G6PD-deficiency infectious haemolysis: a complement dependent innocent bystander phenomenon.
Dramatic haemolysis may accompany viral hepatitis and pneumococcal pneumonia in G6PD-deficient patients. Since red blood cells (RBCs) are richly endowed with receptors for activated complement, particularly C3b, we hypothesized that bulky, complement-activating immune complexes (IC) consisting of microbes and antibody might attract granulocytes (PMNs), facilitating oxidative 'innocent bystander' RBC damage. Indeed, opsonization with only two type-2 pneumococcus (PN3)/anti-PN3/C3b complexes per RBC caused agglutination of RBC, a phenomenon termed immune adherence. Addition of as few as one PMN per 20 opsonized RBCs caused the glutathione (GSH) levels of co-incubated G6PD-deficient RBCs to fall by 30% (from 3.5 to 1.8 +/- 0.8 mumoles GSH/g Hb) compared to identically incubated, but nonopsonized, G6PD-deficient RBCs. GSH levels remained normal (5.2 +/- 0.4 mumoles/g Hb) in PMN-exposed opsonized normal RBCs. GSH depletion in G6PD-deficient RBC was directly related to disease severity--falling a mean 33% in RBCs from two Black G6PD A- subjects but 59% in two Caucasian G6PD deficient RBCs. Prevention of C3b generation (with 10 mM EDTA) during opsonization abrogated both immune adherence and PMN-mediated GSH decline in oxidant-sensitive cells. Similarly, removal of C3b receptors by brief trypsin incubation of RBCs eliminated immune adherence and GSH decline. Thus, both phenomena are dependent on IC complement activation and subsequent binding of the bacterial IC to the RBC complement receptors. Although clearance of IC by RBCs may be beneficial in protecting other tissues from inflammatory damage, G6PD-deficient RBCs are vulnerable to oxidants generated by juxtaposed phagocytes--cells attracted to, and stimulated by, the immune complex/C3b combination. It is suggested that this 'Good Samaritan' activity of RBCs may lead to haemolysis during periods of exuberant antibody response to microbes.
Kasper
M L
ML
Miller
W J
WJ
Jacob
H S
HS
D000743:Anemia, Hemolytic / Q000097:blood; D000907:Antibodies, Bacterial; D000936:Antigen-Antibody Complex / Q000378:metabolism; D000937:Antigen-Antibody Reactions; D003165:Complement System Proteins / Q000276:immunology*; D004912:Erythrocytes / Q000378:metabolism; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000097:blood*; D005978:Glutathione / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D009504:Neutrophils / Q000378:metabolism; D010084:Oxidation-Reduction; D013296:Streptococcus pneumoniae / Q000276:immunology
D000907:Antibodies, Bacterial; D000936:Antigen-Antibody Complex; D003165:Complement System Proteins; D005978:Glutathione