|Year : 2002 | Volume
| Issue : 2 | Page : 119-125
|Disorders of the Complement System: An Overview
Rajiv Gupta, Tejinder Ahuja, Mahendra Agraharkar
Nephrology Division, Department of Medicine, University of Texas, Medical Branch, Galveston Texas, USA
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|How to cite this article:|
Gupta R, Ahuja T, Agraharkar M. Disorders of the Complement System: An Overview. Saudi J Kidney Dis Transpl 2002;13:119-25
The complement system is a multimolecular system composed of more than 20 proteins, synthesized mainly by the liver; seven serum and five membrane regulatory proteins, one serosal regulatory protein and eight cell membrane receptors that bind complement fragments. These proteins are preceded by the letter 'c' and are assigned numbers in order of their discovery. 
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Gupta R, Ahuja T, Agraharkar M. Disorders of the Complement System: An Overview. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2020 Feb 29];13:119-25. Available from: http://www.sjkdt.org/text.asp?2002/13/2/119/33122
The complement system is an interactive system with one reaction leading to another in the form of a cascade, which is initiated by a wide variety of substances [Table - 1], and has two phases.
In the first phase, a series of specific interactions leads to the formation of intrinsic complement proteinases termed C 3 convertase. Both the classical and the alternative pathways, which use different proteins, produce C 3 convertase.
The classical pathway has two units; the recognition unit, which consists of a tricomplex of C 1q , two molecules of C 1r and two molecules of C 1s held together by calcium, and an activation unit C 2 , C 3 and C 4 . The sequence starts with binding of two or more C1q recognition units to Fc nonantigen binding part of antibody. This induces a conformational change leading to autoactivation of C 1r that then cleaves C 1s to its active state. This acts like C 1 esterase and cleaves C 2 and C 4 to form C 2a C 4b , which is the C 3 esterase that cleaves C 3 to form C 3b. C 1q can also be activated by mycoplasma, RNA viruses, bacterial endotoxins and cell membranes of some organelles.
Viruses, fungi, bacteria, parasites, cobra venom, IgA and polysaccharides can activate the alternate pathway. C 3b binds to Factor B that is cleaved by Factor D to B b .
C 3b B b complex then acts as the C 3 convertase and generates more C 3 through an amplification loop. The binding of Factor H to C 3b increases its inactivation by Factor I. Properdin stabilizes C 3b preventing its inactivation by Factors H and I.
The second phase involves the cleavage of C 3b that generates multiple biologically important fragments and large potentially cytolytic complexes.
Only five proteins (C 5 -C 9 ) are involved in direct killing of cells. C2 a 4 b 3 b complex from the classical pathway or C 3b B b cleaves C 5 . C 5b activates the terminal complement pathway by associating C 6 , C 7 and C 8 to form macromolecular complexes denoted as C 5b-8 . C 9 molecules bind to this complex to form ring like pores, which lead to transmembrane channels that cause cell lysis. 
The biologic effects of the complements include promotion of chemotaxis, anaphylaxis, opsonization and phagocytosis of microorganisms and immune complex clearance from the circulation.  The majority of complements are acute phase reactants and their concentration increases in infection, trauma and injury.
C 4a , C 3a and C 5a are anaphylatoxins that bind to mast cells and trigger the release of histamine and other mediators leading to vasodilatation, redness and swelling.
C 3b opsonizes the antigen-antibody complex, which helps phagocytosis. C 3b coated particles bind to B-lymphocytes and activate them to enhance the primary antibody response. They also bind to erythrocytes, which 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 antibody amount is limited, the fixation of C 3b to the viral antigenantibody complex increases neutralization.
The terminal components of the complement system result in lysis of virus infected cells, tumor cells and most microorganisms.
Evaluation of Complement System
Complement function should be evaluated in any patient with collagen vascular disease, chronic nephritis, angioedema, recurrent pyogenic infections, Neisseria More Details meningitidis or disseminated gonococcal infections, or a second attack of septicemia at any age.
It measures the ability of the complements to participate in hemolysis. The total hemolytic complement activity (CH 50 ) tests the capacity of the classical pathway proteins and membrane attack complex to lyse the antibody-coated erythrocytes. The dilution of the serum that lyses 50% of the cells marks the endpoint. CH 50 is zero in congenital deficiencies of C 1 to C 8 and its value is half-normal in C 9 deficiency. Also deficiency in Factor H or I result in a low value due to C 3 consumption. Thus it is very useful as a functional screening test for most diseases of the complement system. 
The alternative hemolytic complement activity (AH 50 ), although less commonly used, measures the alternative pathway function.
Selective Complement Assay
Serum concentrations of C 3 , C 4 and Factor B are easily available. Decrease in C 4 represents the classical pathway activation; decrease in Factor B signifies the alternative pathway activation; decrease in C 3 reflects activation of either pathway.
Low titers of both C 3 and C 4 suggest activation of the classical pathway by the immune complexes. On the other hand, low C 3 and normal C 4 suggest the alternative pathway activation. This difference may be useful in differentiating nephritis due to immune complex deposition from that due to the nephritic factor (NeF). Furthermore, Factor B is reduced in the NeF-induced nephritis. However, normal complement levels do not rule out complement activation that is biologically important but not massive enough to lower the serum concentrations.
Primary Complement Disorders
Congenital complement deficiencies can involve most of the complement components.
1) Classical Pathway
a) C 1q / C 1r / C1s deficiency
It may be hereditary or acquired. It is transmitted as an autosomal recessive trait. A few patients have a dysfunctional protein.
Most patients with C 1q deficiency have systemic lupus erythematosus (SLE) associated with a variety of autoantibodies such as antinuclear antibody, anti double stranded (dsDNA) antibody, autoantibody to C 1q , low CH 50 and C 1q levels with normal levels of the other complements.  SLE is more severe in the homozygous deficiencies suggesting that C 1q is vital in clearing immune complexes through its participation in the generation of C 3 .  Low C1q levels are also found in SLE like syndrome without typical serology, hypocomplementemic urticarial vasculitis syndrome (HUVS), multiple myeloma, hypogammaglobulinemia and membranoproliferative glomerulonephritis (GN). Plasmapheresis has been used for restoration of C 1q levels. However, the use of fresh frozen plasma is associated with the development of antibodies to C1 q , thereby limiting its use.
The loci of C 1r /C 1s are closely linked and the deficiencies usually occur together and are associated with a high incidence of vasculitis.
b) C4 deficiency
It is transmitted as an autosomal recessive trait or may be acquired.  Partial C 4 deficiency predisposes to SLE. Complete C 4 deficiency is rare. Characteristics of SLE with complete C 4 deficiency include early onset, mild renal disease, infection, skin manifestations, and anti SSA antibody without anti dsDNA antibody. However, it may be asymptomatic.
Defective expression or function of C 4 may also lead to SLE associated with drugs such as hydralazine, penicillamine and procainamide, which react with the thioester bond of C 4a and block its function.
c) C 2 deficiency
This is the most common inherited complement deficiency. The transmission is autosomal recessive in nature. Immune complex disease is common.  It may manifest as life threatening septicemia especially due to pneumococci.
d) C 3 deficiency
This is the most important central molecule in the complement system. C 3 deficiency produces recurrent severe pyogenic infections due to pneumococci and meningococci, rash, mesangiocapillary GN and mild immune complex disease.  It is transmitted as an autosomal recessive trait.
2) Alternate Pathway Defect
It has an autosomal recessive mode of transmission. Deficiency in Factor D and Factor B presents with recurrent infection.
3) Membrane Attack Pathway Defect
It is transmitted as an autosomal recessive trait. Most of the patients with deficiency of C 5-9 components have meningococcal meningitis and extragenital or disseminated gonococcal infection. The predisposition to Neisseria may be due to deficient serum bacteriolysis. Some patients may have collagen vascular disease.
4) Control Proteins
a) Factor I/ Factor H deficiency
Factor I deficiency has an autosomal recessive transmission and leads to the prolonged presence of C 3b causing a constant activation of the alternative pathway that ultimately leads to the depletion of C 3 . It was initially reported as C 3 deficiency due to hypercatabolism of C 3 . It presents with severe pyogenic infections.
Factor H helps factor I in the breakdown of C 3 convertase of the alternative pathway. So its deficiency produces the same effects as factor I deficiency.
b) Properdin deficiency
This is transmitted as an X-linked trait. Patients are all male and there is a family history of male deaths due to meningococcal meningitis. CH 50 is normal. Patients may have discoid lupus or dermal vasculitis.
c) C 1 inhibitor deficiency
C 1 inhibitor (C 1 INH) inhibits C 1r and C 1s by binding covalently to them and causes disassembly of the C 1 macromolecular complex. The inhibitor is synthesized in the liver and blood monocytes and its gene is located on chromosome 11. It is transmitted as an autosomal dominant trait. In 85% of patients there is a marked reduction of the inhibitor (as low as 5-30% of normal values). In 15% of the patients a dysfunctional protein is present. The absence of the inhibitor causes uncontrolled C 1 activity with breakdown of C 4 and C 2 and release of a vasoactive peptide from C 2 .
C 1 INH deficiency usually leads to a disease called hereditary angioedema, which manifests as episodic attacks of nonpitting, nonpruritic, localized edema that progresses rapidly without urticaria or redness. Swelling of the intestinal wall can cause intense abdominal cramping with vomiting and diarrhea. Laryngeal edema may prove fatal. Sometimes, subcutaneous edema may be absent. Attacks last 2-3 days and subside gradually. They occur after menses, emotional stress or vigorous exercise. They may begin in the first two years of life, but are usually not severe till late childhood or adolescence. C 4 and C 2 levels may decrease during an acute attack.  Collagen vascular disease and glomerulonephritis have been reported.
Acquired disease may occur from autoantibody to C1 INH or B-cell cancer.
d) Complement receptor 1 (CR 1 ) deficiency
Deficiency of CR1 on erythrocytes leads to impaired clearance of immune complexes thereby contributing to collagen vascular disease. The disorder is possibly inherited.
e) Decay Accelerating factor (DAF)/ CD 59 deficiency
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 and 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 X-chromosome (pig-A) in the hematopoietic stem cell. The gene encodes the glycosyl-phosphatidylinositol molecule, which anchors about 20 proteins (including DAF, CD 59 and C 8 BP) to the cell membrane. The absence of this anchor results in absence of these proteins making the erythrocytes more susceptible to complement mediated lysis.  Isolated DAF deficiency does not cause PNH, while isolated CD 59 deficiency has been reported to cause mild disease.
f) Serosal protease deficiency
Serosal fluids contain a complement regulatory protease that destroys C 5a and interleukin 8 (IL-8) that are chemotactic for neutrophils. Deficiency of this factor in the peritoneal and synovial fluids results in the familial Mediterranean fever More Details characterized by recurrent episodes of fever and painful inflammation of joints, pleural and peritoneal cavities.
Secondary Complement Disorders
1) Immunologic disorders: These are mediated by immune complexes and complements consumed in the process.
Complements are consumed via the classical pathway during active immune complex deposition. Accordingly, patients with active lupus characteristically have decreased C 3 , C 4 and CH 50 . However hypocomplementemia can also be found in SLE patients without active disease activity. Normal C 3 with very low or absent CH 50 is suggestive of a congenital deficiency. C 2 and C 4 deficiencies are common. Split products may correlate more closely with disease activity in SLE.
b) Hypocomplementemic glomerulonephritis
Serum from patients with membranoproliferative GN contains a nephritic factor (NeF), which causes activation of the alternative pathway. The NeF is an IgG autoantibody that binds and stabilizes C 3b B b and prevents its dissociation by Factor H. This leads to prolonged C 3 conversion and depletion. This disorder has been described in partial lipodystrophy. In acute postinfectious nephritis, an IgG nephritic factor that binds and protects C 4 and C 2 has been described. Complement levels eventually return to normal in about eight weeks.
Mesangioproliferative GN has been described in association with complement depletion.  Lupus nephritis is one of the important glomerulonephritidis associated with hypocomplementemia. Other causes like fibrillary GN and immunotactoid GN have been reported.
c) Infectious endocarditis
Circulating immune complexes are found in 90% of the patients with endocarditis; rheumatoid factor is present in 10-70% of the cases. Hypocomplementemia is a frequent but nonspecific marker of GN in bacterial endocarditis. Ninety percent of patients with diffuse GN and about 60% of patients with focal GN have reduced complement levels. Typically, the activation of the classical 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 GN.
d) Miscellaneous causes
Formation of immune complexes with complement consumption has been found in acute hepatitis B and C. , These are responsible for extra-hepatic manifestations of arthralgia and nephritis. Immune complexes are also present in infectious mononucleosis, malaria, dengue fever, lepromatous leprosy and bacteremic shock. In addition, diseases such as Reye's syndrome, primary biliary cirrhosis, celiac disease, multiple myeloma, hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) and urticarial vasculitis have also been implicated.  Burns, hemodialysis with cellophane membranes, cardiopulmonary bypass and injection of iodinated radiocontrast material cause a direct activation of the alternative pathway.
2) Non-immunological causes
Patients with severe malnutrition and anorexia nervosa have low complement levels. The serum concentration of complement may improve after correction of the nutritional deficiency. Severe liver cirrhosis and hepatic failure result in decreased C 3 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 sickle cell disease, postsplenectomy patients and the nephrotic syndrome.
| Management|| |
At present, no specific therapy exists for most complement disorders, except for hereditary angioedema. Vapor heated C1INH infusions abort acute attacks and are also safe and effective for surgical or dental prophylaxis.  Danazol, a synthetic androgen increases the serum concentration of C1INH and prevents attacks in adults. It is not recommended in children. Precipitating factors such as trauma should be avoided. Angiotensin converting enzyme inhibitors are contraindicated in these patients.
Plasmapheresis has been used to replace the deficient complement proteins. But overall it has not proven to be a safe and efficient mode of therapy. Its use in SLE has not been with definite success. Supportive management can prove helpful in these patients. Immunization of the patient and household contacts for pneumococci,
Hemophilus influenzae and Neisseria meningitidis More Details should be undertaken. If fever develops in these patients, cultures should be obtained and antibiotic therapy should be started early. Adequate information should be given to the patient or guardian for possible use by school or physicians. Attempts should be made to identify the specific defect.
Replacement therapy with recombinant complement proteins may soon be possible and gene therapy may become a viable option in the near future.
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