| 1. |
- Dzhambazov, Balik, et al.
(author)
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The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans
- 2005
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In: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 35:2, s. 357-366
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Journal article (peer-reviewed)abstract
- Type II collagen (CII) is a target for autoreactive T cells in both rheumatoid arthritis and the murine model collagen-induced arthritis. The determinant core of CII has been identified as CII260-270, and the alteration of this T cell epitope by posttranslational modifications is known to be critical for development of arthritis in mice. Using CII-specific T cell hybridomas we have now shown that the immunodominant T cell epitope in the normal (healthy) human and rat joint cartilage is O-glycosylated at the critical T cell receptor recognition position 264 with a mono- or di-saccharide attached to a hydroxylysine. In contrast, in the arthritic human and rat joint cartilage there are both glycosylated and non-glycosylated CII forms. Glycosylated CII from normal cartilage could not be recognized by T cells reactive to peptides having only lysine or hydroxylysine at position 264, showing that antigen-presenting cells could not degrade the O-linked carbohydrate. Thus, the variable forms of the glycosylated epitope are determined by the structures present in cartilage, and these vary during the disease course. We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states.
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| 2. |
- Dzhambazov, Balik, et al.
(author)
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The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans
- 2005
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In: EUROPEAN JOURNAL OF IMMUNOLOGY. - : Wiley. - 0014-2980 .- 1521-4141. ; 35:2, s. 357-66
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Journal article (peer-reviewed)abstract
- Type II collagen (CII) is a target for autoreactive T cells in both rheumatoid arthritis and the murine model collagen-induced arthritis. The determinant core of CII has been identified as CII260-270, and the alteration of this T cell epitope by posttranslational modifications is known to be critical for development of arthritis in mice. Using CII-specific T cell hybridomas we have now shown that the immunodominant T cell epitope in the normal (healthy) human and rat joint cartilage is O-glycosylated at the critical T cell receptor recognition position 264 with a mono- or di-saccharide attached to a hydroxylysine. In contrast, in the arthritic human and rat joint cartilage there are both glycosylated and non-glycosylated CII forms. Glycosylated CII from normal cartilage could not be recognized by T cells reactive to peptides having only lysine or hydroxylysine at position 264, showing that antigen-presenting cells could not degrade the O-linked carbohydrate. Thus, the variable forms of the glycosylated epitope are determined by the structures present in cartilage, and these vary during the disease course. We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states.
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| 3. |
- Holmberg, Jens, et al.
(author)
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Pristane, a non-antigenic adjuvant, induces MHC class II-restricted, arthritogenic T cells in the rat.
- 2006
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In: Journal of Immunology. - 1550-6606. ; 176:2, s. 1172-1179
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Journal article (peer-reviewed)abstract
- Pristane-induced arthritis (PIA) in rats, a model for rheumatoid arthritis (RA), is a T cell-dependent disease. However, pristane itself is a lipid and unable to form a stable complex with a MHC class II molecule. Therefore, the specificity and function of the T cells in PIA are as unclear as in rheumatoid arthritis. In this study, we show that activated CD4+ alphabetaT cells, which target peripheral joints, transfer PIA. The pristane-primed T cells are of oligo or polyclonal origin as determined by their arthritogenicity after stimulation with several mitogenic anti-TCRVbeta and anti-TCRValpha mAbs. Arthritogenic cells secreted IFN-gamma and TNF-alpha (but not IL-4) when stimulated with Con A in vitro, and pretreatments of recipient rats with either anti-IFN-gamma or a recombinant TNF-alpha receptor before transfer ameliorated arthritis development. Most importantly, we show that these T cells are MHC class II restricted, because treatment with Abs against either DQ or DR molecules ameliorates arthritis development. The MHC class II restriction was confirmed by transferring donor T cells to irradiated recipients that were syngenic, semiallogenic, or allogenic to MHC class II molecules, in which only syngenic and semiallogenic recipients developed arthritis. These data suggest that the in vivo administration of a non-antigenic adjuvant, like pristane, activates CD4+ alphabetaT cells that are MHC class II restricted and arthritogenic.
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| 4. |
- Holmdahl, Rikard, et al.
(author)
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Arthritis induced in rats with non-immunogenic adjuvants as models for rheumatoid arthritis
- 2001
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In: Immunological Reviews. - : Wiley. - 1600-065X .- 0105-2896. ; 184
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Research review (peer-reviewed)abstract
- Rat models are useful for studies of the pathogenesis of rheumatoid arthritis (RA) since rats are extraordinarily sensitive to induction of arthritis with adjuvants. Injection of not only the classical complete Freund's adjuvant but also mineral oil without mycobacteria and pure adjuvants such as pristane and squalene, induce severe arthritis in many rat strains. Models like pristane-induced arthritis in rats are optimal models for RA since they fulfill the RA criteria including a chronic relapsing disease course. Arthritogenic adjuvants like pristane, avridine, squalene and mineral oil are not immunogenic since they do not contain major histocompatibility complex (MHC) binding peptides. Nevertheless, the diseases are MHC-associated and dependent on the activation of alphabetaTCR (T-cell receptor)-expressing T cells. However, it has not been possible to link the immune response to joint antigens or other endogenous components although immunization with various cartilage proteins induce arthritis but with different pathogeneses. To unravel the mechanisms behind adjuvant-induced arthritis, a disease-oriented genetic approach is optimal. Several loci that control onset of arthritis, severity and chronicity of the disease have been identified in genetic crosses and most of these have been confirmed in congenic strains. In addition, many of these loci are found in other autoimmune models in the rat as well as associated with arthritis in mice and humans.
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| 5. |
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| 6. |
- Liedberg, Ann-Sofie, et al.
(author)
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Extra-articular cartilage affected in collagen-induced, but not pristane-induced, arthritis models.
- 2002
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In: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 127:1, s. 37-42
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting cartilaginous joints but also extra-articular tissues such as the nose and upper respiratory tract. We have investigated extra-articular cartilage involvement in two commonly used animal models for RA, collagen-induced and pristane-induced arthritis, by immunizing rats with different susceptibility to disease (LEW.1 A, LEW.1F and DA rats). We found that nasal and tracheolaryngeal cartilage is affected in LEW.1 A and DA rats to varying degrees in collagen-induced arthritis but not in any strain in the pristane-induced model. Antibodies to matrilin-1, a cartilage-specific protein expressed mainly in tracheolaryngeal and nasal cartilage but not in joints, were positively associated with the presence of inflammation in nasal cartilage. In contrast, no antibody response to matrilin-1 could be detected in pristane-induced arthritis. In addition, nasal vaccination with collagen type II prior to immunization in DA rats significantly decreased the antibody response to matrilin-1 at day 56, but not at earlier time points, indicating a late protective effect on extra-articular cartilage. We conclude that pristane-induced arthritis is a joint-specific model whereas collagen-induced arthritis affect joints as well as extra-articular cartilage. Furthermore, collagen immunization induces an antibody response to matrilin-1.
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| 7. |
- Lu, Shemin, et al.
(author)
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Both common and unique susceptibility genes in different rat strains with pristane-induced arthritis.
- 2002
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In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 10:8, s. 475-483
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Journal article (peer-reviewed)abstract
- Pristane-induced arthritis (PIA) in rats is an animal model for rheumatoid arthritis (RA). We have previously identified seven quantitative trait loci (QTLs), which regulate arthritis development using a cross between the susceptible DA strain and the resistant E3 strain of rats (Pia2-8). In the present study the inbred rat strain LEW.1F was used as the susceptible strain in a cross with the E3 strain. The results confirmed the locus Pia4 on chromosome 12, which previously was shown to be associated with PIA, and also with experimental allergic encephalomyelitis, in crosses between the rat strains E3 and DA. On chromosome 1, linked to the albino locus, we identified a novel QTL, Pia9 in the LEW.F1 cross. This locus was associated with arthritis severity in the early phase of disease. A locus on chromosome 16, denoted Pia11, was also associated with arthritis severity in the early phase of the disease. A suggestive locus was detected on chromosome 14, which was associated with arthritis severity at the time when PIA progresses into a chronic phase. Using a congenic LEW.1F strain, which carries E3 alleles at the Pia9 locus, we confirmed that the E3 allele significantly suppresses arthritis severity during the early phase of the disease. The results revealed synergistic effects between different susceptibility loci using ANOVA analysis. These interactions were influenced by gender. Rats with Pia9 alleles from LEW.1F and Pia11 alleles from E3, were shown to suffer from much more severe arthritis in the early stage of the disease. On the other hand, the Pia9 and the suggestive locus on chromosome 14 affected only males during the chronic phase of the disease. These findings provide clues to how genetic factors by themselves, and in interaction with each other, regulate the development of a disease, which displays many similarities to RA.
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| 8. |
- Lu, Shemin
(author)
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Genetic Factors and Nasal Tolerance in Rat Models for Rheumatoid Arthritis
- 2002
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Doctoral thesis (other academic/artistic)abstract
- We used three animal models of rats for rheumatoid arthritis (RA) in this study. Firstly, We found that CXI induced arthritis (CXIIA) is associated with the RT1 f haplotype and follows a chronic disease course affecting peripheral joints with both progression and relapses. The main difference of pathological changes in CXIIA rats against rats with CIIIA was a larger number of infiltrating lymphocytes which tended to form follicle-like aggregates. Surprisingly, males were more susceptible to CXIIA than females whereas the opposite has been observed in other rat arthritis models, including CIIIA. We also found that nasal and tracheolaryngeal cartilage is affected in LEW.1A and DA rats to varying degree in CIIIA but not in any strain in the pristane induced model. Next, we investigated the role of genetic factors in arthritis development after pristane injection. In newly made MHC congenic strains with DA background, we found that rats with the RT1 f haplotype developed much more severe and chronic diseases as compared with DA rats. Antibodies against T cell receptor (R73) and CD4 T cells but not CD8 T cells could suppress the arthritis. When DA.1F rats were injected with anti-MHC class II molecule antibodies, the anti-RT1B antibody but not anti-RT-1D suppressed the arthritis severity. Since RT1 D molecule is identical between the RT1a and f haplotypes, this indicates that the disease is associated with MHC class II genes. Furthermore we found that in the chronic phase of PIA, only DA.1F rats had a DTH response to CXI, demonstrating that chronicity of the disease is linked with a T cell response specific to cartilage-restricted antigens. In a linkage study of the new cross between E3 and LEW.1F strains, the results confirmed the previously identified locus Pia4 on chromosome 12. On chromosome 1, linked to the albino locus, we identified a novel QTL, Pia9 in the LEW.1F cross. This locus was associated with arthritis severity in the early phase of disease. A locus on chromosome 16, denoted Pia11, was also associated with arthritis severity in the early phase of the disease. By using a congenic LEW.1F strain, which carries E3 allele at the Pia9 locus, we confirmed that the E3 alleles significantly suppress arthritis severity during the early phase of the disease. Rats with Pia9 alleles from LEW.1F and Pia11 alleles from E3, were shown to suffer from even more severe arthritis in the early stage of the disease. On the other hand, the Pia9 and the suggestive locus on chromosome 14 affected only males during the chronic phase of the disease. Finally, we have assessed the efficiency of nasally administrated cartilage-specific collagens to vaccinate against development of arthritis, and to ameliorate already established chronic arthritis. Cartilage specific CIX CII and CXI were used for intranasal vaccination. We found all cartilage specific collagens administrated nasally but not collagen type I can suppress PIA and also have ameliorative effects on established PIA. Concerning CIIIA and CXIIA, only cognate collagens have effects indicating an antigen-specific suppression. These findings demonstrate that there are different mechanisms involved in tolerance induction in different rat models for RA.
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| 9. |
- Lu, Shemin, et al.
(author)
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Immunization of Rats with Homologous Type XI Collagen Leads to Chronic and Relapsing Arthritis with Different Genetics and Joint Pathology Than Arthritis Induced with Homologous Type II Collagen.
- 2002
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In: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411. ; 18:3, s. 199-211
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Journal article (peer-reviewed)abstract
- The most commonly used animal model for rheumatoid arthritis (RA) is collagen-induced arthritis (CIA), induced by immunization with type II collagen (CII), a cartilage restricted protein. In this work we show that type XI collagen (CXI), which is a minor component in cartilage, induces a different form of erosive and chronic relapsing polyarthritis in rats. Using a series of inbred rat strains involving various genetic backgrounds (DA, LEW, E3), and congenic MHC regions (a, u, f, n, c, d), we found that CXI induced arthritis (C(XI)IA) is associated with the RT1f haplotype in contrast to CII induced arthritis (C(II)IA), which is associated with the RT1a and RT1u haplotypes. The C(XI)IA follows a chronic disease course affecting peripheral joints with both progression and relapses, which appear not to cease (occurring >800 days). Susceptible strains showed a sustained antibody response to CXI with time indicating that the autoimmune response was self-perpetuated. Microscopic analysis of the joints at different stages demonstrated the severe destruction of bone and cartilage by pannus tissue consisting of activated macrophages and T cells. The main difference to joints from rats with C(II)IA was larger numbers of infiltrating lymphocytes and these tended to form follicle-like aggregates. Surprisingly, males were more susceptible to C(XI)IA than females whereas the opposite has been observed in other rat arthritis models, including C(II)IA. Taken together, C(XI)IA is a chronic relapsing and erosive polyarthritis that is MHC associated, which in fact fulfills the criteria for diagnosis of RA. Thus the C(XI)IA model will be useful as a novel and relevant animal model for RA.
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| 10. |
- Olofsson, Peter, et al.
(author)
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A comparative genetic analysis between collagen-induced arthritis and pristane-induced arthritis.
- 2003
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In: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 48:8, s. 2332-2342
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Journal article (peer-reviewed)abstract
- Objective To compare the genetic regulation of collagen-induced arthritis (CIA) with that of pristane-induced arthritis (PIA) in rats. Methods A genome-wide linkage analysis of an (E3 × DA)DA backcross of rats with CIA (n = 364 male rats; the same strain combinations as previously used to determine the genetic control of PIA) was performed. The strongest loci in both CIA and PIA (i.e., Cia12/Pia4 and Cia13/Pia7) were isolated in congenic strains. Susceptibility in both congenic strains was tested in rats with CIA and in rats with PIA. Results We found a striking, although not complete, similarity of the arthritis-controlling loci in CIA and in PIA, as well as the previously defined loci associated with cartilage destruction, antibody production, and the acute-phase response. All major PIA quantitative trait loci (QTLs) identified in early severe arthritis were also strong regulators of CIA. The 2 strongest QTLs, Cia12/Pia4 on chromosome 12 and Cia13/Pia7 on chromosome 4, were also analyzed in congenic strains with DA or E3 as the background genome. Consistent with the results of linkage analysis, the congenic strain experiments showed that the chromosome 4 locus was more penetrant in CIA than in PIA, while the chromosome 12 locus almost completely dominated the control of PIA severity. Conclusion The underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage-specific antigen (type II collagen) to induce CIA but not PIA.
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| 11. |
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| 12. |
- Olofsson, Peter, et al.
(author)
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Positional identification of Ncf1 as a gene that regulates arthritis severity in rats.
- 2003
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 33:1, s. 25-32
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Journal article (peer-reviewed)abstract
- The identification of genes underlying quantitative-trait loci (QTL) for complex diseases, such as rheumatoid arthritis, is a challenging and difficult task for the human genome project. Through positional cloning of the Pia4 QTL in rats, we found that a naturally occurring polymorphism of Ncf1 (encoding neutrophil cytosolic factor 1, a component of the NADPH oxidase complex) regulates arthritis severity. The disease-related allele of Ncf1 has reduced oxidative burst response and promotes activation of arthritogenic T cells. Pharmacological treatment with substances that activate the NADPH oxidase complex is shown to ameliorate arthritis. Hence, Ncf1 is associated with a new autoimmune mechanism leading to severe destructive arthritis, notably similar to rheumatoid arthritis in humans.
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