G6PD-deficiency infectious haemolysis: a complement dependent innocent bystander phenomenon

Area of Science:

• Immunology
• Hematology
• Complement System
• Red Blood Cell Biology

Background:

• Viral hepatitis and pneumococcal pneumonia can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• Red blood cells (RBCs) possess receptors for complement component C3b, suggesting a role in immune complex interactions.
• Immune complexes (IC) formed by microbes and antibodies can activate the complement system.

Purpose of the Study:

• To investigate the hypothesis that complement-activating immune complexes attract granulocytes (polymorphonuclear leukocytes, PMNs), leading to oxidative damage of G6PD-deficient RBCs.
• To explore the mechanism of 'innocent bystander' damage to RBCs in G6PD deficiency during microbial infections.

Main Methods:

• Opsonization of RBCs with pneumococcus/anti-pneumococcus/C3b complexes to induce immune adherence.
• Incubation of opsonized RBCs with PMNs and measurement of glutathione (GSH) levels in G6PD-deficient and normal RBCs.
• Experimental manipulation using EDTA to inhibit C3b generation and trypsin to remove C3b receptors on RBCs.

Main Results:

• Opsonized RBCs with as few as two C3b complexes showed immune adherence.
• PMN-RBC interaction significantly depleted GSH in G6PD-deficient RBCs but not in normal RBCs.
• GSH depletion severity correlated with G6PD deficiency status.
• Inhibition of C3b generation or removal of C3b receptors abrogated immune adherence and GSH depletion.

Conclusions:

• Immune adherence and PMN-mediated GSH decline are dependent on complement activation and C3b binding to RBC complement receptors.
• G6PD-deficient RBCs are susceptible to oxidative damage from phagocytes attracted by microbial immune complexes.
• This 'Good Samaritan' activity of RBCs in clearing immune complexes may paradoxically lead to hemolysis in G6PD-deficient individuals during infections.