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Zinc ions inhibit factor I-mediated release of CR1-bound immune complexes and degradation of cell-bound complement
H H Jepsen1, B Teisner, S E Svehag
1Institute of Medical Microbiology, Odense University, Denmark.
Insights
Zinc chloride (ZnCl2) inhibits the release of immune complexes from red blood cells by blocking complement factor I activity. This finding highlights ZnCl2
Area of Science:
- Immunology
- Complement System
- Biochemistry
Background:
- Immune complexes (IC) bound to complement receptor type 1 (CR1) on erythrocytes can be released via complement-mediated pathways.
- Complement factor I plays a crucial role in regulating complement activation by degrading C3b and C4b.
- Understanding modulators of complement regulation is vital for immune system research.
Purpose of the Study:
- To investigate the effect of zinc chloride (ZnCl2) on the release of immune complexes from human erythrocytes.
- To determine if ZnCl2 influences the activity of complement factor I in immune complex processing.
Main Methods:
- Dose-dependent inhibition assays using ZnCl2 on citrate-phosphate-dextrose (CPD) plasma-treated human whole blood.
- Measurement of 125I-labelled BSA-anti-BSA immune complex release from erythrocyte CR1.
- Assessing factor I-mediated degradation of cell-bound C3b/C4b in the presence and absence of ZnCl2.
Main Results:
- ZnCl2 exhibited dose-dependent inhibition of immune complex release, with maximal effect at 10 mM.
- The release of immune complexes by purified factor I was reduced by approximately 90% in the presence of 10 mM ZnCl2.
- ZnCl2 prevented factor I-mediated degradation of cell-bound C3b and C4b, indicating inhibition of factor I activity.
Conclusions:
- Zinc chloride significantly inhibits complement factor I activity.
- This inhibition affects both the release of immune complexes and the degradation of complement fragments C3b/C4b.
- ZnCl2 serves as a potent inhibitor of factor I-mediated complement regulation.
Abstract:
ZnCl2 exerted a dose-dependent inhibition of citrate-phosphate-dextrose (CPD) plasma-induced release of 125I-labelled BSA-anti-BSA immune complexes (IC) bound to complement receptor type 1 (CR1, CD35) in human whole blood. Maximal inhibition was observed at 10 mM of ZnCl2. Furthermore, the release of IC bound to erythrocyte (E)-CR1 by purified factor I, factor I-deficient serum plus purified factor I, or normal human serum was reduced by approximately 90%, 64%, and 52%, respectively, in the presence of 10 mM ZnCl2. The effect of ZnCl2 on factor I-mediated degradation of cell-bound C3b/C4b was also investigated employing CPD blood or E from a factor I-deficient donor. These cells expressed covalently bound C3b and C4b as demonstrated by a simple agglutination technique. Upon incubation of CPD whole blood with purified factor I, or of E with purified factor I or normal CPD plasma, the C-fragments were cleaved and the cells were no longer agglutinated by antibodies to C3c and C4c. The presence of ZnCl2 prevented this factor I-mediated degradation of C3b and C4b, as evidenced by the unaffected agglutination of the cells by the antibodies. We conclude that ZnCl2 inhibited factor I activity since: (1) release of complement-preopsonized IC from E-CR1 by purified factor I was markedly inhibited (90%) in the presence of ZnCl2, (2) preincubation of the cells with ZnCl2 caused only a moderate inhibition (32-38%) of the IC release, and (3) degradation by purified factor I of covalently cell-bound C3b and C4b was abrogated in the presence of 10 mM ZnCl2.