Novel endogenous mechanisms of complement regulation - A delicate balance
Författare
Summary, in English
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.
Avdelning/ar
Publiceringsår
2007
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University Faculty of Medicine Doctoral Dissertation Series
Volym
2007:156
Dokumenttyp
Doktorsavhandling
Förlag
Clinical Chemistry, Malmö
Ämne
- Medicinal Chemistry
Nyckelord
- short leucine rich glycoprotein
- factor H
- C1q
- age-related macular degeneration
- C4b-binding protein
- prion disease
- prion protein
- Complement regulation
- C-reactive protein
Status
Published
Forskningsgrupp
- Clinical Chemistry, Malmö
Handledare
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-85897-34-6
Försvarsdatum
7 december 2007
Försvarstid
13:15
Försvarsplats
Jubileumsaulan, Medicinskt forskningscentrum, Ingång 79 UMAS, Malmö
Opponent
- Andrea Tenner (Dr.)