SUMMARY
1. The Mannose Binding Lectin (MBL) pathway functions in a manner that is very similar to the classical complement pathway. However, instead of activation by antibody bound to microbial antigens, the MBL pathway is activated by the binding of MBL to bacterial carbohydrates.
2. Following this binding, MASP-1 and MASP-2 form a complex with MBL and cleave C3. C3 cleavage generates C3b (the main complement opsonin) and also activates the terminal complement pathway (MAC).
3. Thus, the MBL pathway and classical complement pathway are identical from C3 onwards through the formation of the membrane attack complex. The only difference is the way in which the C3 cleavage enzyme (C4bC2a) is generated (antigen-antibody complexes vs. carbohydrate-MBL complexes).
4. MBL deficiency occurs with high frequency in the population and is inherited as an autosomal recessive trait. Up to 5% of the population has a homozygous mutation in the MBL gene (MBL2) resulting in markedly reduced MBL levels (<100 ng/ml). Approximately 30% of the population is heterozygous for an MBL mutation resulting in moderately reduced MBL levels (<400 ng/ml).
Mannose Binding Lectin (MBL) Deficiency: The deficiency of MBL has been associated with an increased frequency of pyogenic infections with bacteria such as S. pneumoniae. However, most patients with MBL deficiency do not have an increased incidence of infections (this may be due to redundancy in the immune system). An increased incidence of SLE has been reported in individuals with MBL deficiency.
MASP2 Deficiency: This deficiency has been reported in a single patient who had a history of recurrent pneumococcal pneumonia, ulcerative colitis, suspected SLE, and erythema multiforme bullosum. The serum MBL levels were normal but the functional activity was decreased.
Ficolin 3 Deficiency: Ficolin 3 is another lectin that recognizes microbial carbohydrates and activates MASPs to create the C3 convertase. A single patient with a homozygous mutation in Ficolin 3 with no detectable serum levels has been reported. This patient had a history of invasive infections with H. influenza, S. pneumoniae, and Pseudomonas. This patient had normal serum MBL levels but decreased functional activity.
5. Analysis of serum MBL levels is the first step in patient evaluation. MBL levels are normal for patients with MASP2 or Ficolin 3 deficiency.
6. Additional testing includes MBL functional testing (this is low in MBL, MASP2, and Ficolin 3 deficiency). If MBL levels are normal but function is decreased, MASP2 or Ficolin 3 deficiency should be suspected.
7. Treatment strategies for patients include the use of prophylactic antibiotics or the administration of vaccinations for encapsulated bacteria.
OVERVIEW
The mannose binding lectin (MBL) pathway functions in a manner that is very similar to the classical complement pathway. However, instead of activation by antibody bound to microbial antigens, the MBL pathway is activated by the binding of MBL (a pattern recognition molecule) to bacterial carbohydrates (mannose, N-acetyl-d-glucosamine, N-acetyl-mannosamine, fucose, and glucose). The structure of MBL is quite similar to C1q of the classical complement pathway.
Once MBL binds microbial carbohydrates, it forms a complex with the MBL-associated serine proteases (MASP-1 and MASP-2). MASP-1 and MASP-2 are analogous to C1r and C1s, acting to cleave C2 and C4 to form the C3 convertase (C4bC2a) that will go on to cleave C3. C3 cleavage generates C3b (the main complement opsonin) and also goes on to activate the terminal complement pathway (MAC).
Thus, the MBL pathway and classical complement pathway are identical from C3 onwards through the membrane attack complex. The only difference is the way in which the C3 cleavage enzyme (C4bC2a) is generated (antigen-antibody complexes vs. carbohydrate-MBL complexes).
MBL deficiency is an autosomal recessive condition that occurs with high frequency in the general population. Up to 5% of the population has a homozygous mutation in the MBL gene (MBL2) resulting in markedly reduced MBL levels (<100 ng/ml). Approximately 30% of the population is heterozygous for an MBL mutation resulting in moderately reduced MBL levels (<400 ng/ml).
Mannose Binding Lectin (MBL) Deficiency: The deficiency of MBL has been associated with an increased frequency of pyogenic infections with bacteria such as S. pneumoniae particularly in young children and neonates. However, most patients with MBL deficiency do not have an increased incidence of infections. This may be due to redundancy present in the immune system. An increased incidence of SLE has also been reported in individuals with MBL deficiency.
MASP2 Deficiency: This deficiency has been reported in a single patient who had a history of recurrent pneumococcal pneumonia, ulcerative colitis, suspected SLE, and erythema multiforme bullosum. The serum MBL levels were normal but the functional activity was decreased.
Ficolin 3 Deficiency: Ficolin 3 is another lectin that recognizes microbial carbohydrates and activates MASPs to create the C3 convertase. A single patient with a homozygous mutation in Ficolin 3 with no detectable serum levels of protein has been reported. This patient had a history of invasive infections with H. influenza, S. pneumoniae, and Pseudomonas. This patient had normal serum MBL levels but decreased functional activity.
EVALUATION
Step 1: Serum MBL Level
-MBL Level
-This test is commercially available through IBT laboratories and National Jewish laboratories.
-Low or absent levels should be interpreted with caution (many patients have no increased infections despite low MBL levels).
-This test will be normal for patients with MASP2 or Ficolin 3 defects.
-MASP2 and Ficolin 3 protein levels are not available commercially.
Step 2: MBL Function
-MBL Functional Assay
-This test is an enzyme immunoassay that measures the capacity of MBL to activate C4. It is commercially available through IBT laboratories.
-MBL, MASP2, and Ficolin 3 deficiency would all be expected to result in a low MBL function test.
Step 3: Gene Sequencing
-MBL2, MASP2, FCN3 gene sequencing
-These tests can be confirmatory but are available only at specialized research centers.
MANAGEMENT
1. Vaccination for Encapsulated Bacteria - For patients suffering from infections with encapsulated organisms, available vaccinations for these bacteria (S. pneumoniae, H. Influenzae) should be administered.
2. Prophylactic Antibiotics - Administration of prophylactic antibiotics may be an option for patients suffering from frequent infections despite immunizations.
RESOURCES
Diagnostic Resources (LAB ORDER FORMS)
1. NATIONAL JEWISH - MBL Levels
2. IBT - MBL Levels and Function
Literature Resources
1. Kilpatrick 2002
MBL clinical significance and applications
2. Roy 2002
MBL deficiency and risk of invasive pneumococcal disease
3. Frakking 2007
Low MBL levels in neonates at birth is associated with increased risk of sepsis and pneumonia
4. Stengaard-Pedersen 2003
MASP2 Deficiency (1 case)
5. Munthe-Fog 2009
Ficolin 3 Deficiency (1 case)
SLE and complement deficiencies