Novel endogenous mechanisms of complement regulation - A delicate balance
(2007) In Lund University Faculty of Medicine Doctoral Dissertation Series 2007:156.- Abstract
- In this thesis, the biochemical mechanisms for complement activation by endogenous proteins are explored.
The short leucine-rich repeat proteins (SLRPs) help organise extracellular matrices. We found that several SLRPs bind C1q and of these, fibromodulin and osteoadherin trigger complement. These two glycoproteins also bind the complement regulator factor H (FH). Our findings may have implications for inflammatory joint diseases.
C-reactive protein (CRP) is the archetypical acute phase protein. It activates complement and has previously been found to bind both C1q and FH. We discovered that CRP also binds the complement regulator C4b-binding protein (C4BP), both in vitro and in serum. We hypothesise that... (More) - In this thesis, the biochemical mechanisms for complement activation by endogenous proteins are explored.
The short leucine-rich repeat proteins (SLRPs) help organise extracellular matrices. We found that several SLRPs bind C1q and of these, fibromodulin and osteoadherin trigger complement. These two glycoproteins also bind the complement regulator factor H (FH). Our findings may have implications for inflammatory joint diseases.
C-reactive protein (CRP) is the archetypical acute phase protein. It activates complement and has previously been found to bind both C1q and FH. We discovered that CRP also binds the complement regulator C4b-binding protein (C4BP), both in vitro and in serum. We hypothesise that CRP-C4BP interaction reduces superfluous complement activation during inflammation.
The risk for developing age-related macular degeneration (AMD), a very common eye disease, is linked to certain haplotypes of the FH gene. We detected differential binding of AMD-related polymorphic FH-variants to CRP, DNA, necrotic cells and SLRPs. These differences may be important for AMD pathogenesis.
Infection by misfolded prion protein (PrP) leads to severe neurological disease. We demonstrated that C1q binds both native and misfolded human PrP to activate complement. PrP also triggered the alternative pathway. Furthermore, it binds both FH and C4BP and this may lead to inhibition of terminal complement effects. We suggest that these interactions are imperative for complement involvement in prion diseases.
Taken together, the studies presented here indicate that complex interaction patterns exist which normally serve to balance complement activation by endogenous proteins. This balance may be disturbed in disease. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/605109
- author
- Holmér, Andreas LU
- supervisor
-
- Anna Blom LU
- opponent
-
- Dr. Tenner, Andrea, University of California, Irvine, USA
- organization
- publishing date
- 2007
- type
- Thesis
- publication status
- published
- subject
- keywords
- short leucine rich glycoprotein, factor H, C1q, age-related macular degeneration, C4b-binding protein, prion disease, prion protein, Complement regulation, C-reactive protein
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- volume
- 2007:156
- pages
- 167 pages
- publisher
- Clinical Chemistry, Malmö
- defense location
- Jubileumsaulan, Medicinskt forskningscentrum, Ingång 79 UMAS, Malmö
- defense date
- 2007-12-07 13:15:00
- ISSN
- 1652-8220
- ISBN
- 978-91-85897-34-6
- language
- English
- LU publication?
- yes
- id
- 5f479d77-d906-4ab5-be67-02237a20e1df (old id 605109)
- date added to LUP
- 2016-04-01 17:05:15
- date last changed
- 2023-04-18 19:18:46
@phdthesis{5f479d77-d906-4ab5-be67-02237a20e1df,
abstract = {{In this thesis, the biochemical mechanisms for complement activation by endogenous proteins are explored.<br/><br>
<br/><br>
The short leucine-rich repeat proteins (SLRPs) help organise extracellular matrices. We found that several SLRPs bind C1q and of these, fibromodulin and osteoadherin trigger complement. These two glycoproteins also bind the complement regulator factor H (FH). Our findings may have implications for inflammatory joint diseases.<br/><br>
C-reactive protein (CRP) is the archetypical acute phase protein. It activates complement and has previously been found to bind both C1q and FH. We discovered that CRP also binds the complement regulator C4b-binding protein (C4BP), both in vitro and in serum. We hypothesise that CRP-C4BP interaction reduces superfluous complement activation during inflammation.<br/><br>
The risk for developing age-related macular degeneration (AMD), a very common eye disease, is linked to certain haplotypes of the FH gene. We detected differential binding of AMD-related polymorphic FH-variants to CRP, DNA, necrotic cells and SLRPs. These differences may be important for AMD pathogenesis.<br/><br>
Infection by misfolded prion protein (PrP) leads to severe neurological disease. We demonstrated that C1q binds both native and misfolded human PrP to activate complement. PrP also triggered the alternative pathway. Furthermore, it binds both FH and C4BP and this may lead to inhibition of terminal complement effects. We suggest that these interactions are imperative for complement involvement in prion diseases.<br/><br>
<br/><br>
Taken together, the studies presented here indicate that complex interaction patterns exist which normally serve to balance complement activation by endogenous proteins. This balance may be disturbed in disease.}},
author = {{Holmér, Andreas}},
isbn = {{978-91-85897-34-6}},
issn = {{1652-8220}},
keywords = {{short leucine rich glycoprotein; factor H; C1q; age-related macular degeneration; C4b-binding protein; prion disease; prion protein; Complement regulation; C-reactive protein}},
language = {{eng}},
publisher = {{Clinical Chemistry, Malmö}},
school = {{Lund University}},
series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
title = {{Novel endogenous mechanisms of complement regulation - A delicate balance}},
volume = {{2007:156}},
year = {{2007}},
}