Complement in Autoimmunity - the importance of clearing waste
Summary, in English
Complement C1q binds to apoptotic cells and ensures rapid and tolerogenic clearance by phagocytes. C1q can also activate complement. To avoid excessive activation, binding of the complement inhibitor factor H to the apoptotic cells is crucial. In this thesis we have discovered that factor H as well as C1q bind to the phospholipid binding proteins annexin A2 and that C1q also binds A5. These proteins are expressed on apoptotic cells. Further, we have observed that both C1q and factor H bind to the chromatin constituents, DNA and histones. Binding of C1q to these ligands led to complement activation indicating the need for factor H on the apoptotic cells.
NETs constitute one mechanism of how neutrophils can protect the body from pathogens. By releasing chromatin covered with antimicrobial enzymes the neutrophil can catch and kill pathogens. In this thesis we confirm that NETs are not degraded properly in 30% of patients with SLE. Further, C1q binds to NETs, prevents degradation and also activates complement. Consequently, the patients with decreased ability to degrade NETs more often suffer from complement consumption and glomerulonephritis, manifestations of severe SLE. This initial study was followed-up by a longitudinal study where temporal associations such as glomerulonephritis, pleuritis and elevated levels of histone antibodies could then be linked to a decreased ability to degrade NETs.
NET degradation was also affected in some patients with antiphospholipid syndrome and systemic sclerosis. However the effect was not as pronounced as in SLE and was more evident the more SLE-like the APS was.
In conclusion, complement may both prevent and contribute to the pathogenesis in SLE. In this thesis, ligands for complement C1q and factor H have been revealed on the apoptotic cells and further, the interactions of complement with NETs have been elucidated. Additionally, the ability to degrade NETs has been analyzed in SLE and SLE like diseases, which may be used to better diagnose or treat these patients in the future.
Lund University Faculty of Medicine Doctoral Dissertation Series
Protein Chemistry, Lund University
- Other Basic Medicine
- Complement system
- neutrophil extracellular traps
- systemic lupus erythematosus
- factor H
- Protein Chemistry, Malmö
- ISSN: 1652-8220
- ISBN: 978-91-87449-07-9
26 April 2013
Lilla Aulan, Jan Walderströmsgata 5, Malmö
- Francesco Tedesco (prof.)