement deficiency is characterized by onset at earlier age, photosensitivity, and lower frequency of renal involvement. Patients with C2 deficiency and SLE typically present with low or negative antinuclear antibody (ANA) or anti-dsDNA antibody.

Age

Meningococcal disease and complement deficiency

Serum bactericidal activity (ie, bacterial lysis mediated by complement in the presence of specific antibody) is the main host defense against meningococcal disease. Newborns and infants are protected by maternal-derived transplacental IgG antibodies. Susceptibility is highest in children aged 3-24 months. Thereafter, the incidence of meningococcal disease declines as serum bactericidal activity against the various N meningitidis serogroups develops following nasal colonization. Ninety percent of all meningococcal disease occurs in children younger than 2 years. The median age of patients presenting with their initial episode of meningococcal disease is 3 years in the general population and 17 years in individuals with late complement component deficiency.

Clinical

History

The following may be associated with complement deficiency:

• Patient or family history of recurrent systemic infection caused by encapsulated bacteria, especially meningococci
• Family history of fulminant meningococcal disease occurring in males, suggestive of X-linked properdin deficiency
• Meningococcal disease occurring in persons older than 10 years, especially when caused by non–group B meningococci (especially serogroups Y and W-135)
• Family history of systemic lupus erythematosus (SLE) or occurrence of atypical features of SLE, especially negative lupus serology findings (negative antinuclear antibody [ANA] and negative dsDNA findings)
• Specific syndromes such as partial lipodystrophy, angioedema, and paroxysmal nocturnal hemoglobinuria (PNH): Consider evaluation of the complement system in patients with these syndromes.
• Recurrent pyogenic infection, including severe pneumococcal diseases in infants and young children with normal humoral immune workup findings

Physical

• Classical pathway deficiencies - C1, C4, and C2
  • Deficiencies of the classical complement pathway have been strongly linked to the development of autoimmune disorders, especially those in which excessive immune complexes are formed. Patients may develop collagen vascular disorders, mainly SLE. Ninety-five percent of patients with C1q deficiency, 75% of those with C4 deficiency, 30% of those who are deficient in C2, and 50-55% of those who are deficient in C1r and C1s (deficiency usually involves both C1r and C1s) develop collagen vascular diseases (mainly SLE). Evidence suggests that this may result from the combination of impaired complement-dependent B-cell tolerance and impaired clearance of immune complex and apoptotic cells.
  • C1 deficiency generally leads to severe immune complex disease with features of SLE and glomerulonephritis. Serum levels of anti-C1q antibodies were increased significantly in patients with SLE and proliferative nephritis. Among different serological parameters for assessing the renal activity of SLE, only anti-C1q antibodies titers showed significant differences between quiescent and active lupus nephritis. Patients with C2 deficiency are reported to reveal anti-C1q antibody in the absence of anti-dsDNA.
  • Complete C4 deficiency is rare. Two genes, C4A and C4B, encode the C4 complement. Both genes are highly polymorphic, and, to date, at least 35 different alleles have been described. Almost all patients with complete C4 deficiency have discoid or SLE, with or without associated glomerulonephritis.
  • C2 deficiency has been the most commonly reported classical pathway defect. Skin and joint manifestations are common, and renal disease is relatively rare. Patients with C2 deficiency are also reported to have recurrent or invasive infections.
• C3 deficiency
  • C3 deficiency is rare. Because of its importance as a convergence point of the 3 complement pathways, all patients with C3 deficiency develop recurrent, severe, pyrogenic infections early in life. Some patients may also develop membranoproliferative glomerulonephritis.
  • C3 deficiency leads to an inability to formulate membrane attack complex (MAC), thus markedly compromising chemotactic and bactericidal activities of the complement cascade.
  • Patients with C3 deficiency generally have less than 1% of the normal amount of C3 antigen and C3 function in their serum.
  • Because of ineffective opsonization of pathogens, patients with C3 deficiency present with severe recurrent pyogenic infections, mainly caused by meningococci and pneumococci.
  • According to published studies, 78% of patients have repeated infections, and 79% experience autoimmune disorders, such as arthralgia and vasculitic rashes, lupuslike syndrome, and membranoproliferative glomerulonephritis.
• Alternate pathway deficiencies (properdin, factor B, factor D)
  • These deficiencies are rare. Properdin deficiency is associated with increased risk of infections with encapsulated bacterial organisms. Patients often present with a history of invasive meningococcal diseases, as well as severe pneumococcal and H influenzae infection. Recurrent infections may be rare in patients with properdin deficiency because the classical pathway can take over the actions of the alternate pathway once antigen-specific adaptive immune responses are established with immunoglobulin (Ig)G and IgM antibody formation.
  • Only 3 adults with factor D deficiency have been described in the literature. A 6-day-old newborn boy with pneumococcal sepsis and meningitis was diagnosed with complete deficiency of factor D and diminished functional factor B. The addition of purified factor D restored the capacity of the patient's serum to generate the alternate pathway fluid-phase C3 convertase (C3bBbP) in response to zymosan. This also restored activity of factor B in the patient's serum. In contrast, the addition of factor B did not alter factor D activity in the serum, indicating requirement of factor D for function of factor B.
• Late complement component deficiencies - C5, C6, C7, C8, and C9
  • MAC cannot be formed; hence, bactericidal activity is depressed.
  • Patients are susceptible to recurrent pyogenic infections.
  • Patients typically present with meningococcal meningitis or extragenital gonococcal infection.
  • Two thirds of patients experience at least one episode of meningococcal disease, and as many as one half of patients experience recurrent neisserial infections.
  • Patients with C9 deficiency have the ability to kill Neisseria, but at a slower rate.
• Deficiency of C1INH (HAE): This leads to recurrent episodes of angioedema. See Angioedema (Hereditary).
• Mannose-binding lectin (MBL) pathway deficiency
  • Newborns with MBL deficiency are at increased risk for infection. Individuals with MBL deficiency have a higher propensity for severe infection in early life.
  • In young children and newborns with repeated infections, MBL defects should be considered.
  • Worsening clinical features are also reported in patients with rheumatoid arthritis and MBL deficiency.
  • In a study of patients with cystic fibrosis (CF) with or without MBL variant alleles, Garred et al found the following:¹
    • Lung function in carriers of MBL variant alleles was significantly reduced compared with patients with normal homozygotes.
    • The negative impact of variant alleles on lung function was especially confined to patients with CF and chronic Pseudomonas aeruginosa infection.
    • Burkholderia cepacia (previously named Pseudomonas cepacia) infection was significantly more frequent in patients with CF and MBL variant alleles.
    • Using a modified life table analysis, the authors estimated that the predicted age of survival was reduced by 8 years in patients with CF who carried variant alleles compared with normal homozygotes with CF.
• C3 nephritic factor (C3NeF) and mesangiocapillary glomerulonephritis (MCGN)
  • C3Nef is an autoantibody that binds to and stabilizes the C3 convertase (C3bBb).
  • The association of C3NeF and MCGN, especially MCGN type II, has been well defined. Different isotypes of C3NeF are recognized, the main one being an IgG autoantibody against factor H. Factor H is an important regulator of the C3 conversion step in the alternate pathway. C3NeF inhibits functions of factor H, which leads to overwhelming complement activation at the stage of C3 conversion. Continuous C3 activation in vivo results in the well-known consequences of very low serum levels of C3 in MCGN.
  • C3NeF may act directly within glomeruli to cause local complement activation and ensuing renal damage.
  • C3Nef is also associated with partial lipodystrophy.
• Factor H deficiency
  • Factor H deficiency is associated with hemolytic-uremic syndrome (HUS), especially in familial cases that involve homozygous factor H deficiency.
  • Factor H deficiency also occurs with membranoproliferative glomerulonephritis.
  • Parents have one half the normal levels of factor H.
  • HUS associated with factor H deficiency is characterized by verotoxin-negative (diarrhea-negative) HUS. Atypical and recurrent HUS is also seen in CD46 deficiency.

Causes

• Classical pathway deficiencies (C1, C4, C2) are inherited in an autosomal recessive pattern.
• C3 deficiency is inherited in an autosomal recessive pattern.
• No known homozygous deficiency of factor B has been reported, although one heterozygous case has been described. Properdin deficiency is the only X-linked complement deficiency. All reported cases of properdin deficiency involve males.
• Late complement component deficiencies (ie, C5, C6, C7, C8, C9) are inherited in an autosomal recessive fashion.

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