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Cartilage proteins and their arthritogenic properties in arthritis

Carlsén, Stefan LU (2005)
Abstract (Swedish)
Popular Abstract in Swedish

I denna avhandling behandlas brosk proteiners roll såsom antigen och tillgänglighet av immunsystemet i artrit. Sex artiklar omfattas, där fyra presenterar nya djur modeller för reumatoid artrit (RA), en visar hur en genetisk störning av ett broskprotein kan förvärra artrit och den sista hur posttransnationell modifiering av kollagen typ II (CII) påverkar T-cells tolerans. I artikel I undersöktes kollagen typ IX's (CIX) potential som ett antigen i artrit. Artrit kunde induceras med CIX i råtta, men toleransen var tvungen att brytas med pepsin. CIX har artritogena egenskaper och är en användbar modell för att förstå hur proteiner i ledbrosk tolariseras. I artikel II undersöktes kollagen typ XI... (More)
Popular Abstract in Swedish

I denna avhandling behandlas brosk proteiners roll såsom antigen och tillgänglighet av immunsystemet i artrit. Sex artiklar omfattas, där fyra presenterar nya djur modeller för reumatoid artrit (RA), en visar hur en genetisk störning av ett broskprotein kan förvärra artrit och den sista hur posttransnationell modifiering av kollagen typ II (CII) påverkar T-cells tolerans. I artikel I undersöktes kollagen typ IX's (CIX) potential som ett antigen i artrit. Artrit kunde induceras med CIX i råtta, men toleransen var tvungen att brytas med pepsin. CIX har artritogena egenskaper och är en användbar modell för att förstå hur proteiner i ledbrosk tolariseras. I artikel II undersöktes kollagen typ XI (CXI) som ett antigen i artrit. Homologt CXI inducerar en kronisk livslång artrit i råttor med liknande histologiska yttringar såsom i RA. CIX inducerad artrit är därför en väsentlig modell för RA. I artikel III undersöktes cartilage oligomeric matrix protein (COMP) som ett antigen i artrit. Uppseendeväckande inducerade COMP artrit i en annars artrit resistent stam. COMP är ett exponerat protein i ledbrosk och är därför intressant för att förstå tolarisering och gener som kontrollerar inflammation. I artikel IV undersöktes COMP som ett antigen i mus och visade att COMP inducerad artrit inte är art beroende. Bakgrundsgener hade en stor inverkan eftersom endast C3H stammen utvecklade en kronisk återfallande artrit och inte i den CII artrit känsliga B10 stammen. MHC associationen var av p-haplotyp och den tidigare förklarade regulatoriska E-molekylen. I artikel V undersöktes genetiskt modifierade möss med frånvaro av CIX och immunsystemets tillgänglighet till brosk. Möss med frånvaro av CIX utvecklade en svårare artrit eftersom antikroppar mot CII-epitoper hade bättre åtkomst till brosket. Broskets jämvikt var också störd eftersom mössen utvecklade en svårare spontan artrit. I artikel VI undersöktes tolerisations mönstret för T-celler i möss uttryckande humant HLA-DR4, CD4 och CII och resultatet jämfördes med RA patienter. Tolariseringen var inte fullständig för posttranslationellt modifierat glykosyllerade CII-peptider, men möss och RA patienter var tolariserade mot den icke modifierade peptiden. (Less)
Abstract
In this thesis the role of cartilage proteins and their potential as antigen and availability to the immune system in arthritis were investigated. Six papers are included; where four present new animal models for Rheumatoid arthritis (RA), one shows how genetic disorders in cartilage may affect arthritis and the last how posttranslational modification of collagen type II (CII) affects tolerance. Paper I investigated collagen type IX (CIX) potential as an antigen in arthritis. Arthritis could be induced with CIX in rats, but tolerization needed to be broken by pepsin. CIX has arthritogenic properties and is a useful model for understanding how proteins in cartilage are tolerized. Paper II investigated collagen type XI (CXI) potential as an... (More)
In this thesis the role of cartilage proteins and their potential as antigen and availability to the immune system in arthritis were investigated. Six papers are included; where four present new animal models for Rheumatoid arthritis (RA), one shows how genetic disorders in cartilage may affect arthritis and the last how posttranslational modification of collagen type II (CII) affects tolerance. Paper I investigated collagen type IX (CIX) potential as an antigen in arthritis. Arthritis could be induced with CIX in rats, but tolerization needed to be broken by pepsin. CIX has arthritogenic properties and is a useful model for understanding how proteins in cartilage are tolerized. Paper II investigated collagen type XI (CXI) potential as an antigen in arthritis. Homologous injection of CXI in rats gave chronic life-long disease course with histological manifestations similar to RA. Therefore, CXI induced arthritis is a relevant model to RA. Paper III investigated cartilage oligomeric matrix protein (COMP) as a potential antigen in arthritis. Interestingly, COMP induced arthritis in a rat strain, which is resistant to other arthritis models. COMP is an exposed molecule in cartilage and is a useful tool to understand tolerization and genes that controls pathogenesis. Paper IV investigated COMP as an arthritogen in mice and shows that COMP is not species restricted. Background genes had a high impact since only the C3H strain developed relapsing chronic arthritis and not collagen type II induced arthritis (CIA) susceptible B10 strain. MHC association was with the p-haplotype and the previously reported regulatory E-molecule. Paper V investigated mice deficient for CIX and accessibility of the immunesystem to cartilage. CIX deficient mice developed a severe arthritis since antibodies could easily access the CII-epitopes. Cartilage homeostasis was also disturbed in these mice, since deficient mice had a severe spontaneous arthritis. Paper VI investigated tolerization patterns for T-cells in mice expressing human HLA-DR4, CD4 and CII, and the results were correlated to RA patients. Tolerization was incomplete to posttranslationally modified glycosylated CII-peptides but mice and patients were tolerized to the non-modified peptide. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • PhD Williams, Richard, Faculty of Medicine Imperial College of Science Technology and Medicine, Kennedy Institute of Rheuma
organization
publishing date
type
Thesis
publication status
published
subject
keywords
transplantation, Immunologi, serologi, serology, Immunology, HLA-DR4, tolerance, COMP, CXI, CIX, arthritis, Cartilage, collagen
pages
127 pages
publisher
Faculty of Medicine, Lund University
defense location
Segerfalkssalen Wallenberg Neurocenter BMC Sölvegatan 19 Lund
defense date
2005-10-15 09:00
ISSN
1652-8220
ISBN
91-85439-85-1
language
English
LU publication?
yes
id
a4ac6e0a-8f40-4265-8ede-0ce3b217fb5b (old id 545449)
date added to LUP
2007-09-10 12:59:04
date last changed
2016-09-19 08:44:54
@phdthesis{a4ac6e0a-8f40-4265-8ede-0ce3b217fb5b,
  abstract     = {In this thesis the role of cartilage proteins and their potential as antigen and availability to the immune system in arthritis were investigated. Six papers are included; where four present new animal models for Rheumatoid arthritis (RA), one shows how genetic disorders in cartilage may affect arthritis and the last how posttranslational modification of collagen type II (CII) affects tolerance. Paper I investigated collagen type IX (CIX) potential as an antigen in arthritis. Arthritis could be induced with CIX in rats, but tolerization needed to be broken by pepsin. CIX has arthritogenic properties and is a useful model for understanding how proteins in cartilage are tolerized. Paper II investigated collagen type XI (CXI) potential as an antigen in arthritis. Homologous injection of CXI in rats gave chronic life-long disease course with histological manifestations similar to RA. Therefore, CXI induced arthritis is a relevant model to RA. Paper III investigated cartilage oligomeric matrix protein (COMP) as a potential antigen in arthritis. Interestingly, COMP induced arthritis in a rat strain, which is resistant to other arthritis models. COMP is an exposed molecule in cartilage and is a useful tool to understand tolerization and genes that controls pathogenesis. Paper IV investigated COMP as an arthritogen in mice and shows that COMP is not species restricted. Background genes had a high impact since only the C3H strain developed relapsing chronic arthritis and not collagen type II induced arthritis (CIA) susceptible B10 strain. MHC association was with the p-haplotype and the previously reported regulatory E-molecule. Paper V investigated mice deficient for CIX and accessibility of the immunesystem to cartilage. CIX deficient mice developed a severe arthritis since antibodies could easily access the CII-epitopes. Cartilage homeostasis was also disturbed in these mice, since deficient mice had a severe spontaneous arthritis. Paper VI investigated tolerization patterns for T-cells in mice expressing human HLA-DR4, CD4 and CII, and the results were correlated to RA patients. Tolerization was incomplete to posttranslationally modified glycosylated CII-peptides but mice and patients were tolerized to the non-modified peptide.},
  author       = {Carlsén, Stefan},
  isbn         = {91-85439-85-1},
  issn         = {1652-8220},
  keyword      = {transplantation,Immunologi,serologi,serology,Immunology,HLA-DR4,tolerance,COMP,CXI,CIX,arthritis,Cartilage,collagen},
  language     = {eng},
  pages        = {127},
  publisher    = {Faculty of Medicine, Lund University},
  school       = {Lund University},
  title        = {Cartilage proteins and their arthritogenic properties in arthritis},
  year         = {2005},
}