| 1. |
- Dzhambazov, Balik, et al.
(författare)
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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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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 35:2, s. 357-366
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Tidskriftsartikel (refereegranskat)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.
(författare)
-
The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans
- 2005
-
Ingår i: EUROPEAN JOURNAL OF IMMUNOLOGY. - : Wiley. - 0014-2980 .- 1521-4141. ; 35:2, s. 357-66
-
Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: Journal of Immunology. - 1550-6606. ; 176:2, s. 1172-1179
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Tidskriftsartikel (refereegranskat)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.
(författare)
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The molecular pathogenesis of collagen-induced arthritis in mice--a model for rheumatoid arthritis.
- 2002
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Ingår i: Ageing Research Reviews. - 1872-9649. ; 1:1, s. 135-147
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Forskningsöversikt (refereegranskat)abstract
- The most widely used model for rheumatoid arthritis is the collagen-induced arthritis (CIA) in mice. This model has gained acceptance since it is reproducible, well defined and has proven useful for development of new therapies for rheumatoid arthritis, as exemplified by the most recent advancement using TNFalpha neutralization treatment. The collagen-induced arthritis model, however, represents only certain pathways leading to arthritis and there is no consensus on how they operate. Nevertheless, we are beginning to understand the immune recognition structures, such as MHC molecules, lymphocyte receptors and type II collagen epitopes, which are of crucial importance for the development of this disease. These provide useful tools for further investigations of the pathogenesis of CIA as well as for understanding the pathogenesis of rheumatoid arthritis.
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| 5. |
- Matsuzaki, G, et al.
(författare)
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Mechanism of murine V gamma 1(+) gamma delta T cell-mediated innate immune response against Listeria monocytogenes infection
- 2002
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Ingår i: European Journal of Immunology. - 1521-4141. ; 32:4, s. 928-935
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Tidskriftsartikel (refereegranskat)abstract
- Murine gammadelta T cells participate in innate immune response against infection of the intracellular bacterium Listeria monocytogenes. In the present report, we analyzed the mechanism of the gammadelta T cell-mediated response against L. monocytogenes infection. gammadelta T cell-enriched spleen cells of L. monocytogenes-infected mice produced IFN-gamma in vitro in response to L. monocytogenes-infected spleen cells, The IFN-gamma production was abrogated by depletion of Vgamma1(+) gammadelta T cells. IFN-gamma production of the Vy1(+) gammadelta T cells in response to L. monocytogenes-infected spleen cells required IL-12. However, addition of Fab fragment of anti-TCR gammadelta monoclonal antibodies (mAb) failed to block the response, suggesting that the response requires no TCR-mediated antigen recognition. Interestingly, Vgamma1(+) gammadelta T cells of naive mice also produced IFN-gamma in response to L. monocytogenes-infected spleen cells in an IL-12-dependent manner. Furthermore, the IL-12 receptor (IL-12R) gene was expressed on the Vgamma1(+) gammadelta T cells of naive mice as well as those of L. monocytogenes-infected mice although naive alphabeta T cells lack IL-12R expression. All the results suggest that the Vgamma1(+) gammadelta T cells participate in immune surveillance against intracellular bacterial infection through quick production of IFN-gamma in response to infection-induced IL-12 without antigen-driven clonal expansion and maturation.
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| 6. |
- Raposo, Bruno, et al.
(författare)
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T cells specific for post-translational modifications escape intrathymic tolerance induction
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Establishing effective central tolerance requires the promiscuous expression of tissue-restricted antigens by medullary thymic epithelial cells. However, whether central tolerance also extends to post-translationally modified proteins is not clear. Here we show a mouse model of autoimmunity in which disease development is dependent on post-translational modification (PTM) of the tissue-restricted self-antigen collagen type II. T cells specific for the non-modified antigen undergo efficient central tolerance. By contrast, PTM-reactive T cells escape thymic selection, though the PTM variant constitutes the dominant form in the periphery. This finding implies that the PTM protein is absent in the thymus, or present at concentrations insufficient to induce negative selection of developing thymocytes and explains the lower level of tolerance induction against the PTM antigen. As the majority of self-antigens are post-translationally modified, these data raise the possibility that T cells specific for other self-antigens naturally subjected to PTM may escape central tolerance induction by a similar mechanism.
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| 7. |
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