Complement in Disease - Extracellular Proteins as Complement Regulators
Author
Summary, in English
We found that complement-activating SLRPs also bind the complement inhibitor C4b-binding protein (C4BP) leading to a downregulation of the terminal complement pathway. This may be a mechanism to minimize release of anaphylatoxins and direct the complement response towards clearance of released cartilage constituents.
We further found that one member of the SLRP-family, PRELP, inhibits complement directly by binding C9 and inhibiting the formation of the lytic membrane attack complex. PRELP was also found to inhibit the assembly of the alternative pathway C3-convertase and thereby affects two stages of the complement cascade.
We found that cartilage oligomeric matrix protein (COMP), which has been shown to be released into the circulation during erosive joint diseases, has a dual role in complement activation; COMP inhibits the classical and lectin pathways whereas it activates the alternative pathway. COMP-induced complement activation can be seen in vivo by the presence of circulating COMP-C3b complexes. Such complexes are present in several rheumatic diseases but absent in healthy controls. COMP-C3b reflects disease activity in RA and levels are decreased upon TNF-α inhibition, which might provide an opportunity to use COMP-C3b as a marker of disease progression in RA. COMP is to our knowledge the first cartilage component whose complement activating properties have been demonstrated in vivo.
We further showed that serglycin, a proteoglycan secreted by multiple myeloma cells, inhibits the classical and lectin pathways of complement and that cell surface expression of serglycin leads to protection of these cells from complement attack. This might interfere with immunotherapies that aim at directing complement responses towards multiple myeloma cells.
Taken together, several novel interactions between endogenous ligands and complement have been found, which might regulate the progression of different disease processes.
Department/s
- Protein Chemistry, Malmö
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2011
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2011:93
Full text
Document type
Dissertation
Publisher
Department of Laboratory Medicine, Lund University
Topic
- Other Basic Medicine
Keywords
- rheumatoid arthritis
- joint disease
- Complement
- proteoglycan
- cancer
Status
Published
Research group
- Protein Chemistry, Malmö
Supervisor
- Anna Blom
- Dick Heinegård
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-86871-42-0
Defence date
7 October 2011
Defence time
13:15
Defence place
Lilla Aulan, entrance 59, university hospital MAS, Malmö
Opponent
- Matthew Pickering (Professor)