SUMMARY
1. The classical complement pathway is activated by immune complexes that contain IgM or IgG antibodies bound to antigen. Activation of this pathway leads to opsonization (by C3b) of antibody coated bacteria with subsequent targeting by phagocytes that possess complement receptors.
2. The terminal complement components (C5-C9) form the membrane attack complex (MAC) which functions to lyse certain bacteria such as Neisseria species.
3. Autosomal recessive deficiencies in each individual complement component (C1 - C9) have been described in humans.
Early complement deficiencies (C1q, C1r, C1s, C4, and C2): These typically do not result in a significant increased susceptibility to infections. Rather, patients develop autoimmune complications, particularly systemic lupus erythematosus (SLE). C1q plays a role in clearance of apoptotic cells. A defect in this pathway may create conditions that allow for the development autoimmunity to self-antigens. Patients with C1q deficiency have the highest incidence of SLE (90%).
C3 deficiency: These patients develop recurrent infections with encapsulated organisms (pneumococcus, H. influenzae). The complement fragment C3b acts as the main opsonin of the complement system.
Terminal complement (C5-C9) deficiencies: Patients with these deficiencies have recurrent systemic infections with Neisseria species (N. meningitides and N. gonorrhoeae). Meningococcal infections with unusual serotypes (W-135, X, Y, and Z) are seen rather than typical serotypes (A, B, and C).
4. The CH50 (total hemolytic complement) is the primary screening test for classical complement deficiencies. A complete deficiency of any one component results in an undetectable CH50. Serum specimens left at room temperature for too long can result in erroneous low CH50 values.
5. Individual complement compenents should be measured if the CH50 is low or undetectable. C2, C4, and C1q are the most common deficiencies followed by terminal complement (C5-C9) deficiencies.
6. Treatment strategies for patients with recurrent infections include the use of prophylactic antibiotics or vaccination against encapsulated organisms (pneumococcus, H. influenza). Patients with terminal complement deficiencies should have meningococcal vaccinatons due to the high risk of invasive meningococcal disease.
OVERVIEW
The classical complement pathway is activated by immune complexes that contain antigen bound to IgM or IgG (IgG1, IgG2, or IgG3). Initiation of this pathway results in the activation of two key antimicrobial mechanisms. First, C3b is deposited on the surface of microbes and acts as an opsonin that binds complement receptors expressed on the surface of phagocytes (thus greatly increasing the efficiency of phagocytosis). Second, the terminal complement components (C5-C9) form the membrane attack complex (MAC) which creates a pore in the membrane of certain microorganisms (resulting in cell lysis). Autosomal recessive deficiencies in each individual complement component (C1-C9) have been described in humans.
SPECIFIC DEFICIENCIES:
Early complement deficiencies (C1q, C1r, C1s, C4, and C2)
Early complement component deficiencies are the most common deficiencies (C2 deficiency is the most common). These deficiencies typically do not result in an increased susceptibility to severe infections. However, patients with C2 deficiency have been reported to develop infections with encapsulated organisms including Streptococcus, H. influenza, and Neisseria species.
The most common clinical feature is the development of autoimmune syndromes, particularly SLE. The incidence of SLE is 90% for C1q, 75% for C4, and 55% for C1r and C1s deficiency. This increased risk may be explained by that fact that C1q is important for the clearance of immune complexes and apoptotic cells.
C3 deficiency
The cleavage of C3 generates C3b which is the key opsonin of the complement system. Opsonization is particularly important for defense against encapsulated organisms. Patients with homozygous C3 deficiency can develop recurrent infections with encapsulated bacteria. Immune complex disease in the form of glomerulonephritis (without features of SLE) has also been reported.
Terminal complement (C5-C9) deficiencies
The terminal complement components (C5-C9) form the membrane attack complex. Patients with these deficiencies have recurrent systemic infections with Neisseria species (N. meningitides and N. gonorrhoeae). Meningococcal infections with unusual serotypes (W-135, X, Y, and Z) are seen rather than typical serotypes (A, B, and C). C9 deficiency is the most common complement deficiency in Japan occurring in 0.1% of the population.
EVALUATION
An evaluation for classical complement deficiencies should be considered in patients with recurrent infections with encapsulated organisms. A history of autoimmune disease (SLE) may be seen in early complement deficiencies. Recurrent Neisserial infections can be a feature of terminal complement deficiencies.
Step 1: Total Hemolytic Complement
-CH50 Assay
-This test measures the ability of a patients serum to lyse sheep red blood cells coated with antibody.
-All components of the classical compement pathway (C1-C9) are required yield a normal CH50 value.
-A complete deficiency of any of the classical complement components will yield a very low or undetectable CH50 value. An AH50 (alternative pathway) Assay may be quite useful for determining the location of the defect.
-If AH50 levels are also undetectable in addition to CH50, this would indicate that there is a deficiency in C3, C5, C6, C7, C8, or C9, but not in the early complement components (C1, C2, C4). However, if CH50 levels are low but the AH50 is normal, this would indicate that the deficiency may be present in an early complement component (C1, C2, C4).
Step 2: Individual Classical Complement Component Levels (if CH50 is low)
-C1q, C1s, C1r, C2, C3, C4, C5, C6, C7, C8, C9 Levels
-Testing for each of the above individual complement component levels is available through National Jewish (see resources section).
-C2, C4, and C1q are the most common deficiencies.
-Testing for terminal components C5-C9 should be a priority for patients who have undetectable CH50 and recurrent Neisserial infections.
Step 3: Gene Sequencing
-Identification of mutations in complement protein genes can confirm the diagnosis.
MANAGEMENT
Treatment of Autoimmune Disease appropriate management of autoimmune disease will be the key issue for many patients with early complement deficiencies.
1. Vaccination for Encapsulated Bacteria
For patients suffering from infections with encapsulated organisms, available vaccinations for these bacteria (pneumoccus, H. Influenzae) should be administered. Patients with terminal complement component deficiencies should receive meningococcal vaccinations. Periodic evaluations to confirm the presence of protective specific antibody titers is recommended.
2. Prophylactic Antibiotics
-Prompt antibiotic management of infections is essential. Administration of prophylactic antibiotics may be an adjuncive therapy for patients suffering from frequent infections despite vaccination.
RESOURCES
Diagnostic Resources
1. National Jewish - CH50
2. National Jewish - AH50
3. National Jewish - Individual Complement Components (C1q, C1s, C1r, C2, C3, C4, C5, C6, C7, C8, C9 Levels)
Literature Resources
Infectious diseases associated with complement deficiencies
2. Sjoholm 2006
Complement deficiencies and disease (review)
SLE and complement deficiency
C7 deficiency in 9 families
5. Fijen 1999
Assessment of complement deficiency in patients with meningococcal disease