Cartilage proteins and their arthritogenic properties in arthritis

Detta är en avhandling från Faculty of Medicine

Sammanfattning: 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.

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