SUMMARY

 

1. The alternative complement pathway is a spontaneously activating system unlike the classical complement pathway or the lectin pathway. C3 is continuously cleaved at a low rate in plasma and the alternative pathway is initiated by the formation of C3(H20).

 

2. Subsequent binding to factor B and cleavage by factor D generates the C3 convertase - C3bBb (this enzyme cleaves C3 to generate the opsonin C3b). This C3 convertase is further stabilized by the protein properdin.

 

3. Following the cleavage of C3, the terminal complement pathway is identical to the classical complement pathway with generation of the membrane attack complex by components C5-C9.

 

4. Deficiencies of the early alternative complement pathway are rare but have been described for Factor D (AR) and Properdin (X-linked). Homozygous Factor B deficiency has not been described in humans. Both Factor D and Properdin deficiency are associated with recurrent Neisserial infections.

 

5. The AH50 (alternative pathway hemolytic complement) is the primary screening test for alternative complement deficiencies. Unfortunately, some patients with properidin deficiency can have normal AH50 levels despite having absent levels.

 

6. If the AH50 is low or absent and the CH50 is normal, then Factor D and Properdin levels or function should be tested.

 

7. Patients with factor D or properdin deficiency should receive meningococcal vaccination and prompt treatment of infections.

 

 

 

                                                                                                                                       

OVERVIEW

 

The alternative complement pathway is a spontaneously activating system unlike the classical complement pathway or the lectin pathway.  C3 is continuously cleaved at a low rate in plasma and the alternative pathway is initiated by the formation of C3(H20).   Subsequent binding to factor B and cleavage by factor D generates the C3 convertase - C3bBb (this enzyme cleaves C3 to generate the main complement opsonin C3b).  This C3 convertase is further stabilized by the protein properdin (this acts to prolong the half-life of the C3 convertase).     

 

Following the cleavage of C3, the terminal complement pathway is identical to the classical complement pathway with generation of the membrane attack complex by components C5-C9.  

 

Deficiencies of the early alternative complement pathway are rare but have been described for Factor D (AR) and Properdin (X-linked).  Homozygous Factor B deficiency has not been described in humans.  

 

Factor D Deficiency

     This rare autosomal recessive complement deficiency has been described in a very small number of patients.  Patients most commonly present with systemic Neisseria infections that are more severe than those seen in patients with terminal complement (C5-C9) deficiencies.  An association with autoimmune disease has not been described.  All reported patients have had very low or absent Factor D levels and absent AH50 activity (CH50 is normal).  

 

Properdin Deficiency

     This is the only X-linked complement deficiency.  Properdin deficiency has been reported in more than 70 patients.  This condition is associated with severe invasive infections with Neisseria meningitides and Neisseria gonorrhoeae.  Mortality from these infections is much greater than in patients with terminal complement (C5-C9) deficiencies (75% vs 3%).  Three subsets of properidin deficiency have been described.  

 

     -Type I:    Properdin levels are undetectable
     -Type II:   Circulating properdin levels are 1-10% of normal but function is intact
     -Type III:  Properdin levels are normal but function is absent (this has been described in 1  
                     family).  

                                                         

                       

EVALUATION

 

An evaluation for alternative complement pathway deficiencies should be considered in patients with recurrent Neisserial infections (particularly with unusual serotypes) who demonstrate intact classical complement pathway (normal CH50).

 

Step 1:  Alternative Complement Hemolytic Assay

         

                 - AH50 Assay

 

This test is analogous to the CH50 and is based on the lysis of unsensitized rabbit erythrocytes. Unfortunately, cases of patients with Type I properdin deficiency with normal AH50 results have been reported. If the family history is suggestive of X-linked inheritance, properidin levels should be measured. All reported cases of Factor D deficiency have been characterized by low AH50 activity

 

Step 2:  Individual Alternative Complement Component Levels or function

 

                 -Factor D Function by Hemolytic Assay

                 -Properdin Level by ELISA

 

Both tests are commercially available through National Jewish Laboratories. It is critical to follow the instructions for proper handling of the sample (see resources section).

                 

Step 3: Gene Sequencing

 

Gene sequencing for mutations can be confirmatory and can be useful for genetic counseling.    

 

                                                                                  

MANAGEMENT

 

1. Vaccination for Neisseria - Patients with Factor D deficiency or Properdin deficiency should receive meningococcal vaccinations. Periodic evaluations to confirm the presence of protective menigococcal antibody titers is recommended.

 

2. Prophylactic Antibiotics - Prompt antibiotic management of infections is essential. Administration of prophylactic antibiotics may be an approach for patients suffering from frequent infections despite vaccination.

 

 

                                                                           

RESOURCES

 

Diagnostic Resources 

 

1.  National Jewish AH50 and sample requirements 

2.  Factor D Function by hemolytic assay 

3.  Properdin Levels

 

 

 

            Literature Resources

1.  Sjoholm 2006

     Complement Deficiencies and Disease

2.  Biesma 2001

     A Family with Factor D Deficiency

3.  Sprong 2006

     Factor D Deficiency and Meningococcal Infections

4.  Matthew 2006

     Complement and Properidin Deficiencies in Meningococcal Disease