How does properdin deficiency mechanistically increase the risk of infections from encapsulated organisms, such as Neisseria meningitidis, through the alternative pathway of the complement system?

Properdin Deficiency and Increased Risk from Encapsulated Organisms: Mechanism of Alternative Pathway Dysfunction

Properdin deficiency significantly increases susceptibility to encapsulated bacteria, particularly Neisseria meningitidis, by impairing the stabilization of C3 convertase on bacterial surfaces, which critically compromises the alternative pathway of complement activation and subsequent bacterial clearance. 1

Role of Properdin in the Alternative Pathway

Properdin serves two essential functions in the alternative pathway of complement activation:

• Acts as a positive regulator that stabilizes the alternative pathway C3 convertase (C3bBb) on bacterial surfaces, extending its half-life and enabling sustained complement activation 2
• Functions as an initiator and stabilizer of the alternative complement activation pathway, which is critical for defense against encapsulated organisms 3

Mechanism of Increased Susceptibility in Properdin Deficiency

Impaired C3 Convertase Stability

• In normal immune function, properdin binds to and stabilizes the C3bBb complex on bacterial surfaces, preventing its rapid dissociation 2
• Without properdin, the C3bBb convertase complex becomes unstable and rapidly dissociates, significantly reducing C3b deposition on bacterial surfaces 2
• Even at high serum concentrations (80%), maximal alternative pathway-mediated C3 deposition on Neisseria species requires properdin 2

Compromised Bacterial Recognition and Clearance

• Properdin deficiency results in markedly decreased alternative pathway activity while classical and lectin pathways remain intact 3
• Encapsulated bacteria like N. meningitidis rely heavily on alternative pathway activation for recognition and clearance 1
• The polysaccharide capsules of these organisms resist classical pathway activation, making the alternative pathway crucial for defense 1

Impact on Opsonization and Bacterial Killing

• Properdin deficiency impairs alternative pathway-dependent generation of C3b when activated by bacteria 4
• Higher antibody levels are needed for other clearance mechanisms (like opsonization) to function effectively in properdin-deficient individuals 1
• Vaccination can enhance classical pathway-mediated killing but only moderately improves alternative pathway-mediated killing in properdin-deficient sera 5

Clinical Significance and Manifestations

• N. meningitidis is the primary bacterial pathogen affecting persons with properdin deficiency 1
• Properdin deficiency is associated with a high mortality rate when infected with N. meningitidis 3
• Properdin deficiency has been significantly associated with recurrent otitis media and pneumonia 3
• Properdin deficiency can be associated with fulminant forms of meningococcal disease in approximately 2/3 of cases 6

Vaccination Considerations in Properdin Deficiency

• Persons with properdin deficiency should receive a 2-dose primary series of meningococcal conjugate vaccine administered 8-12 weeks apart 1
• Booster doses should be administered every 5 years for those who received primary vaccination at age 7 years or older 1
• While vaccination promotes classical pathway-mediated killing, it only moderately enhances alternative pathway function in properdin-deficient individuals 5
• Antibody titers wane more rapidly in persons with complement component deficiencies, necessitating more frequent booster doses 1

Comparison with Other Complement Deficiencies

• Properdin deficiency is X-linked, unlike most other complement deficiencies 3
• While late complement component deficiencies (C5-C9) primarily affect the membrane attack complex formation, properdin deficiency specifically impairs the alternative pathway activation and C3b deposition 1
• Properdin-deficient individuals may mount normal antibody responses to vaccination but still have impaired alternative pathway function 5

Clinical Implications

• Screening for properdin deficiency should be considered in all patients presenting with N. meningitidis infection before age 6 months or after age 5 years 6
• Identification of properdin-deficient patients enables family screening and appropriate prophylaxis 6
• In polymicrobial infections, properdin also plays a protective role beyond defense against Neisseria species 4