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Complement activation in sickle cell disease: a liposome model
1Department of Immunology/Microbiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612.
Insights
Abnormal red blood cell membranes in sickle cell disease (SCD) may cause chronic alternative complement pathway (ACP) activation. This study used liposomes to show altered phospholipids on sickle cells activate the ACP.
Area of Science:
- Biochemistry
- Hematology
- Immunology
Background:
- Patients with sickle cell disease (SCD) exhibit poorly understood abnormalities in their alternative complement pathway (ACP).
- Previous research indicated chronic ACP activation in SCD patients.
Purpose of the Study:
- To investigate the mechanism behind chronic ACP activation in SCD.
- To determine if abnormal phospholipid organization in sickle cells contributes to ACP activation.
Main Methods:
- Serum concentrations of complement control proteins (factors I and H) were measured in SCD patients and controls.
- A liposome model was employed to assess ACP activation by sickle cell membrane phospholipids.
- Liposomes mimicked the phospholipid composition of sickle cell outer and inner leaflets.
Main Results:
- No significant difference in factors I and H concentrations was found between SCD patients and controls.
- Liposomes mimicking sickle cell outer leaflet phospholipids (enriched in phosphatidylserine and phosphatidylethanolamine) significantly increased ACP activation.
- Liposomes mimicking the erythrocyte inner membrane leaflet also showed enhanced ACP activation compared to normal outer leaflet liposomes.
Conclusions:
- Phospholipid composition of cell membranes influences their ability to promote ACP activation.
- Altered phospholipid organization in sickle cells likely contributes to the chronic ACP activation observed in sickle cell disease.
Abstract:
Patients with sickle cell disease (SCD) have poorly defined abnormalities of their alternative complement pathway (ACP). We have previously shown chronic activation of the ACP in these patients. To determine the mechanism of this finding, we studied concentrations of the complement control proteins factors I and H in serum from patients with SCD and found no significant difference when they were compared with a control population. Because certain membrane surfaces promote ACP activation and changes occur in erythrocyte membrane phospholipid organization with sickling, we used a liposome model to determine whether ACP activation could be caused by abnormal phospholipid organization of sickle cells. Liposomes with the composition of the sickle cell outer leaflet, which is enriched in phosphatidylserine and phosphatidylethanolamine, activated the ACP significantly more than liposomes with normal outer leaflet phospholipid content. Similarly, liposomes with the composition of the erythrocyte inner membrane leaflet, containing large amounts of phosphatidylethanolamine and phosphatidylserine, activated the ACP more than liposomes with the phospholipid content of the outer leaflet. These findings suggest that phospholipid composition of membranes may play a role in their ability to promote ACP activation, and that changes in phospholipid organization in sickle cells may contribute to the chronic ACP activation observed in patients with SCD.