Hypocomplementemia

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 20 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 and are assigned numbers in the order of their discovery.

Pathophysiology

The complement system consists of 7 serum and 5 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.

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 newly 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.

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 antibody. 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.

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 C3 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.

Lectin pathway

The lectin or mannan-binding pathway is activated similar to the classic pathway except that lectin replaces the antibody and an associated protease replaces C1. Instead, mannose-binding protein binds to sugar residues on the surface of a pathogen. Such lectins are associated with a serine protease, similar to the C1r and C1s subcomponents of the classic pathway, that also activates C4 and C2.

Membrane attack complex

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

Regulation

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

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, 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.

Alternate 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. 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.

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.

C4a, C3a, and C5a are anaphylatoxins and bind to mast cells, triggering the release of histamine and other mediators, leading to vasodilation, erythema, and swelling. 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 most microorganisms. They also have a role in neutralization of endotoxins in vitro and protection from their lethal effects in experimental animal models.

Treatment

Medical Care

No specific therapy is recommended at present for most of the complement disorders. However, hereditary angioedema does respond to specific therapy.

• With regard to hereditary angioedema, epinephrine administered early may produce some improvement.
• • Clonal C1-INH administered by infusion aborts acute attacks, and it also is safe and effective for surgical or dental prophylaxis. It has not yet been approved by the US Food and Drug Administration for use in the United States.

  • 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 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 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 recommended.

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

Medication

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

Drug Category: Androgens, synthetic

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

Drug Name	Danazol (Danocrine)
Description	Increases C4 levels and reduces attacks associated with angioedema.
Adult Dose	200 mg PO bid/tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; seizure disorders; hepatic, renal, or cardiovascular insufficiency; pregnancy; lactation; undiagnosed genital bleeding; porphyria; a history of thromboembolism
Interactions	Inhibits hepatic metabolism of carbamazepine, warfarin, cyclosporin, and (possibly) tacrolimus; reduces maintenance requirement for alfacalcidol
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in renal, hepatic, or cardiac insufficiency; caution in seizure disorders and epilepsy; use care in patients with diabetes mellitus, polycythemia, and a history of thrombosis

Drug Name	Stanozolol (Winstrol)
Description	Synthetic androgen with immunosuppressive properties. Increases C1 esterase inhibitor and C4 levels.
Adult Dose	2 mg PO tid initially; reduce to maintenance dose of 2 mg/d or 2 mg qod after 1-3 mo
Pediatric Dose	<6 years: 1 mg/d PO 6-12 years: 2 mg/d PO >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; nephrosis, breast or prostate cancer
Interactions	Increases hypoprothrombinemic effects of oral anticoagulants and hypoglycemic effects of insulin and sulfonylureas
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause peliosis hepatitis, liver cell tumors, and blood lipid changes, with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur