OVERVIEW: What every practitioner needs to know

Are you sure your patient has a complement deficiency? What are the typical findings for this disease?

Complement, a part of the innate immune system, is composed of more than 30 plasma- and cell membrane–bound proteins that function cooperatively in antimicrobial and inflammatory reactions. The complement system is composed of three pathways: the classical pathway, the alternative pathway, and the lectin pathway (Figure 1). The classical pathway is typically activated by antibody. The alternative and lectin pathways are evolutionarily older than the classical pathway and do not require antibody for activation.

Most of the genetically determined deficiencies of the complement system are inherited as autosomal recessive traits, with the exception of C1 esterase inhibitor, which is inherited as an autosomal dominant trait, and properdin deficiency, which is inherited as an X-linked recessive trait. A complete deficiency of a complement component is rare, and partial deficiencies are rarely of any clinical significance. Infections are prominent in many complete complement deficiencies, and the kinds of infections are determined by the function of the deficient protein in host defense. Many deficiencies are also associated with rheumatologic disorders for reasons that are not completely clear.

Complement has many functions, including promoting phagocytosis of pathogens by acting as an opsonin, inducing lysis of bacteria or susceptible cells and generatinginflammation by products formed during complement activation. A wide range of diseases are therefore associated with abnormalities or deficiencies in complement and depend on the specific protein that is abnormal.

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The classical complement cascade is composed of 11 proteins and these are, in order, C1q, C1r, C1s, C4, and C2-C9. Activation of the alternative pathway begins with the C3 molecule. C3 is the central protein of all three complement pathways and plays a critical role in the opsonization of pathogens. In addition, all three complement pathways result in the formation of the membrane attack complex, which is vital to bactericidal activity. C5a, a product of C5, also acts as a chemotactic factor and directs migration of phagocytes.

The lectin pathway is initiated by the binding of mannose-binding lectin to certain sugars, which are often present on the cell surfaces of pathogens, and joins the classical pathway at the level of C3. A second set of initiating proteins, the ficolins, interact with acetylated sugars and proceed as in the mannose-binding lectin (MBL) pathway.

In general, C3-deficient individuals therefore have an increased rate of infection involving high-grade pathogens of all types. Individuals with defects in C5-C8 have particular problems with systemic infections involving the genus Neisseria because these pathogens typically require lysis. Abnormalities in the level of MBL are common, and it estimated that one third of the population has levels of MBL below normal. There are reports these patients are subject to an increased incidence of infections with a variety of pathogens.

Complement is often associated with unregulated inflammation, and many mechanisms exist for downregulation of complement activation. This is underscored by a recent report that activation of C5 contributes to tissue damage in pneumococcal meningitis. Although deficiencies in complement components are rare, defects in the proteins that regulate complement are far more common. For example, C1 esterase inhibitor deficiency is the underlying defect in hereditary angioedema, discussed in a separate chapter.

A series of proteins are important in the regulation of C3. Two of these proteins, factors H and I, are circulatory proteins. Defects in factor H have been associated with glomerulonephritis, the presence of macular degeneration in the aged, and atypical hemolytic uremic syndrome. Membrane proteins, CD46 and CD55, also control C3 levels, and defects in CD46 have also been associated with atypical hemolytic uremic syndrome and macular degeneration. Similarly, gain of function mutations in C3 and factor B of the alternative pathway are associated with these diseases.

CD59 on hematologic cells is required to prevent unregulated complement lysis. This protein is bound to cells by a phosphoinositol linkage and this linkage is defective in individuals with paroxysmal nocturnal hemoglobinuria. These patients present with unregulated erythrocyte hemolysis and recently have been treated with a monoclonal antibody to C5.

C1, C2, and C4 deficiencies are associated with pyogenic infections and rheumatologic disorders, particularly systemic lupus erythematosus. C3 deficiency is also associated with pyogenic infections and rheumatologic disorders. Infections are usually caused by encapsulated organisms, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. C5, C6, C7, C8, and C9 deficiencies are associated with increased susceptibility to infection with Neisseria organisms. Properdin deficiency is also associated with increased susceptibility to infection with Neisseria organisms.

MBL deficiency is associated with recurrent infections, including upper respiratory tract infections, abscesses, and sepsis. Low levels may also be associated with more severe lung disease in cystic fibrosis. Heterozygous deficiency of C1 inhibitor is associated with hereditary angioedema. CD46 deficiency is associated with atypical hemolytic uremic syndrome. Factor H deficiency is associated with glomerulonephritis and atypical hemolytic uremic syndrome. A polymorphism of factor H is also associated with age-related macular degeneration. Factor I deficiency is associated with pyogenic infections and atypical hemolytic uremic syndrome. CD59 deficiency leads to paroxysmal nocturnal hemoglobinuria.

What other disease/condition shares some of these symptoms?

Certain conditions can lead to secondary deficiencies in complement proteins. This include systemic lupus erythematosus and related disorders, vasculitis, serum sickness, and sepsis. Any process that results in complement activation or consumption can lead to reduced, but not absent, levels of complement proteins. Certain conditions, for example cirrhosis or malnutrition, may decrease liver synthesis and lead to reduced, but not absent, levels of complement proteins.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Deficiencies of the early components of the classical pathway (C1, C4, and C2), C3, and the terminal components (C5-C9) can be detected with a total serum hemolytic complement (CH50) assay. A deficiency in any one of these proteins leads to a marked reduction or absence of total hemolytic complement activity. The alternative pathway hemolytic assay (AH50) is abnormal with deficiencies of C3, the terminal components (C5-9), and alternative pathway control proteins, including factor D, factor I, and properdin. An enzyme-linked immunoassay is typically used to measure MBL levels. The ability to measure C3 and C4 levels is widely available, and more specialized laboratories can measure the levels of other specific complement proteins.

Would imaging studies be helpful? If so, which ones?

Imaging studies are rarely required for diagnosis but may be useful in the evaluation of associated infectious or rheumatologic complications.

If you are able to confirm that the patient has a complement deficiency, what treatment should be initiated?

Standard therapy includes early detection of infections and aggressive treatment with appropriate antimicrobial therapy. Consultation with an infectious disease subspecialist may be necessary. Overall, the management of inherited complement deficiencies is largely supportive. Patients who have recurrent infections may benefit from antimicrobial prophylaxis. Patients should also receive all routine vaccinations, particularly those against organisms to which they are most susceptible.

Complement proteins have rapid turnover, so replacement of specific complement components is typically not recommended. In addition, a patient may generate an immune response to the infused protein. Autoimmune disorders require management by a subspecialist and careful use of immunosuppressive therapy.

What causes this disease and how frequent is it?

Little is known regarding the incidence and prevalence of complement deficiencies.

How can complement deficiency be prevented?

Families with inherited complement deficiencies should receive genetic counseling.

What is the evidence?

Walport, MJ. “Complement. First of two parts”. N Engl J Med. vol. 344. 2001. pp. 1058-66.

Walport, MJ. “Complement. Second of two parts”. N Engl J Med. vol. 344. 2001. pp. 1140-4.

Frank, MM, Austen, KF, Frank, MM, Atkinson, JP. “Complement system”. 2001.

Botto, M, Kirschfink, M, Macor, P. “Complement in human diseases: lessons from complement deficiencies”. Mol Immunol. vol. 46. 2009. pp. 2774-83.

Liszewski, MK, Atkinson, JP, Volanakis, JA, Frank, MM. “Regulatory proteins of complement”. 1998. pp. 149-66.

Frank, MM. “Complement disorders and hereditary angioedema”. J Allergy Clin Immunol. vol. 125. 1010. pp. S262-71.