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Complement in Disease - Extracellular Proteins as Complement Regulators

Happonen, Kaisa LU (2011) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2011:93.
Abstract
Complement activation occurs during inflammatory joint diseases such as rheumatoid arthritis (RA) and is thought to contribute to the chronic inflammation observed within the joints. Previous studies have shown that certain cartilage components of the small leucine-rich repeat protein (SLRP)-family regulate complement activity, thereby possibly contributing to disease progression. The aim of this thesis is to find new interactions between cartilage components and complement, which could provide useful information for the development of novel therapeutic and diagnostic approaches.

We found that complement-activating SLRPs also bind the complement inhibitor C4b-binding protein (C4BP) leading to a downregulation of the terminal... (More)
Complement activation occurs during inflammatory joint diseases such as rheumatoid arthritis (RA) and is thought to contribute to the chronic inflammation observed within the joints. Previous studies have shown that certain cartilage components of the small leucine-rich repeat protein (SLRP)-family regulate complement activity, thereby possibly contributing to disease progression. The aim of this thesis is to find new interactions between cartilage components and complement, which could provide useful information for the development of novel therapeutic and diagnostic approaches.

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. (Less)
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author
supervisor
opponent
  • Professor Pickering, Matthew, Imperial College, London
organization
publishing date
type
Thesis
publication status
published
subject
keywords
rheumatoid arthritis, joint disease, Complement, proteoglycan, cancer
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2011:93
pages
162 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Lilla Aulan, entrance 59, university hospital MAS, Malmö
defense date
2011-10-07 13:15
ISSN
1652-8220
ISBN
978-91-86871-42-0
language
English
LU publication?
yes
id
961af9fc-0645-4d1a-a9e9-01ab469eb33c (old id 2158434)
date added to LUP
2011-09-30 09:03:59
date last changed
2016-09-19 08:44:48
@phdthesis{961af9fc-0645-4d1a-a9e9-01ab469eb33c,
  abstract     = {Complement activation occurs during inflammatory joint diseases such as rheumatoid arthritis (RA) and is thought to contribute to the chronic inflammation observed within the joints. Previous studies have shown that certain cartilage components of the small leucine-rich repeat protein (SLRP)-family regulate complement activity, thereby possibly contributing to disease progression. The aim of this thesis is to find new interactions between cartilage components and complement, which could provide useful information for the development of novel therapeutic and diagnostic approaches. <br/><br>
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. <br/><br>
 <br/><br>
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. <br/><br>
 <br/><br>
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.<br/><br>
 <br/><br>
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. <br/><br>
 <br/><br>
Taken together, several novel interactions between endogenous ligands and complement have been found, which might regulate the progression of different disease processes.},
  author       = {Happonen, Kaisa},
  isbn         = {978-91-86871-42-0},
  issn         = {1652-8220},
  keyword      = {rheumatoid arthritis,joint disease,Complement,proteoglycan,cancer},
  language     = {eng},
  pages        = {162},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Complement in Disease - Extracellular Proteins as Complement Regulators},
  volume       = {2011:93},
  year         = {2011},
}