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Complement Deficiencies

A series of circulating enzymatic serum proteins with nine functional components make up complement. Components of complement are labeled C1 through C9. The first four complement components are numbered out of sequence (in order of their discovery)­C1, C4, C2, and C3 -but the remaining five are numbered sequentially.

When immunoglobulin G (IgG) or IgM reacts with antigens as part of an immune response, they activate C1 , which then combines with C4, initiating the classic complement pathway, or cascade. (An alternative complement pathway involves the direct activation of C3 by the serum protein properdin, bypassing the initial components [CI, C4, C2] of the classic pathway.)

Complement then combines with the antigen-antibody complex and undergoes a sequence of reactions that amplify the immune response against the antigen. This complex process is called complement fixation.

Complement deficiency or dysfunction may increase susceptibility to infection due to defective phagocytosis of bacteria, for example. There may also be a relation to certain autoimmune disorders. Theoretically, any complement component may be deficient or dysfunctional, and many such disorders are under investigation.

Primary complement deficiencies are rare. The most common ones are C2, C4, C6, and C8 deficiencies and C5 familial dysfunction.

More common secondary complement abnormalities have been confirmed in patients with lupus erythematosus, in some with dermatomyositis, in one with scleroderma (and in his family), and in a few with gonococcal and meningococcal infections. The prognosis varies with the abnormality and the severity of associated diseases.

Causes

Primary complement deficiencies are inherited as autosomal recessive traits, except for deficiency of C1 esterase inhibitor, which is autosomal dominant. Secondary deficiencies may follow complement-fixing (complement-consuming) immunologic reactions, such as drug-induced serum sickness, acute streptococcal glomerulonephritis, and acute active systemic lupus erythematosus.

Signs and symptoms

Clinical effects vary with the specific deficiency as follows:

• C2 and C3 deficiencies and C5 familial dysfunction increase susceptibility to bacterial infection (which may involve several body systems simultaneously).
• C2 and C4 deficiencies are also associated with collagen vascular disease, such as lupus erythematosus, and with chronic renal failure.
• C5 dysfunction, a familial defect in infants, causes failure to thrive, diarrhea, and seborrheic dermatitis.
• Defects in latter components of the complement cascade (C5 to C9) may lead to increased susceptibility to infections with Neisseria species.
• C1 esterase inhibitor deficiency (hereditary angioedema) may cause periodic swelling in the face, hands, abdomen, or throat, with potentially fatal laryngeal edema.

Diagnosis

There are blood tests which determine the activity of the complement system. The two most common screening tests, CH50 and APH50, tell the physician which group of complement components have a defect. More specific blood tests for the individual complement components (e.g., C3 or C4 complement) are then performed. Other specialized blood tests, including C1 esterase level, Ham test, and a white blood count , may also be performed.

Treatment

Primary complement deficiencies have no known cure. Associated infection, collagen vascular disease, or renal disease requires prompt, appropriate treatment.

Transfusion of fresh frozen plasma to provide replacement of complement components is controversial because replacement therapy doesn't cure complement deficiencies.and any beneficial effects are transient. Bone marrow transplantation may be helpful but can cause a potentially fatal graft-versushost (GVH) reaction. Anabolic steroids, such as danazol, and anti fibrinolytic agents are often used to reduce acute swelling in patients with hereditary angioedema.

Prevention

There is currently no way to prevent complement deficiencies.