Complement-Related Disorders 

Updated: Jan 15, 2016
Author: M Michael Glovsky, MD; Chief Editor: Michael A Kaliner, MD 

Overview

Background

In the late 19th century, serum was found to contain a nonspecific heat-labile complementary principle that interacted with antibodies to induce bacteriolysis. Ehrlich and Morgan termed this factor complement.

The complement system as understood today is a multimolecular system composed of more than 32 proteins and consisting of serum proteins, serosal proteins, and cell membrane receptors that bind to complement fragments. They constitute 10% of the globulin fraction of serum. Many of these proteins are designated by the letter C (C1, 4, 2, 3, 5, 6, 7, 8, and 9) and are assigned numbers in the order of their discovery. See tables 1-6 in Pathophysiology for more information.

Pathophysiology

The complement system consists of 7 serum and 9 membrane regulatory proteins, 1 serosal regulatory protein, and 8 cell membrane receptors that bind complement fragments. Most are synthesized mainly by the liver. Exceptions are C1, factor D, and properdin. These are probably synthesized by macrophages and even by T lymphocytes.

The tables in this section were adapted from Middleton's Textbook of Allergy and Immunology, 6th edition; data are chiefly from Morley BJ, Walport MJ, eds: The complement facts book, San Diego, 2000. Acute-phase levels are estimates based on limited data.

Activation

The complement system functions as an interactive sequence, with one reaction leading to another in the form of a cascade. It is initiated by a wide variety of substances and has 2 phases. In the first phase, a series of specific interactions leads to formation of intrinsic complement proteinase, termed C3 convertase. Depending on the nature of complement activators, the classic pathway, the alternative pathway, or the more recently discovered lectin pathway is activated predominantly to produce C3 convertase. Each of these pathways uses different proteins. The second phase for each involves cleavage of C3b, generating multiple biologically important fragments and large, potentially cytolytic complexes. See the image below.

Activation of the complement pathways. Activation of the complement pathways.

Classic pathway

This pathway has 2 units. One, the recognition unit, consists of a trimolecular complex of C1q, 2 molecules of C1r, and 2 molecules of C1s held together by calcium. The other is an activation unit of C2, C3, and C4. The sequence starts with the binding of 2 or more C1q recognition units to the Fc nonantigen binding part of IgG and IgM molecules. This induces a conformational change, leading to autoactivation of C1r that then cleaves C1s to its active state. This then acts similarly to C1 esterase and cleaves C2 and C4 to form C2aC4b, which is the C3 esterase that cleaves C3 to form C3b. C1q can also be activated by mycoplasmal organisms, RNA viruses, bacterial endotoxins, and cell membranes of some organelles without the presence of antibody.

Table 1. Proteins of the Human Complement (C) System, Classical Pathway* (Open Table in a new window)

Component

Mol Wt (~kD)

Normal Serum levels (µg/mL)

Acute Phase Serum levels (% Increase)

Chromosomal Location

C1q

460

70

13%

1p34-36.3

C1r

83

34

 

12p13

C1s

83

31

47%

12p13

C4

200

600

34%

6p21.3

C2

102

23

 

6p21.3

*C-reactive protein (CRP, not shown) leads to classic pathway activation analogous to lectin pathway activation by MBL and ficolins.

 

Alternate pathway

This was discovered by Pillemer and colleagues in 1954 but was recognized universally some years later. This pathway is activated by viruses, fungi, bacteria, parasites, cobra venom, immunoglobulin A, and polysaccharides and forms an important part of the defense mechanism independent of the immune response. Here, C3b binds to factor B that is cleaved by factor D to Bb. C3bBb complex then acts as the C3 convertase and generates more C3b through an amplification loop. Binding of factor H to C3b increases its inactivation by factor I. Properdin stabilizes it, preventing its inactivation by factors H and I. The alternate pathway does not result in a truly nonspecific activation of complement because it requires specific types of compounds for activation. It simply does not require specific antigen-antibody interactions for initiation.

Table 2. Proteins of the Human Complement (C) System, Alternative Pathway (Open Table in a new window)

Component

Mol Wt (~kD)

Normal Serum levels (µg/mL)

Acute Phase Serum levels (% Increase)

Chromosomal Location

Factor D

25

2

 

19

Factor B

93

93

65%

6p21.1-21.3

 

Lectin pathway

The lectin or mannan-binding pathway is activated similar to the classic pathway except that lectin replaces the antibody and mannan-binding lectin–associated proteases replace C1 enzymatic activity. Instead, mannan-binding lectin binds to sugar residues on the surface of a pathogen. Mannan-binding lectin is associated with serine proteases, similar to the C1r and C1s subcomponents of the classic pathway, that also activate C4 and C2, forming the classical pathway C3 convertase C4b2a.

Table 3. Proteins of the Human Complement (C) System, Lectin Pathway (Open Table in a new window)

Component

Mol Wt (~kD)

Normal Serum levels (µg/mL)

Acute Phase Serum levels (% Increase)

Chromosomal Location

MBL

288-576

2

Up to 1000%

10q11.2-21.0

MASP-1

97

6

...

3q27-28

MASP-2

80

...

...

1p36.23-36.31

MASP-3

105

...

...

3q27-28

Map19

19

...

...

1p36.23-36.31

L-ficolin/P35

630

13.7

...

9

H-ficolin/Hakata antigen

630

15

...

...

MBL = mannan-binding lectin; MASP = MBL-associated serine protease

 

Membrane attack complex

Only 5 proteins are involved in the direct killing of cells. C2a4b3b complex from the classic or MBL pathways or C3bBb from the alternative pathway cleaves C5. C5b activates the terminal complement pathway by associating with C6, C7, and C8 to form macromolecular complexes denoted as C5b-8, which can bind to cell membranes. C9 binds to this complex, inducing a conformational change that exposes a new antigenic site known as C9 neoantigen. Additional C9 molecules bind to membrane-bound C5b-9, forming ringlike pores, leading to transmembrane channels that cause cell lysis.

Table 4. Proteins of the Human Complement (C) System, C3 and Terminal Components (Open Table in a new window)

Component

Mol Wt (~kD)

Normal Serum levels (µg/mL)

Acute Phase Serum levels (% Increase)

Chromosomal Location

C3

185

1200

30%

19p13.2-13.3

C5

190

75

55%

9q33

C6

128

45

 

5p12-14

C7

120

55

 

5p12-14

C8

163

68

 

1p32; 9q34.3

C9

79

60

49%

5p13

 

Regulation

The complement system serves a very important role in host defense, but if it is directed against self, it can lead to serious illness. Therefore, it is closely regulated at almost every step. See the image below.

Control proteins of the complement pathways. Control proteins of the complement pathways.

Classic pathway

The classic pathway requires the identification of a target by the presence of an antibody. C1 inhibitor (C1-INH) inhibits C1r and C1s by binding covalently to them, causing disassembly of C1 macromolecular complex. The inhibitor is synthesized in the liver and blood monocytes; its gene is located on chromosome 11. C2a4b is very labile and undergoes spontaneous decay with release of C2a and loss of enzymatic activity. C4 binding protein binds C4, which accelerates its rate of dissociation from C2a and makes C4b more susceptible to proteolysis by factor I. Membrane-bound decay-accelerating factor (DAF) promotes release of C2a from C4b2a by physically interfering with C4b and C2a association.

Table 5. Proteins of the Human Complement (C) System, Control Proteins in Serum (Open Table in a new window)

Component

Mol Wt (~kD)

Normal Serum levels (µg/mL)

Acute Phase Serum levels (% Increase)

Chromosomal Location

C1 inhibitor

105

150

21%

11q11-13.1

C4-binding protein

550

225

...

1q3.2

Factor H

150

550

...

1q3.2

Factor I

88

35

...

4q25

Properdin

223

5

-14%

Xp11.23-11.30

S protein

75

340

...

17q11

Clusterin

80

340

...

8p21

Anaphylotoxin inactivator

290

35

...

8p22-23, 10

 

Alternative pathway

Carbohydrate composition and its sialic acid content on the cell surface play an important role in the activation of the alternate pathway. Sialic acid blocks activation by favoring the binding of factor H to C3b, which is then inactivated by factor I.[1] Microorganisms lacking sialic acid are killed, whereas human cells covered with glycophorin A, a sialoglycoprotein, are protected.

C3bBb is relatively labile and undergoes spontaneous decay through dissociation of Bb. Properdin is synthesized by monocytes and T lymphocytes. Properdin binds to C3bBb and stabilizes it, preventing its decay. Factor H competes with factor B for binding to C3b and displaces Bb from C3bBb. It accelerates the inactivation of C3b by factor I. Factor I inactivates C3b to iC3b, a molecule that cannot function enzymatically. Complement receptor 1 (CR1) has factor H–like activity, permitting factor I to cleave C3b. Membrane cofactor protein also has factor H–like activity, mainly for alternative C3 convertase.

Membrane attack complex

Homologous restriction factor, C8 binding protein, is a cell membrane protein with significant sequence homology to both C8 and C9 and is widely distributed on peripheral blood cells. It prevents the interaction of C8 and C9. Membrane-bound CD59, also known as homologous restriction factor 20, prevents the binding of C5b-8 to C9 and inhibits the unfolding of C9 that is required for polymerization and formation of macroscopic pores in the cell membrane. S protein (vitronectin) binds to C5b-7 and abolishes its activity. SP-40,40 (clusterin) has effects similar to vitronectin.

Table 6. Proteins of the Human Complement (C) System, Membrane Receptor and Control Proteins (Open Table in a new window)

Component

Mol Wt (~kD)

Ligands

Chromosomal Location

DAF

70

C4b2a

1q3.2

MCFP

60

C3b

1q3.2

CD59

20

C8, C9

11p13-14

CR1

250

C3b, C4b

1q3.2

CR2

145

C3dg, C3d, EBV

1q3.2

CR3

250

iC3b, LPS, β-glucans

16p11-13.1, 21q22.3

CR4

245

iC3b, LPS

16p11.2, 21q22.3

C3aR

100

C3a, C4a

12p13

C5aR

50

C5a

19q13.3-13.4

DAF = decay-accelerating factor; MCFP = membrane cofactor protein; EBV = Epstein-Barr virus; LPS = lipopolysaccharides

 

Biologic Effects

The biologic effects of complement include promotion of chemotaxis and anaphylaxis, opsonization and phagocytosis of microorganisms, and removal of immune complexes from the circulation. Most complement components are acute phase reactants, and their concentration increases in states of infection, trauma, and injury.

C3a and C5a are anaphylatoxins and bind to mast cells, triggering the release of histamine and other mediators, leading to vasodilation, erythema, and swelling. When C3a or C5a is injected into the skin, it elicits an immediate wheal and flare response, similar to that found with allergen injection into the skin of individuals with allergies. C3a and C5a also produce bronchoconstriction with human tracheal or bronchial muscle strips in vitro. C5a is a major stimulus for influx of neutrophils, basophils, monocytes, and eosinophils.

C3b fixes to the antigen-antibody complex and permits its adherence to cells (eg, neutrophils, basophils, eosinophils, monocytes) that have receptors for C3b. This particular action of opsonization helps in phagocytosis. C3b-coated particles also bind to B lymphocytes and activate them to enhance the primary antibody response. Immune complexes formed in the circulation are coated with C3b and bind to erythrocytes, which then transport them to the liver and spleen for removal. This process maintains the solubility of the immune complexes. In the early phases of viral infection, when the amount of antibody is limited, the fixation of C3b to the viral antigen-antibody complex increases neutralization.

The terminal components of the complement system result in lysis of virus-infected cells, tumor cells, and some gram-negative microorganisms. They also have a role in neutralization of endotoxins in vitro and protection from their lethal effects in experimental animal models. C5b-9 neoantigen is found in the muscle in dermatomyositis, implying that the terminal complement system may have a role in the pathophysiology of that disease.

 

Presentation

Causes

Causes may be primary or secondary in nature.

Primary Complement Disorders

Congenital complement deficiencies involve all of the complement components and most of the regulatory components.[2]

Classic pathway disorders

C1q

Although any one of the 3 subcomponents of the C1 complex may be deficient, C1q deficiency is the most common. C1q deficiency may be hereditary or acquired. Hereditary deficiencies are usually complete and are transmitted as an autosomal recessive trait. Low-to-absent levels of C1q are found; a dysfunctional protein has been found in some patients.

Most patients (>90%) with C1q deficiency have systemic lupus erythematosus (SLE) and demonstrate a variety of autoantibodies, such as immunoglobulin G (IgG) autoantibodies to C1q, antinuclear antibody and double-stranded DNA (dsDNA) antibody; low total hemolytic complement activity (CH50) values; and low C1q levels, with normal levels of other complement proteins. SLE is more severe in persons with homozygous deficiencies, suggesting that C1q is vital in clearing immune complexes, by binding to the C1q receptor or through its participation in the generation of C3. Deposition of this C3 on autoimmune complexes facilitates their removal from the circulation through binding to CR1 on erythrocytes, with subsequent transport to the liver and spleen.

Low levels of C1q also are found in persons with SLE-like syndrome without typical serology, hypocomplementemic urticarial vasculitis syndrome,[3] multiple myeloma,[4] hypogammaglobulinemia, and membranoproliferative glomerulonephritis.

Plasmapheresis has been used for restoration of C1q levels. The use of fresh frozen plasma is associated with the development of antibodies to C1q, thereby limiting its use.

C1r/C1s

The loci of these 2 components are closely linked, and the deficiencies usually occur together. The transmission is autosomal recessive in nature. A high prevalence of SLE is found, with prominent renal and cutaneous sequelae.

C4

C4 is encoded as 2 tandem, highly polymorphic genes, C4A and C4B, located in the major histocompatibility complex on chromosome 6. Two copies of each gene determine the phenotype. Null alleles are called C4a*Q0 and C4b*Q0. Deletion of the C4A gene is the most common mechanism. A single null allele reduces the C4 level by 35-40%. Four null alleles encode a complete deficiency of C4. It is transmitted as an autosomal recessive trait.

Partial C4 deficiency predisposes to SLE. Deficiency of C4A or C4B has been associated with the development of scleroderma, immunoglobulin A nephropathy, Henoch-Schönlein purpura, diabetes mellitus, chronic hepatitis and membranous nephropathy. Complete C4 deficiency is rare. Characteristics of SLE with complete C4 deficiency include early onset, mild renal disease, skin manifestations, anti-SSA antibody, and an absence of anti-dsDNA antibody. Complete C4 deficiency also may manifest with infection or may not be associated with any symptoms.

Defective expression or function also may lead to SLE, as occurs with medications such as hydralazine, penicillamine, and procainamide, which react with the thioester bond of C4a and block its function.

C2

This is the most common inherited complement deficiency. The transmission is autosomal recessive in nature. Homozygous deficiency of C2 occurs in 1 in 10,000 whites, with up to 30% presenting with an SLE-like illness or with no disease.

It may also manifest as recurrent pyogenic infections due to encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. It is also sometimes associated with IgG subclass deficiency.

The gene frequency of heterozygous C2 deficiency is 1%. Immune complex disease is common. It may manifest as life-threatening septicemia, especially due to infection with pneumococci.

C3

C3 is the most important central molecule in the complement system because both the classic and alternative pathways activate it, and its activation products mediate opsonization and anaphylactic activity and activate the terminal pathway.

C3 deficiency is transmitted as an autosomal recessive trait. Patients with C3 deficiency develop severe episodes of recurrent pneumonia, meningitis, peritonitis, or sepsis. The most common pathogens are S pneumoniae, N meningitidis, H influenzae, and Staphylococcus aureus. The infectious profile is similar to that found with Bruton agammaglobulinemia. Lupuslike illness and mesangiocapillary glomerulonephritis may occur in 15-20% of patients.

Membrane attack pathway: C5b-C9

Deficiency is transmitted as an autosomal recessive trait. Patients with deficiency of C5-9 components usually have a history of meningococcal meningitis and even extragenital or disseminated gonococcal infection. The reasons for the predisposition to Neisseria infection are not clear, but deficient serum bacteriolysis may be the predisposing cause. Patients with terminal complement component deficiencies and polymorphisms for Fc gamma RIIa (CD32), which have lower affinity for IgG (Fc Gamma RIIa-R131), appear to have more severe and frequent neisserial infections, at least after age 10 years, suggesting that phagocytosis is also important for resistance to these organisms.[5] Some patients develop collagen-vascular disease. C6 homozygous deficiency is associated with increased risk of membranoproliferative glomerulonephritis.

Alternative pathway

These are inherited by autosomal recessive mode of transmission. Deficiency in factor D or factor B manifests as recurrent infection.

Control proteins

Factor I

It has an autosomal recessive transmission and leads to the prolonged presence of C3b, causing a constant activation of the alternative pathway that ultimately leads to a depletion of C3. It was initially reported as C3 deficiency due to hypercatabolism of C3. It manifests as severe pyogenic infections.

Factor H

It helps factor I in the breakdown of C3 convertase of the alternative pathway, so its effects are essentially the same. The C3 level, factor B level, CH50 value, and alternate pathway activity are low or undetectable. Patients have sustained systemic infections, especially from meningococci. Membranoproliferative glomerulonephritis and hemolytic uremic syndrome are associated with it.[6] Associations between familial hemolytic uremic syndrome and mutations in the genes for factor H and factor I have also been reported.

Properdin

It is transmitted as an X-linked trait. All patients are male, and a family history of male deaths due to meningococcal meningitis is common. CH50 results are without abnormality. Patients may have discoid lupus or dermal vasculitis.

C4 binding protein

It is a control protein of the classical pathway and binds to C4b. It may be relevant in preventing activated C4b2a from depleting C3 and other late components in hereditary angioedema.

C1 inhibitor

C1-INH disorders are transmitted as an autosomal dominant trait. However, 50% of patients may have spontaneous mutations, and a family history may be absent. In 85% of patients, a marked protein reduction of the inhibitor is found (5-30% of normal values are present). In 15% of patients, a dysfunctional protein is present. Protein values of the C1 inhibitor may be normal or high, yet functional enzymatic tests are markedly reduced. Autoantibody to the C1 inhibitor occurs in patients with neoplastic disease, such as carcinoma and lymphoproliferative disease. The association of acquired angioedema with low values of C1q differentiate the acquired disease from the familial or hereditary angioedema.

The absence of the C1 inhibitor causes uncontrolled C1 activity with breakdown of C4 and C2 and release of a vasoactive peptide from C2. Since the C1 inhibitor also blocks the coagulation cascade, factor XIIa, fibrinolysis, and the kallikrein-bradykinin cascade, bradykinin is thought to be the active permeability factor causing the edema and pathologic effects of the disease. Drugs that block kallikrein activation and bradykinin receptor binding as well as purified C1 inhibitor preparations have been shown to markedly reduce the time and severity of acute angioedema attacks.

The deficiency of C1 esterase inhibitor leads to hereditary angioedema, which is manifested by episodic attacks of nonpitting, nonpruritic, localized edema that progresses rapidly without urticaria or erythema.[7] Swelling of the intestinal wall can cause intense abdominal cramping associated with vomiting and diarrhea. Laryngeal edema may prove fatal. Attacks last 2-3 days and gradually subside. Attacks occur after menses, emotional stress, trauma, or vigorous exercise. They may begin in the first 2 years of life but usually are not severe until late childhood or adolescence. Collagen-vascular disease and glomerulonephritis have been reported. The diagnosis is suggested by a positive family history, edema with lack of accompanying pruritus or urticaria, and decreased C4 levels. Further laboratory testing is performed by measuring the amount of C1-INH, but some kindred have a dysfunctional protein and require a functional assay.

Acquired disease may occur from autoantibody to C1-INH, usually associated with B-cell cancer.

See Hereditary angioedema for more information.

Complement receptor 1, 2, or 3

Deficiency of CR1 on erythrocytes leads to impaired clearance of immune complexes, thereby contributing to collagen-vascular disease. The disorder possibly is inherited.

An inherited deficiency of complement receptor 3 causes recurrent and severe bacterial (eg, S aureus and/or Pseudomonas) infections. This condition is known as leukocyte adhesion deficiency syndrome (CD11/CD18 deficiency). It is suspected if delayed separation of the umbilical cord occurs and omphalitis develops. Most patients die in childhood of refractory infections involving soft tissue and mucosal surfaces.

DAF, CD59, C8 binding protein

The vascular endothelium of the skin of patients with diffuse or limited scleroderma has been shown to be deficient in DAF. This may lead to vascular injury, finally leading to fibrosis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by hemolytic anemia, venous thrombosis, and deficient hematopoiesis. It is an acquired clonal disease due to a somatic mutation of a gene on the X chromosome (PIGA) in a hematopoietic stem cell that encodes the glycosyl-phosphatidylinositol molecule, which anchors approximately 20 proteins (including DAF, CD59, and C8 binding protein) to cell membranes. The absence of this anchor results in an absence of these proteins, making the erythrocytes more susceptible to complement-mediated lysis. A monoclonal antibody to C5, eculizumab, has been shown to reduce the need for transfusions, increase the quality of life, and decrease the thrombotic episodes in 43 patients with PNH.[8]

Isolated DAF deficiency does not cause PNH. Isolated CD59 deficiency has been reported to cause mild PNH.

Age-related macular degeneration (AMD) is an age-related cause of blindness and the most common cause of blindness in individuals older than 55 years. It can be present in a dry form (90%) or in a wet (exudative) form (10%). In 50% of patients with the dry form, an association has been found with a single amino acid mutation in the gene for the regulatory Factor H of the complement alternative pathway. The pathogenesis of AMD is related to the deposition of drusen, a yellow-gray material in the Bruch membrane associated with retinal pigment epithelial changes (atrophy, clumping, detachment). These drusen deposits have been found to be associated with C5 and C5b-9 complexes, as well as with the deposit of other inflammatory proteins. Thus, the deficiency of control of activated C3 convertase is an important factor in the production of drusen, and the inflammatory response in this milieu is thought to be responsible for the pathologic changes.[9]

Serosal protease

Evidence suggests that serosal fluids contain a complement regulatory protease that destroys C5a and interleukin 8, which are chemotactic for neutrophils. Deficiency of this regulatory protein in peritoneal and synovial fluids results in familial Mediterranean fever, characterized by recurrent episodes of fever and painful inflammation of joints, pleura, and the peritoneal cavity.

Inherited lectin pathway deficiencies

Point mutations of the MBL mannose-binding lectin (MBL) gene occur in the coding exons and promoter region. MBL contains 3 identical polypeptide chains. Substitutions in these exons lead to the formation of chains that do not interact normally. Persons with mutations of both MBL alleles (3-5% of the population) have undetectable or extremely low levels of MBL. People with 1 normal and 1 abnormal allele have a sixth to an eighth of the normal functional level of MBL.

MBL deficiency is associated with an increased frequency of pyogenic infections in children. In the presence of MBL deficiency, chronic inflammatory conditions may be more severe. A 2- to 3-fold increase in MBL deficiencies is noted in persons with SLE9.[10] More frequent and more severe infections occur in patients treated with steroids and cytotoxic agents.

A deficiency of MBL-associated proteases has been described that results in severe pneumococcal pneumonia and immune disorders, including ulcerative colitis and erythema multiforme bullosum.

Secondary Complement Disorders

A number of diseases that are not inherited affect the complement system.

Immunologic

These are mediated by immune complexes, and complement proteins are consumed in the process.

Systemic lupus erythematosus

Complement is consumed via the classic pathway during active immune complex deposition; therefore, patients with active lupus characteristically have decreased C3 levels, C4 levels, and CH50 results. However, hypocomplementemia can also be found in patients with SLE without active disease.[10]

A subset of patients has congenital complement deficiencies. Normal C3 levels with very low or absent CH50 values are suggestive of a congenital deficiency. C2 and C4 deficiencies are common.

Elevated levels of complement activation products may be useful in predicting SLE flares.[11, 12]

Hypocomplementemic glomerulonephritis

Serum from patients with membranoproliferative glomerulonephritis contains nephritic factor (NeF), which causes activation of the alternative pathway. NeF is an IgG autoantibody that binds and stabilizes C3bBb and prevents its dissociation by factor H. This leads to prolonged C3 conversion, leading to its depletion. This disorder has been described in association with partial lipodystrophy. Exposure to NeF destroys adipocytes, which can synthesize C3, factor D, and factor B.

An IgG NeF that binds and protects C4,2 has been described in association with acute postinfectious nephritis. Complement levels usually return to normal in 8 weeks.

Mesangioproliferative glomerulonephritis, idiopathic proliferative glomerulonephritis, and focal sclerosing glomerulonephritis have been described in association with complement depletion. Lupus nephritis is one of the important causes. Other causes, such as fibrillary glomerulonephritis and immunotactoid glomerulonephritis, have been reported.[13, 14]

Infective endocarditis

Circulating immune complexes have been found in 90% of patients with endocarditis. Rheumatoid factor is present in 10-70% of cases. Hypocomplementemia is a frequent but nonspecific marker of glomerulonephritis in persons with bacterial endocarditis. Approximately 90% of patients with diffuse glomerulonephritis and approximately 60% of patients with focal glomerulonephritis have reduced complement levels. Typically, the classic pathway has been implicated, but reports of primary alternative pathway activation are found in the literature. Complement levels return to normal with bacteriological cure and resolution of glomerulonephritis.

Miscellaneous causes

Formation of immune complexes with complement consumption has been found in association with acute hepatitis B and C, often in sufficient amounts to form mixed cryoglobulins.[15] These are responsible for extrahepatic manifestations of arthralgias and nephritis. Immune complexes also are present in association with infectious mononucleosis, malaria, dengue fever, lepromatous leprosy, and bacteremic shock.

Reye syndrome, primary biliary cirrhosis, celiac disease, multiple myeloma,[4] hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and urticarial vasculitis have also been implicated. Burns, hemodialysis with cellophane membranes, cardiopulmonary bypass, and perhaps the injection of iodinated radiocontrast material can also cause direct activation of the alternative pathway and serious effects thereof.

Nonimmunologic

Patients with severe malnutrition and anorexia nervosa have low complement levels. Improvement in serum concentration of complement has occurred after correction of the nutritional deficiency. Severe cirrhosis of the liver and hepatic failure result in decreased C3 production. Preterm infants, and even newborn children, have mild-to-moderate deficiency of all complement components. Deficiencies in the alternate pathway and suboptimal opsonization have been described in persons with sickle cell disease, postsplenectomy patients, and persons with nephrotic syndrome.

 

Workup

Laboratory Studies

Candidates for evaluation

Complement function should be evaluated in any patient with collagen-vascular disease, PNH, chronic nephritis, recurrent pyogenic infections, severe recurrent angioedema not responsive to antihistamines, N meningitides or disseminated gonococcal infections, or a second attack of septicemia at any age.

A family history of recurrent systemic infections caused by encapsulated bacteria, especially meningococci, should suggest complement deficiency.

Hemolytic assays

Hemolytic assays were devised as early as the beginning of the 20th century, and they measure the ability of the complements to participate in hemolysis.

CH50 tests the capacity of proteins of the classic pathway and membrane attack complex to lyse antibody-coated sheep erythrocytes. The dilution of the serum that lyses 50% of the cells marks the end point.

The CH50 value is zero in homozygous congenital deficiencies of C1 to C8, and its value is half-normal in C9 deficiency. Also, deficiencies in factors H or I result in a low value due to C3 consumption. The test does not measure deficiencies of the alternative pathway activation proteins.

It is very useful as a screening test for most diseases of the complement system. Because of the unstable nature of several of the complement proteins, the CH50 assay requires appropriate collection, processing, and storage of specimens. Serum samples should be assayed the day of collection or stored frozen. A common cause of a decreased CH50 values is improper specimen handling.

The alternative hemolytic complement activity (AH50), although less commonly used, measures alternative pathway function that requires the presence of adequate factor B, factor D, and properdin.

Selective complement assay

Serum concentrations of C1q, C1r, C1s, C4, C2, C3, C5, C6, C7, C8, C9, and factor B are measured by radial immunodiffusion, and testing is easily available. A decrease in C4 levels with normal C3 levels represents classic pathway activation, a decrease in factor B levels with normal C4 levels signifies alternative pathway activation, and a decrease in C3 levels reflects activation of either pathway. Partial (heterozygous) deficiencies of C4, factor B, or C3 could mimic the above findings in the absence of activation.

In hereditary angioedema, depression of C4 and C2 levels during an attack may or may not reduce the CH50 value. The C4 level is characteristically low with a normal C3 level. Concentration of C1-INH can be determined with an antibody-based assay. A functional test for C1-INH should be performed in patients in whom a high index of suspicion exists but the protein level is normal.

Low titers of both C3 and C4 suggest activation of the classic pathway by immune complexes. On the other hand, low C3 and normal C4 levels suggest alternative pathway activation. This difference may be useful in differentiating nephritis due to immune complex deposition from that due to NeF. Also, factor B levels are reduced in persons with NeF-induced nephritis. However, normal complement levels do not exclude complement activation that is biologically important but not massive enough to lower the serum concentrations.

Tests for MBL levels are fairly widely available and should be considered in any patients with recurrent pyogenic infections in whom tests for antibody deficiency are being considered.

Abnormal elevations of Ba, Bb, C3a, C4a, and iC3b levels have been found to correlate with lupus flares in patients. However, larger prospective studies are required before this type of testing is recommended for routine use. Synovial fluid from patients with rheumatoid arthritis or gout has markedly increased levels of C3a, whereas C5a levels are within the reference range. C3a is a more sensitive marker of in vivo complement activation than C5a, which is rapidly cleared from the circulation. Cerebrospinal levels of C5b-9 are increased in persons with autoimmune neurologic diseases, such as multiple sclerosis and lupus cerebritis.

 

Treatment

Medical Care

No specific therapy is recommended at present for most of the complement disorders. However, hereditary angioedema does respond to specific therapy.[16] With regard to hereditary angioedema, epinephrine administered early may produce some (usually minimal) improvement.

Clonal C1-INH administered by infusion aborts acute attacks, and it also is safe and effective for surgical or dental prophylaxis. Cinryze, a purified C1 inhibitor protein, was recently approved by the US Food and Drug Administration (FDA) for the prophylactic treatment of hereditary angioedema (HAE).[17] It has not yet been FDA-approved for the treatment of acute HAE.[18] Other kallikrein inhibitors and a bradykinin receptor antagonist have been shown to reduce and shorten attacks of HAE but have not been approved for use by the FDA. The kallikrein inhibitor ecallantide (Kalbitor) was recently approved by the FDA to treat HAE.[19] Berinert, a C1 esterase inhibitor, was recently approved by the US FDA for treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE.[20]

In the absence of clonal C1-INH, infusion of fresh frozen plasma has been used successfully in acute attacks of angioedema. Fresh frozen plasma has been used prior to dental and surgical procedures; however, this also provides substrate for C1-INH protein and may worsen angioedema, and, hence, it is not recommended for life-threatening laryngeal edema.

Danazol, a synthetic androgen, increases the serum concentration of C1-INH and prevents attacks in adults. It is not recommended in children.

Stanozolol is another attenuated androgen. It is no longer produced in the United States but may be given to the pediatric population.

Precipitating factors, such as trauma, estrogens, and angiotensin-converting enzyme inhibitors, should be avoided.

The antifibrinolytic agents, epsilon-aminocaproic acid and tranexamic acid, may be effective in both hereditary and acquired C1-INH deficiency. However, these drugs may be associated with intravascular thrombosis.

Fresh frozen plasma also has been used to restore C3 levels in persons with C3 deficiency. Therapeutic plasma exchange using fresh frozen plasma has been used to replace the deficient complement proteins, but, overall, it has not proved to be a safe and efficient mode of therapy. Its use in patients with SLE has not met with definite success.

Supportive management can prove helpful in these patients.

Every attempt should be made to identify the specific component or inhibitor defect.

With the development of fever in these patients, cultures should be obtained and the threshold for beginning antibiotic therapy should be low. The use of prophylactic antibiotics is controversial. Prophylactic antibiotics reduce the frequency of infection in patients with C6 deficiency, who are susceptible to meningococcal infection. However, concern for the development of antibiotic resistance and the duration of prophylaxis remain unresolved issues.

Make certain adequate information is provided to the patient or guardian for possible use by school, camp, or other health care personnel or physicians.

Immunization of the patient and household contacts for pneumococci, H influenzae, and N meningitidis is strongly recommended.

Replacement therapy with recombinant complement proteins may soon be possible; gene therapy may become a viable option in the future.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Androgens, synthetic

Class Summary

In hereditary angioedema, stanozolol and danazol increase level of deficient C1-INH and prevent attacks. Danazol not recommended in children.

Danazol

Increases C4 levels and reduces attacks associated with angioedema.

Kallikrein Inhibitor

Class Summary

Elicits specific kallikrein inhibitor activity resulting in bradykinin reduction. Useful for treating acute episodic attacks.

Ecallantide (Kalbitor)

Potent, selective, reversible inhibitor of plasma kallikrein. Binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of high molecular weight kininogen to bradykinin. By directly inhibiting plasma kallikrein, reduces conversion of high molecular weight kininogen to bradykinin, thereby treating the disease during acute episodic attacks of hereditary angioedema (HAE). Indicated for treating acute HAE attacks.

Blood Product Derivative

Class Summary

These agents are used for prophylaxis and treatment against attacks in adolescents and adults with hereditary or acquired angioedema.

C1 inhibitor, human (Cinryze, Berinert)

Serine proteinase inhibitor found in human blood that regulates activation of the complement pathway, intrinsic coagulation system, and fibrinolytic system. Binds to and neutralizes substrates that activate these systems, thereby suppressing activity. Available as a pasteurized, lyophilized preparation derived from purified human plasma. One unit corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma. Indicated for acute abdominal and facial angioedema attacks in adolescents and adults with hereditary angioedema (HAE).

Cinryze is indicated for routine prophylaxis against attacks in adolescents and adults with hereditary or acquired angioedema.

Berinert is indicated for abdominal or facial HAE attacks.